Urogenital Pain in Clinical Practice

UrogenItal Pain in

Clinical Practice

Baranowski_978-0849399329_TP.ind1 1

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UrogenItal Pain in

Clinical Practice

Edited by

Andrew PAUL Baranowski The Centre for Urogenital Pain Medicine The National Hospital for Neurology and Neurosurgery London, UK PAUL ABRAMS Bristol Urological Institute Southmead Hospital Bristol, UK Magnus Fall Sahlgrenska Academy University of Göteborg Sahlgrenska University Hospital Göteborg, Sweden

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11/13/07 10:06:33 AM

Informa Healthcare USA, Inc. 52 Vanderbilt Avenue New York, NY 10017 q 2008 by Informa Healthcare USA, Inc. Informa Healthcare is an Informa business No claim to original U.S. Government works Printed in the United States of America on acid-free paper 10 9 8 7 6 5 4 3 2 1 International Standard Book Number-10: 0-8493-9932-7 (Hardcover) International Standard Book Number-13: 978-0-8493-9932-9 (Hardcover) This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequence of their use. No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, please access www.copyright.com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC) 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Library of Congress Cataloging-in-Publication Data Urogenital pain in clinical practice / edited by Andrew Paul Baranowski, Paul Abrams, Magnus Fall. p. ; cm. Includes bibliographical references and index. ISBN-13: 978-0-8493-9932-9 (hb : alk. paper) ISBN-10: 0-8493-9932-7 (hb : alk. paper) 1. Genitourinary organs–Diseases–Treatment. 2. Pain–Treatment. I. Baranowski, Andrew. II. Abrams, Paul, 1947- III. Fall, Magnus. [DNLM: 1. Female Urogenital Diseases–therapy. 2. Male Urogenital Diseases–therapy. 3. Pain–therapy. WJ 140 U765 2007] RC871.U62 2007 616.6’06–dc22 2007021735 Visit the Informa Web site at www.informa.com and the Informa Healthcare Web site at www.informahealthcare.com

Preface

It is difficult to get a handle on the true incidence and prevalence of urogenital pain. However, the general consensus is that chronic pain is one of the most common reasons for seeking primary care medical advice, and that appears as true for urogenital visits as for any other system disorder. In a proportion of cases, the pain will be indicative of a pathological process that is amenable to evidence-based management, with the condition and disease mechanisms being clearly defined. This book is not about that group of patients; it is about the even larger group of patients where the diagnosis is not clear-cut, and the mechanisms of the pathology and pain are even more obscure. This book aims to help professionals who are called upon to manage that group of patients—specialists from many fields: pain medicine, urology, gynecology, internal medicine, neurology, psychology, counseling, nursing, and family medicine, to name but a few. We have tried to be comprehensive so that basic principles are covered for those with limited experience in the field, and also to present the specialist end to support specialists in an evidenced-based approach. Because this book is the first attempt to be truly multidisciplinary and comprehensive in managing all the needs of this group of patients, we have divided it into four parts: (i) General Mechanisms—Anatomy, Physiology, and Pathophysiology; (ii) The Multidisciplinary Approach; (iii) The Pain Syndromes; and (iv) The Therapeutic Spectrum. Doctors offer this group of suffering patients poorly defined conditions with names like prostatitis, orchitis, and vulvodynia that have no relationship to underlying mechanisms. Such spurious terms may result in inappropriate investigations as well as treatments, unreasonable doctor and patient expectations. Doctors send patients from one specialist to another in the hope that the specialist will find a cause and also to pass on the responsibility of caring for the patient. Patients “doctor shop,” a phenomenon that is fueled by the internet and, on occasion, by other patients. The article, “A New Classification is Needed for Pelvic Pain Syndromes—Are Existing Terminologies of Spurious Diagnostic Authority Bad for Patients?” [to which the three editors of this book contributed (1)] highlights this problem and makes a plea for a chronic pelvic pain disorders classification system that is easy to use and reflects the limitations of our current understanding. We hope that this book takes up the theme of that editorial in which a new approach to the management of chronic urogenital pain is suggested. The editors have a long history of trying to move this process forward, and they have also contributed to several reviews and guidelines with the aim of seeing improvement in the management of this difficult area (2–4). Pain is a symptom, and, in the absence of a classical disease process that requires treatment in its own right, the symptom needs to be managed. There are two aspects to this: 1. The mechanism of the pain can be managed. 2. The effects of the pain on the patient can be managed. Part of this book covers urogenital pain mechanisms and their management. In certain cases, recent understanding of what was a poorly understood disease process has led to

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Preface

a better description of the underlying disease (for instance, pudendal neuralgia or pelvic floor muscle triggerpoints), and specific treatments related to that process have been suggested (e.g., pudendal nerve blocks and decompressive surgery, or trigger-point release, respectively). In many cases, the evidence base remains weak, but progress is being made. In many other cases, the pathology remains a complete mystery. Many chapters deal with such pain conditions, trying to lay out clearly what is known and to provide an evidence-based approach to management. Major advances in understanding the nature of pain, its pathways, and its chemical neuromodulation are likely to lead to new interventions. Pain can thus be treated as a disease process in its own right. Several of the chapters in this book cover that. This book also looks at the effect of the pain on the patient and its impact on the patient’s family, society, and the medical profession. Multiple chapters cover the emotional and sexual problems associated with chronic urogenital pain. It is well established that management of secondary effects can produce major benefits for patients by reducing disability (physical, emotional, and sexual), and thereby improving quality-of-life. This section of the book is as important as the sections on physical mechanisms and their management. Many would say more important! Much of the work of the editors over the years has involved trying to rationalize the management of this group of patients. There are two important processes that need to be undertaken. Firstly, a better classification system of the pain syndromes needs to be developed. Secondly, the need for multidisciplinary integrated management has to be taken on board. The International Continence Society document (Abrams) recognized that when the mechanism for a patient’s urogenital pain condition cannot be clearly defined, it is better to present the patient as suffering with a pain syndrome that describes the symptoms and anatomical site, if possible, of the perceived pain. This process was adopted, along with the International Association for the Study of Pain classification (5), in the European Association of Urology guidelines on chronic pelvic pain (3) and is currently being developed to include the multidimensional aspects of pain such as psychological, sexual, and social. In classifying a person and his or her pain this way, it is intended that the patient is managed in a holistic way and that the role of the multidisciplinary group is clearly identified. Andrew Paul Baranowski Paul Abrams Magnus Fall REFERENCES 1. Abrams P, Baranowski A, Berger RE, et al. A new classification is needed for pelvic pain syndromes— are existing terminologies of spurious diagnostic authority bad for patients? J Urol 2006; 175(6): 1989–90. 2. Abrams P, Cardozo L, Fall M, et al. The standardization of terminology of lower urinary tract function: report from the Standardization Sub-committee of the International Continence Society. Neurourol Urodyn 2002; 21(2):167–78. 3. Fall M, Baranowski AP, Fowler CJ, et al. EAU guidelines on chronic pelvic pain. Eur Urol 2004; 46(6):681–9. 4. Hanno P, Baranowski AP, Fall M, et al. Painful bladder syndrome (including interstitial cystitis). In: Report from Committee 21 of the 3rd International Consultation on Incontinence. Monte Carlo, Monaco, June 2004:26–9. 5. Merskey H, Bogduk N. Classification of Chronic Pain. Seattle, WA: IASP Press, 1994.

Contents

Preface . . . . . . iii Contributors . . . . . . ix GENERAL MECHANISMS

ANATOMY, PHYSIOLOGY, AND PATHOPHYSIOLOGY . . . . . .

1. Classifications and Definitions of Urogenital Pain . . . . . . Ursula Wesselmann and Andrew Paul Baranowski 2. Epidemiology of Urogenital Pain . . . . . . Mary McLoone and John Lee

3

17

3. Anatomy of the Urogenital Pain Systems . . . . . . D. Pattern and J. Hughes 4. Physiology of the Urogenital System . . . . . . Vinay Kalsi, Sohier Elneil, and Clare J. Fowler

45

5. Acute and Chronic Pain Mechanisms Sarah Harper

55

. . . . . .

23

6. Visceral Pain Mechanisms . . . . . . 61 W. Paul Farquhar-Smith and Siaˆn Jaggar 7. Gender and Pain . . . . . . 71 Pushparaj S. Shetty and Anita Holdcroft THE MULTIDISCIPLINARY APPROACH

. . . . . . 77

8. Multidisciplinary Pain Management Teams Cathy Price

. . . . . . 79

9. Doctors and the Female Pelvic Pain Patient . . . . . . Ying Cheong and R. William Stones

83

10. Initial Assessment in the Pain Management Center . . . . . . Natasha Curran and Andrew Paul Baranowski 11. Imaging in Pelvic Pain . . . . . . Chris Hare

89

95

12. Measuring Pain and Disability in Chronic Urogenital Pain Toby R. O. Newton-John 13. Men and Urogenital Pain . . . . . . Andrew Paul Baranowski

111

. . . . . .

103

1

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Contents

14. Women and Urogenital Pain . . . . . . 119 Caroline F. Pukall, Kelly B. Smith, and Katherine S. Sutton 15. Lower Urogenital Tract Pain and Sexuality Howard I. Glazer 16. Training in Urogenital Pain Management Florella Magora THE PAIN SYNDROMES

. . . . . .

125

. . . . . . 131

. . . . . . 137

17. Renal Disease and Pain . . . . . . 139 Maria Adele Giamberardino, Giannapia Affaitati, and Raffaele Costantini 18. Loin Pain in Hematuria Syndrome . . . . . . Guy H. Neild and Christopher M. Bass

147

19. Bladder Pain Syndrome/Interstitial Cystitis—Etiology and Animal Research C. A. Tony Buffington 20. Bladder Pain Syndrome/Interstitial Cystitis—Clinical Considerations Philip Hanno

. . . . . . 169

. . . . . .

21. Bladder Pain Syndrome/Interstitial Cystitis—Treatment Options Magnus Fall and Ralph Peeker

. . . . . .

197

22. Prostate Pain Syndrome—Etiology, Epidemiology, and Research Michel A. Pontari and Brett Lebed

. . . . . .

211

23. Prostate Pain Syndrome—Treatment Options Henning Schneider and Wolfgang Weidner 24. Scrotal Pain Conditions P. Granitsioti

. . . . . .

223

. . . . . . 235

25. Urethral Pain Syndrome and Pain Perceived as Related to the Penis Magnus Fall and Andrew Paul Baranowski 26. Chronic Pelvic Pain in Women . . . . . . John F. Steege 27. Dysmenorrhea Ian Milsom

185

. . . . . .

. . . . . . 245

251

263

28. Pelvic Pain in Gynecological Practice—Endometriosis-Related Urogenital Pain . . . . . . 277 Lennart Hahn 29. Vulvar Pain Syndrome—Etiology, Epidemiology, and Research . . . . . . 279 David C. Foster 30. Vulvar Pain Syndrome—Treatment and Quantitative Sensory Testing Sophie Bergeron, Caroline F. Pukall, and Genevie`ve Mailloux 31. Gastroenterological Causes of Pelvic Pain Howard Y. Chang and Anthony J. Lembo

. . . . . .

309

. . . . . .

295

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32. Pain Perceived to be Related to the Anus . . . . . . Anton Emmanuel

321

33. Pelvic Floor Muscle Dysfunction and Pelvic Pain . . . . . . Bert Messelink 34. Musculoskeletal Causes of Pelvic Pain ¨ stgaard Hans Christian O 35. Groin Pain in Sport . . . . . . Roger G. Hackney

. . . . . .

341

353

36. Pudendal Neuralgia: Clinical Signs and Diagnosis Jean-Jacques Labat 37. Pudendal Neuralgia—Treatment T. Riant

327

. . . . . .

361

. . . . . . 373

38. Pudendal Neuralgia—Surgery . . . . . . 385 Roger Robert, Olivier Hamel, and Mansour Khalfallah THE THERAPEUTIC SPECTRUM 39. Acute Pain in Urology Brigitta Brandner

. . . . . .

393

. . . . . . 395

40. Chronic Pain Associated with Urological Malignancy . . . . . . John E. Williams 41. Psychological Intervention in Persistent Pelvic Pain . . . . . . Anna L. Mandeville

405 415

42. Pharmacotherapy for Neuropathic Pain with Special Reference to Urogenital Pain . . . . . . 427 M. S. Chong and Joan Hester 43. Opioids for the Management of Persistent Noncancer Pain . . . . . . Cathy Stannard

441

44. Nerve Blocks in Urogenital Pain . . . . . . 451 Diana E. Dickson and Vanessa R. Humphrey 45. Neuromodulation in Urogenital Pain Management Adnan A. Al-Kaisy

. . . . . .

471

46. Surgical Considerations for Chronic Urogenital Syndromes . . . . . . Christopher R. Chapple and Jacob M. Patterson 47. Complementary Therapies and Their Role in the Management of Urogenital Pain . . . . . . 495 Adam Ward 48. The Role of Counseling in Chronic Pain . . . . . . Beatrice Sofaer-Bennett Index

. . . . . . 521

515

481

Contributors

Giannapia Affaitati Pathophysiology of Pain Laboratory, Ce.S.I., “G. D’Annunzio” Foundation and Department of Medicine and Science of Aging, University of Chieti, Chieti, Italy Adnan A. Al-Kaisy London, U.K.

Pain Management Centre, Guy’s & St. Thomas’ NHS Foundation Trust,

Andrew Paul Baranowski The Centre for Urogenital Pain Medicine, Pain Management Centre, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, U.K. Christopher M. Bass Department of Psychological Medicine, John Radcliffe Hospital, Oxford, U.K. Sophie Bergeron Department of Sexology, Universite´ du Que´bec a` Montre´al and Sex and Couple Therapy Service, Department of Psychology, McGill University Health Centre, Royal Victoria Hospital, Montre´al, Que´bec, Canada Brigitta Brandner Department of Anaesthesia, University College Hospital, University College London Hospitals NHS Foundation Trust, London, U.K. C. A. Tony Buffington Department of Veterinary Clinical Sciences, The Ohio State University Veterinary Hospital, Columbus, Ohio, U.S.A. Howard Y. Chang Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, U.S.A. Christopher R. Chapple Department of Reconstruction, Female Urology, and Urodynamics and Department of Urology, The Royal Hallamshire Hospital, Sheffield, U.K. Ying Cheong Academic Unit of Reproductive & Developmental Medicine, School of Medicine and Biomedical Sciences, The University of Sheffield, Sheffield, and Princess Anne Hospital, University of Southampton, Southampton, U.K. M. S. Chong Departments of Neurology and Pain Management, Kings College Hospital, London, U.K. Raffaele Costantini Department of Experimental and Clinical Surgical Science, “G. D’Annunzio” University of Chieti, Chieti, Italy Natasha Curran London, U.K. Diana E. Dickson

University College London Hospitals NHS Foundation Trust, School of Medicine, University of Leeds, Leeds, U.K.

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Contributors

Sohier Elneil Department of Uro-Neurology, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, U.K. Anton Emmanuel Department of Gastroenterology, University College Hospital, London, U.K. Magnus Fall Department of Urology, Sahlgrenska University Hospital, Go¨teborg, Sweden W. Paul Farquhar-Smith Royal Marsden Hospital, London, U.K. David C. Foster University of Rochester School of Medicine and Dentistry, Rochester, New York, U.S.A. Clare J. Fowler Department of Uro-Neurology, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, U.K. Maria Adele Giamberardino Pathophysiology of Pain Laboratory, Ce.S.I., “G. D’Annunzio” Foundation and Department of Medicine and Science of Aging, University of Chieti, Chieti, Italy Howard I. Glazer Department of Psychiatry, Weill Cornell Medical College, New York Presbyterian Hospital, New York, New York, U.S.A. P. Granitsioti

Urology Department, Southern General Hospital, Glasgow, U.K.

Roger G. Hackney

The General Infirmary at Leeds, Leeds, U.K.

Lennart Hahn Department of Obstetrics & Gynecology, Sahlgren’s University Hospital, Gothenburg, Sweden Olivier Hamel Nantes, France

Neurotraumatology Department, Centre Hospitalier Universitaire de Nantes,

Philip Hanno Department of Surgery, Division of Urology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, U.S.A. Chris Hare Department of Imaging, University College London Hospitals, NHS Foundation Trust, London, and Department of Imaging, General Hospital, Jersey, Channel Islands, U.K. Sarah Harper Department of Anaesthesia, Gloucestershire Royal Hospitals, NHS Foundation Trust, Gloucestershire, U.K. Joan Hester Departments of Neurology and Pain Management, Kings College Hospital, London, U.K. Anita Holdcroft Magill Department of Anaesthesia, Chelsea and Westminster Hospital London, Imperial College London, London, U.K. J. Hughes The James Cook University Hospital, Middlesbrough, U.K. Vanessa R. Humphrey School of Medicine, University of Edinburgh, Edinburgh, Scotland, U.K. Siaˆn Jaggar Royal Brompton Hospital, London, U.K. Vinay Kalsi Department of Uro-Neurology, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, U.K. Mansour Khalfallah Neurosurgery Department, Bayonne Hospital, Bayonne, France

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Contributors

Jean-Jacques Labat Clinique Urologique, Centre Hospitalier Universitaire de Nantes, Nantes, France Brett Lebed Department of Urology, Temple University School of Medicine, Philadelphia, Pennsylvania, U.S.A. John Lee Pain Management Centre, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, U.K. Anthony J. Lembo Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, U.S.A. Florella Magora Department of Anesthesiology/Intensive Care, Hadassah Medical Center, Ein Kerem, Jerusalem, Israel Genevie`ve Mailloux Department of Psychology, Universite´ du Que´bec a` Montre´al, Montre´al, Que´bec, Canada Anna L. Mandeville National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, U.K. Mary McLoone

St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada

Bert Messelink Netherlands

Department of Urology, University Medical Centre, Groningen,

Ian Milsom Department of Obstetrics and Gynecology, Sahlgrenska Academy at Go¨teborg University, Sahlgrenska University Hospital, Go¨teborg, Sweden Guy H. Neild Institute of Urology and Nephrology, University College London, London, U.K. Toby R. O. Newton-John Innervate Pain Management, Hunter Specialist Medical Center, Newcastle, Australia ¨ stgaard Department of Orthopedics, Sahlgren University Hospital, Hans Christian O ¨ Molndal, Sweden D. Pattern

University of Durham, Durham, U.K.

Jacob M. Patterson Department of Reconstruction, Female Urology, and Urodynamics and Department of Urology, The Royal Hallamshire Hospital, Sheffield, U.K. Ralph Peeker Department of Urology, Sahlgrenska University Hospital, Go¨teborg, Sweden Michel A. Pontari Department of Urology, Temple University School of Medicine, Philadelphia, Pennsylvania, U.S.A. Cathy Price Pain Clinic, Division of Unscheduled Care and Cancer, Southampton University Hospitals NHS Foundation Trust, Southampton, U.K. Caroline F. Pukall Department of Psychology, Queen’s University, Kingston, Ontario, Canada T. Riant M. Bensignor’s Pain Clinic, Centre Catherine de Sienne, Nantes, France Roger Robert Neurotraumatology Department, Centre Hospitalier Universitaire de Nantes, Nantes, France

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Contributors

Henning Schneider Departments of Urology and Pediatric Urology, Justus-Liebig University of Giessen, Giessen, Germany Pushparaj S. Shetty

Imperial School of Anaesthesia, London, U.K.

Kelly B. Smith Department of Psychology, Queen’s University, Kingston, Ontario, Canada Beatrice Sofaer-Bennett Department of Pain Medicine, University of Brighton, Brighton and Sussex University Hospitals NHS Trust Eastbourne, East Sussex, U.K. Cathy Stannard Macmillan Center, Frenchay Hospital, North Bristol NHS Trust, Bristol, U.K. John F. Steege Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, U.S.A. R. William Stones Princess Anne Hospital, University of Southampton, Southampton, U.K. Katherine S. Sutton Department of Psychology, Queen’s University, Kingston, Ontario, Canada Adam Ward Department of Musculoskeletal Medicine, Royal London Homoeopathic Hospital, University College Hospitals London NHS Foundation Trust, London, U.K. Wolfgang Weidner Departments of Urology and Pediatric Urology, Justus-Liebig University of Giessen, Giessen, Germany Ursula Wesselmann Departments of Neurology, Neurological Surgery, and Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, U.S.A. John E. Williams Royal Marsden Hospital, London, U.K.

General Mechanisms—Anatomy, Physiology, and Pathophysiology

A

good medical practice is based upon a good understanding of the science of the medical problem: The first part of this book aims to provide that scientific basis. To a certain extent, this is not easy, for the pain syndromes are, by definition, poorly understood. However, knowledge does significantly help us manage pain patients on a day-today basis. Classification and taxonomy are key to placing our knowledge in context, and they are of utmost importance when it comes to data collection and research. For this reason, “Classifications and Definitions of Urogenital Pain” is the first chapter in this book. Placing the pain syndromes in context with other illnesses demonstrates the importance of the area that we are studying, as shown in Chapter 2, “Epidemiology of Urogenital Pain.” Next, we look at the anatomy (Chapter 3, “Anatomy of the Urogenital Systems”) and physiology (Chapter 4, “Physiology of the Urogenital System”) of the urogenital system, two areas that are vital to our day-to-day management. All interventional procedures require an understanding of anatomy. However, for the urogenital pain syndromes, anatomy is a cornerstone for understanding the interaction among the body systems and, indeed, the individual organs. Associated with the urogenital pain syndromes, there are, in addition to pain, functional abnormalities in the systems, with symptoms and complaints other than the sensory symptoms. Understanding normal physiology helps us understand and manage these. The area of chronic pain science has hugely expanded over the past 10 to 15 years. This scientific knowledge provides a very sound basis for a mechanistic approach to understanding both the genesis of urogenital pain and the associated signs and symptoms of the urogenital pain syndromes. We include two chapters covering these areas. Chapter 5, “Acute and Chronic Pain Mechanisms,” covers important general principles as an introduction to the more specific, “Visceral Pain Mechanisms,” Chapter 6. Finally, we consider the influence of sex and gender (Chapter 7, “Gender and Pain”) and how they may account for some of the variations seen.

1

Classifications and Definitions of Urogenital Pain Ursula Wesselmann

Departments of Neurology, Neurological Surgery, and Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, U.S.A.

Andrew Paul Baranowski

The Centre for Urogenital Pain Medicine, Pain Management Centre, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, U.K.

INTRODUCTION Chronic nonmalignant pain syndromes (longer than six months duration) of the urogenital area in men and women are well described, but poorly understood. The urogenital area is often considered taboo in our society, and many patients are embarrassed to suffer from a chronic pain syndrome in this area of the body. In many cases, the etiology of chronic urogenital pain remains unknown. Rarely are these pain syndromes the manifestation of a psychiatric disease. Currently, many available treatment options are empirical only. The purpose of this chapter is to (i) highlight the current status of the classification of these pain syndromes, which is often confusing; (ii) discuss the challenges of revising existing classifications and introducing new ones; and (iii) point out the opportunities presented by classifications, as they are important for patient care and research. At the end of the chapter is a glossary of terms used in this book. DEFINITIONS OF CHRONIC PAIN SYNDROMES Definitions are important if a body of reliable information is to be built up in the scientific literature, and they will eventually lead to a better understanding of the pathophysiology of chronic pain. At present, one of the major problems of research into the urogenital pain syndromes is the lack of agreed-upon definitions, which would allow comparison between studies. On the other hand, the lack of understanding of the pathophysiological mechanisms of the urogenital pain syndromes makes it difficult to decide on criteria for defining chronic nonmalignant urogenital pain conditions (1). Pain is defined by the International Association for the Study of Pain (IASP) as an unpleasant sensory and emotional experience associated with actual or potential tissue damage or is described in terms of such damage (2). In 1979, Bonica expressed the need for a classification of pain, indicating that the development and widespread adoption of universally accepted definitions of terms and a classification of pain syndromes are among the most important objectives and responsibilities of IASP (2). A Task Force on Taxonomy of the IASP was established in 1986 and again in 1994. The most recent edition [2nd edition; (2)] of the “Classification of Chronic Pain” barely mentions the urogenital pain syndromes (they are listed under “XXIV: Diseases of the Bladder, Uterus, Ovaries, and Adnexa and XXV: Pain in the Rectum, Perineum, and External Genitalia”). The classification system of the IASP uses an axial system based on Axis 1 (region, i.e., pelvic region), Axis II (system, i.e., genitourinary system), Axis III (temporal characteristics of pain, i.e., paroxysmal), Axis IV (patient’s statement of intensity), Axis V (etiology, i.e., trauma or unknown). The lack of emphasis on the urogenital pain syndromes in the current IASP definitions on pain published in 1994 (2) can quite easily be explained by historical aspects. Urogenital pain belongs to the category of visceral pain (3,4). While chronic visceral pain is a much greater

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Wesselmann and Baranowski

clinical problem than pain from the skin, until relatively recently, the focus of experimental work on pain mechanisms mainly related to cutaneous sensation. While it was often assumed that concepts derived from cutaneous studies could be transferred to the visceral domain, emerging experimental data over the last 15 years are indicating that the neural mechanisms involved in pain and hyperalgesia of the skin are different from the mechanisms involved in painful sensations from the viscera. This is supported by differences between somatic and visceral pain based on clinical observation. In contrast to somatic pain, visceral pain cannot be evoked from all viscera and is not necessarily linked to visceral tissue injury. Further, visceral pain tends to be a diffuse and poorly localized sensation whereas somatic pain can be localized exactly. Different from somatic pain, visceral pain can be referred to other visceral structures and somatic structures of the same segmental level. For example, patients with chronic urogenital and pelvic pain typically report multiple urogenital and pelvic pain problems, and they present with pain radiating to the lower back and legs (5,6). As basic scientific research on urogenital pain in animal models has advanced (7,8), and epidemiological studies have documented that urogenital pain syndromes in men and women are indeed quite frequent (1), there has been an increased effort, spearheaded by urologists and gynecologists, in several medical societies to revise and extend the barely existing classification of urogenital pain syndromes.

CLASSIFICATION OF UROGENITAL PAIN: INTERNATIONAL SOCIETY FOR THE STUDY OF VULVOVAGINAL DISEASE One of the earliest consensus committees on the terminology of urogenital pain was focused on vulvodynia. Vulvar pain in the absence of an infectious, dermatological, metabolic, autoimmune, or neoplastic disease had long been recognized as a common clinical problem. Hyperesthesia of the vulva was described in American and European gynecological textbooks more than 100 years ago (9). Surprisingly, despite early detailed reports, “chronic vulvar dysesthesia” disappeared to a large extent from the medical literature until the mid 1970s. In 1976, the International Society for the Study of Vulvovaginal Disease (ISSVD) identified idiopathic vulvar pain as a unique entity and introduced the term “burning vulva syndrome,” based on the observation that most women describe the pain as a hot-burning sensation. The ISSVD subsequently coined the term vulvodynia (defined as chronic vulvar discomfort especially that characterized by the patient’s complaint of burning, and sometimes stinging, irritation, or rawness) to describe this disorder (see Refs. 10,11 for review). The ISSVD stated that vulvodynia was a symptom rather than a diagnosis and that multiple etiologies might be possible. Subsequently, two subsets of vulvodynia were identified. One subgroup of patients complained about entrance dyspareunia (pain with tampon insertion and pain at vaginal penetration during sexual intercourse), rather than diffuse vulvar pain. The term “vulvar vestibulitis” was introduced for this subset of vulvodynia and the following diagnostic criteria were established: (i) presence of severe pain on vestibular touch or attempted vaginal entry, (ii) tenderness to pressure localized within the vulvar vestibule, and (iii) physical findings confined to vestibular erythema of various degrees. The other main subgroup of patients with vulvodynia presented with generalized, spontaneous vulvar pain occurring in the absence of physical findings. The term “dysesthetic (or essential) vulvodynia” was suggested for this symptom complex. Clinically, two different groups of patients with vulvar vestibulitis have been described: primary vulvar vestibulitis is defined as dyspareunia from the first attempt of sexual intercourse, whereas in secondary vulvar vestibulitis, the dyspareunia appears after a period of pain-free sexual intercourse. Based on the concern that the suffix “-itis” in vulvar vestibulitis incorrectly implies an inflammatory etiology, the term vestibulodynia has been suggested (see Ref. 11 for review). The most recent revision of the ISSVD of the terminology of vulvodynia has been published in 2004 (11). This classification suggests categorizing a generalized and a localized (vestibulodynia, clitorodynia, hemivulvodynia, etc.) form of vulvodynia and to differentiate subgroups within those two categories based on the observation whether the vulvar pain is provoked, unprovoked, or mixed (provoked and unprovoked).

Classifications and Definitions of Urogenital Pain

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AN ANATOMICAL CLASSIFICATION OF UROGENITAL PAIN: INTERNATIONAL CONTINENCE SOCIETY, AMERICAN COLLEGE OF OBSTETRICIANS AND GYNECOLOGISTS, AND THE EUROPEAN ASSOCIATION OF UROLOGY The first major document was published in 2002 by a committee of the International Continence Society [ICS; (12)]. This consensus report was a significant milestone in advancing the terminology of urogenital pain, because an attempt was made to classify different urogenital pain syndromes under “umbrella headings,” thus acknowledging that many of the urogenital pain syndromes in men and women may have common as well as distinguishing features. Definitions in this report are descriptive of observations, without implying underlying assumptions that may later prove to be incorrect or incomplete. The urogenital pain syndromes are described as follows: genitourinary pain syndromes are all chronic in their nature. Pain is the major complaint, but concomitant complaints are of a lower urinary tract, bowel, sexual, or gynecological nature. Seven pain conditions were introduced: painful bladder syndrome [PBS, which is likely to be replaced by bladder pain syndrome (BPS) in the next round of terminologies], urethral pain syndrome, vulvar pain syndrome, vaginal pain syndrome, scrotal pain syndrome, perineal pain syndrome, and pelvic pain syndrome. (For the definitions, please see the glossary at the end of the chapter.) Two years later, in 2004, guidelines on chronic pelvic pain (CPP) were published in the U.S.A. by the American College of Obstetricians and Gynecologists (ACOG) and the European Association of Urology (EAU). These guidelines included definitions on pelvic and urogenital pain (13,14), recognizing that pelvic and urogenital pain often overlap or are clinically not perfectly separate entities. The ACOG guideline (13) proposed the following definition for CPP limited to the females: CPP is noncyclic pain of six or more months’ duration that localizes to the anatomic pelvis, anterior abdominal wall at or below the umbilicus, the lumbosacral back, or the buttocks and is of sufficient severity to cause functional disability or lead to medical care. A lack of physical findings does not negate the significance of a patient’s pain, and normal examination results do not preclude the possibility of finding pelvic pathology. The EAU guidelines included definitions for pelvic/urogenital pain in men and women and extended the definitions put forward by the ICS in 2002 (12), and were based on the axial system used by the IASP terminology (2). Prostate Pain Syndrome The EAU working group suggested a practical classification of the poorly defined condition termed “prostatitis.” Chronic prostatitis is a chronic bacterial condition if a pathogen has been demonstrated and a culture-negative disease where inflammation is found microscopically in the absence of an identified pathogen. Discomfort or pain in the pelvic region with a negative culture of specimens and insignificant numbers of white blood cells in prostate-specific specimens, including semen, expressed prostatic secretions, and urine collected after prostatic massage and an absence of any overt urological or neurological disease, is defined as “prostate pain syndrome.” This acknowledges that the etiology of these symptoms is unclear. Bladder Pain Syndrome The EAU suggested defining BPS as pain in the bladder area (suprapubically, increasing with bladder filling), urinary frequency, and nocturia. Pain may radiate to the groins, vagina, clitoris, penis, rectum, or sacrum and is relieved by voiding. Urethral Pain Syndrome This is defined in the EAU guidelines as dysuria with and without frequency, nocturia, urge, and urge incontinence in the absence of urinary infection.

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Scrotal Pain Syndrome This is defined in the EAU guidelines as chronic scrotal pain for at least six months. The differential diagnosis includes chronic epididymitis, painful cystic lesions, sequelae following trauma or orchitis or pain referred from prostatitis, prostate cancer, anorectal disorders or distal ureteric stones. Pelvic Pain Syndrome This is considered in the EAU guidelines as pelvic pain in gynecological practice, including pain associated with pathology, such as endometriosis, childbirth-related injuries, or urinary and gastrointestinal disease. Pelvic Floor and Pudendal Nerve–Related Pain These are considered separate categories in the EAU guidelines, acknowledging that pelvic floor overactivity and pudendal nerve compression might be contributing factors to CPP.

CLASSIFICATION OF UROGENITAL PAIN: NATIONAL INSTITUTES OF HEALTH While the guidelines published by the ICS, ACOG, and EAU discussed above were driven by the need to establish a common terminology to result in better patient diagnosis and care, these efforts were preceded by the work of the National Institutes of Health (NIH) in the United States which, from the late 1980s had established a terminology for urogenital pain syndromes [specifically for “interstitial cystitis” (IC) and prostatitis] for research purposes. Although these NIH terminologies were initially published to identify a homogenous group of patients to be enrolled in research studies, these NIH criteria were often used in clinical practice for diagnosing patients. As it became obvious that these NIH research criteria were “too narrow” for clinical practice, the symptom-oriented classifications published by the different medical associations, as described above, have filled a major clinical need (15). The NIH/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) research criteria for IC were based on the clinical symptoms of urinary urgency, frequency and suprapubic, pelvic or perineal pain and the cytoscopic findings of glomerulations or Hunner’s ulcers (16,17). The NIH/NIDDK classified four different subgroups of prostatitis: (i) acute bacterial prostatitis; (ii) chronic bacterial prostatitis; (iii) chronic pelvic pain syndrome (CPPS) inflammatory: WBC in semen/EPS/voided bladder urine and noninflammatory: no WBC in semen/EPS; and (iv) asymptomatic inflammatory prostatitis (18).

THE FUTURE OF THE CLASSIFICATION OF UROGENITAL PAIN—CHALLENGES AND OPPORTUNITIES The chronic urogenital pain syndromes are often confusing and frustrating for the patient as well as for the health care provider, since the medical work-up is in many cases unrevealing. In fact, many of the urogenital pain syndromes are diagnosed by excluding other organic causes of pain (19), and the patient is left with the term “urogenital pain of unknown etiology.” The pathological classification system has been criticized, since terms used to describe some of the urogenital pain syndromes imply an etiology of the pain complaint that has not been confirmed (20,21). Instead, a descriptive rather than an etiologic approach has been suggested (20). Examples illustrating how misleading some of the terms of the current terminology can be include IC and “vulvar vestibulitis,” which imply an inflammatory/infectious process that has not been documented, despite many investigations driven by the hypothesis of an infectious pathogenesis. In addition, terms such as “prostate pain syndrome” or IC imply that the origin of the pain syndrome is the prostate or the bladder. However, although the pain is experienced in the area where these organs are located, it is often not confirmed, with certainty, that these organs are indeed involved in the etiopathology.

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It is felt by many that the EAU classification system (14), based on combining the axial structure of the original IASP classification [2nd edition; (2)] with the syndrome approach of the ICS classification (12), was a good start, but it still needs development. Pain of Urogenital Origin, a special interest group of IASP, has started to set about further developing this approach with input from membership of National Institute of Health, EAU, ICS, ISSVD, and the European Society for the Study of IC/PBS (ESSIC). At this stage, it is likely that the axial structure of the IASP classification system will be kept, as this will allow: (i) A branching approach to diagnosis, and (ii) a descriptive approach to diagnosis. (For more on this topic, please see the explanatory notes associated with Table 1.) At a recent meeting of the ESSIC, 2006 (personal communication with J. Nordling), ESSIC has decided to do away with the term “interstitial.” They will in the future use the term BPS (PBS also eventually to be dropped). This will be defined as suggested by the ICS for PBS (12), with minor modifications. However, they have also extended the classification system as below (Table 2). This modification takes the NIH/NIDDK research criteria approach for prostate pain (18) a step further, and is likely to influence classifications in the future. Although the pain of the chronic urogenital pain syndromes is typically localized to the urogenital area, careful clinical history and examination show that patients with urogenital pain often suffer from “more than one pain.” The clinical observations are supported by epidemiological data. Data from the “Interstitial Cystitis Database Study” (22) show that 93.6% of the patients enrolled with a diagnosis of IC reported having some pain in an other part of their body. Of the patients having pain, 80.4%, 73.8%, 65.7%, and 51.5% reported having pain in their lower abdomen, urethra, lower back, and vaginal area, respectively. Although IC has been traditionally viewed as a bladder disease, there is increasing clinical and epidemiological evidence of non-bladder-related symptoms and co-occurrence of IC with other chronic pain syndromes, raising the question of systemic alterations of pain modulatory mechanisms rather than local organ-based mechanisms (23–25). This clinical and epidemiological observation can be explained by neurophysiological characteristics of visceral pain. There are two components of visceral pain, which have already been described more than 100 years ago (26): “true visceral pain”—deep visceral pain arising from inside the body and “referred visceral pain”—pain that is referred to segmentally related somatic and also other visceral structures. Secondary hyperalgesia usually develops at the referred site. While several mechanisms have been entertained to explain the referred pain phenomenon over the last 70 years, the most convincing experimental evidence is provided by the observation of convergence. Convergence of afferent input is a typical characteristic of second-order neurons in the spinal cord that receive visceral input. These visceroceptive spinal neurons receive convergent somatic input from skin and musculature (27,28). In addition, viscero-visceral convergence of input onto second-order spinal neurons is common (e.g., colon and bladder). This mechanism offers a ready explanation for the segmental nature of referred pain, but does not address explicitly the issue of hyperalgesia in the referred zone. To interpret “referred pain with hyperalgesia” two main theories have been proposed, which are not mutually exclusive. The first is known as convergence-facilitation theory. It proposes that the abnormal visceral input can produce an irritable focus in the relevant spinal cord segment, thus facilitating messages from somatic structures innervated by that segment. The second theory postulates that the visceral afferent barrage induces the activation of a reflex arc whose afferent limb is represented by visceral afferent fibers, and the efferent limb by somatic efferents and sympathetic efferents that pass to the somatic structures (muscle, subcutis, and skin). The efferent impulses towards the periphery would then sensitize nociceptors in the parietal tissues of the referred area, thus resulting in the phenomenon of hyperalgesia. The mechanisms of referred viscero-visceral pain might explain the substantial overlap observed in epidemiological studies between chronic urogenital pain and other abdominal symptoms (5,6,29,30). The mechanisms of viscero-somatic interactions might explain the overlap of urogenital pain and musculoskeletal pain syndromes (31). The current classifications have not addressed the overlap of multiple urogenital pains and other abdominal and musculoskeletal pains, and future classification systems will need to take these comorbidities of the chronic urogenital pain syndromes into account.

Gynecological

Urological

Anorectal Neurological Muscular Nonpelvic pain e.g. neurological syndromes e.g. urological

Pelvic PS

Axis II System

e.g. pudendal neuralgia

Other

Penile PS Vaginal PS Vulvar PS

Scrotal PS

Bladder PS Urethral PS Prostate PS

Generalized vulvar PS Localized Vestibular PS vulvar PS Clitoral PS Endometriosis-associated PS

(See Table 2 on ESSIC classification) Type A inflammatory Type B noninflamatory Testicular PS Epidydimal PS Post-vasectomy PS

Axis III End organ as pain syndrome as identified from history, examination, and investigations Suprapubic Inguinal Urethral Penile/clitoral Perineal Rectal Back Buttocks

Axis IV Referral characteristics Onset Acute Chronic Ongoing Sporadic Cyclical Continuous Time Filling Emptying Immediate post Late post Provocated

Axis V Temporal characteristics Aching Burning Stabbing Electric Other

Axis VI Character Urinary Frequency Nocturia Hesitance Poor flow Pis en deux Urge Urgency Other Gynecological Menstrual Sexual Female dysparunia, impotance Anorectal Incontinence Constipation Muscular Hyperalgesia Cutaneous Allodynia

Axis VII Associated symptoms

Cognitive Behavioral Emotional

Axis VIII Psychological symptoms

Note: This table is a modified version of the EAU table published in 2004 (14). It includes extra axis that are aimed at further subdividing syndromes on the basis of associated symptoms and psychological responses. This approach to describing a patient is considered important, as it encourages a symptomatic approach to management. Developments in this version of the table are likely as ongoing discussions about taxonomy and phenotyping of urogenital pain continue. a This axial classification starts on the left and, as the features of the pain evolve, the practitioner moves across to the right. If, from the history, examination, and investigations, it is felt that the pain is in the pelvis and the condition is not well defined, then the patient is labeled as suffering from pelvic pain syndrome. If, for example, the symptoms can be localized to the prostate and there is no well-proven diagnosis, then the diagnosis is prostate pain syndrome. If the pain is localized to the bladder, then the diagnosis is bladder pain syndrome (see Table 2). All conditions can be further classified using descriptors (some still to be defined) from the other axis. Abbreviations: GI, gastrointestinal; PS, pain syndrome.

Chronic pelvic pain

Axis Ia Region

TABLE 1 Modified Version of the European Association of Urology Classification (Still Being Developed)

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TABLE 2 Proposed Subclassification of Painful Bladder Syndrome (Bladder Pain Syndrome) Devised by the European Society for the Study of IC/PBS, June 2006 Cystoscopy with hydrodistension Biopsy

Not done Normal Inconclusive Positivec

Not done

Normal

Glomerulationsa

Hunner’s lesionb

XX XA XB XC

1X 1A 1B 1C

2X 2A 2B 2C

3X 3A 3B 3C

a

Cystoscopy: glomerulations grade 2 3. With or without glomerulations. Histology showing inflammatory infiltrates and/or detrusor mastocytosis and/or granulation tissue and/or intrafascicular fibrosis. Addendum: Type XX, XA, XB, 1X, 1A, and 1B were formerly known as painful bladder syndrome (PBS). Type XC, 1C, and all types 2 and 3 were formerly known as interstitial cystitis (IC).

b c

CLASSIFICATION AND DEFINITIONS GLOSSARY As the above illustrates, the terminology relating to pain and particularly that relating to urogenital pain is constantly changing. In the preface of this book, the editors voice their strong views about terminology and classification. These views are also to be found in their article, published with others, in Journal of Urology 2006 (20). The editors are working with others to update the terminology and envisage some radical changes in the future. However, at this point in time, the preferred terminology and classifications are as published in: The International Association for the Study of Pain. Classification of chronic pain, In: Merskey H, Bogduk N, eds. IASP Task Force on Taxonomy, 2nd ed. Seattle: IASP Press, 1994:209–14. & Abrams P, Cardozo L, Fall M, et al. The standardization of terminology of lower urinary tract function: report from the Standardization Subcommittee of the International Continence Society. Am J Obstet Gynecol 2002; 187:116–26. & Fall M, Baranowski AP, Fowler CJ, et al. EAU guidelines on chronic pelvic pain. Eur Urol 2004; 46(6):681–9. &

For this book, the editors have chosen not to make assumptions relating to the terms used by contributors in their chapters, and therefore the editors have not changed the terms used by contributors. On the other hand, contributors were encouraged to use our preferred terminology where possible. Despite the deficiencies of the older terms, it must be recognized that those terms cannot always be directly changed to our preferred terms. The following glossary is based upon the above three publications where indicated (comments by the editors appears in italics). These comments illustrate some of the strengths and some of the deficiencies of the terms and classifications. They also indicate as to how the terms and classification may be developed in the future. The editors are very lucky to work with like-minded colleagues, too many for us to recognize in full. Allodynia pain due to a stimulus which does not normally provoke pain (2). This is particularly relevant to many urogenital pains. For instance, filling of the bladder or light pressure on the testis producing pain represents visceral allodynia. Allodynia is a centrally (within the spinal cord and brain) generated phenomenon. Dynamic allodynia refers to pain with a dynamically changing stimulus, such as brush stroke. Static allodynia refers to allodynia associated with a static stimulus such as constant pressure. Analgesia absence of pain in response to stimulation which would normally be painful (2). Sensory analgesia may be due to a peripheral nerve injury, but may also be due to central (within the spinal cord and brain) phenomena. Central analgesia may produce patterns of analgesia that are complex and beyond what is intuitively expected. Anesthesia dolorosa pain in an area or region which is anesthetic (2). Usually associated with a peripheral nerve injury. Patients often find it difficult to understand as to how something can be numb but painful.

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Anismus the occurrence of anal pain related to the process of defecation and caused by the failure of the striated pelvic floor musculature, including the external anal sphincter, to relax (14). How this relates to anorectal pain syndrome is not clear. Anorectal pain syndrome the occurrence of persistent or recurrent, episodic rectal pain with associated rectal trigger points/tenderness that is related to symptoms of bowel dysfunction. There is no proven infection or other obvious pathology (14). Chronic pain mechanisms are now well described. The definition needs to be altered to reflect this (see CPPS). Biopsychosocial model a model that links psychological, social, and biological mechanisms in health and disease. For instance, depression is not only psychological but has a biological basis and can thus result in physical illness and social problems. Bladder pain syndrome/painful bladder syndrome suprapubic pain related to bladder filling, accompanied by other symptoms such as increased daytime and night-time frequency, in the absence of proven urinary infection or other obvious pathology (ICS definition). Chronic pain mechanisms are now well described. The definition needs to be altered to reflect this (see CPPS). At a recent meeting of the ESSIC (2006), they have decided to drop the term IC, as IC is poorly defined, and there has been no proven infection or “obvious pathology.” ESSIC has decided to subdivide BPS into three groups. Type 1—no obvious pathology on biopsy or cystoscopy, type 2—histological changes on biopsy, no changes on cystoscopy, and type 3—obvious changes on cystoscopy. Type 3 to be further divided according to the cystoscopy and biopsy findings. Catastrophic thinking always thinking the worst, panicking. For instance, a patient might think “If I exercise too much, I will harm myself and could end up in hospital and may even be paralysed, so I will do nothing.” All pain patients do this to a certain degree. Too much catastrophic thinking results in increased depression and increased disability. Causalgia an old term that equates to complex regional pain syndrome (CRPS) type 2. This term should not be used nowadays! Central pain pain initiated or caused by a primary lesion or dysfunction in the central nervous system (2). Of importance here is the fact that spinal cord injury can produce pelvic pain. Central sensitization a term that covers those changes that occur in the central nervous system which magnify sensory perceptions. The enhanced responsiveness of nociceptive neurons in the central nervous system is due to multiple complex mechanisms (refer Chapter 6). Chronic pain Essentially there are two types of chronic/persistent pain. (i) acute pain that has persisted for long enough to be arbitrarily called persistent or chronic, e.g., for three months. However, for CPP, six months is often chosen, as pain may be cyclical on a monthly basis. (ii) Pain involving chronic pain mechanisms such as central sensitization. Chronic pelvic pain nonmalignant pain perceived in structures related to the pelvis of either men or women. In the case of documented nociceptive pain that becomes chronic, the pain must have been continuous or recurrent for at least six months. If nonacute pain mechanisms are documented then the pain may be regarded as chronic irrespective of the time period. In all cases, there may be associated negative cognitive, behavioral, and social consequences (EAU definition). There are several important parts to this complex definition: 1. The term pelvic pain is used to cover all nonmalignant pains that are perceived or felt to be within the pelvic area. Areas outside of the anatomical pelvis are also included such as the testis, penis, and vulvar region. Including these areas is controversial, but is generally accepted because of the close links in function, physiology, and pathology. This definition is also accepting that pathology outside of the pelvis may cause CPP; for instance, pain may be “perceived” in the pelvis such as referred mechanical back pain where the pain is mainly in the testis. 2. Unlike most other definitions, this accepts that CPP may occur in both sexes! Many of the mechanisms may overlap. 3. There are two reasons as to why the pain may be chronic. a. Acute nociceptive mechanisms are the cause of the persistent pain. If the pain has been present for six months, then despite the mechanisms being nociceptive, the pain is

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considered chronic. A time scale of six months was chosen to take account of those pains that are intermittent but with monthly cycles. b. Chronic pain mechanisms are the cause of the persistent pain. In this case the pain is automatically considered chronic irrespective of duration. (See Chapter 5, How and why does pain become chronic? An overview of the neurophysiology of chronic pain). 4. As well as pain, by definition there will be psychosocial consequences. 5. CPP may be divided into well-defined pain syndromes (e.g., pudendal neuralgia, infective orchitis) and chronic pelvic pain syndrome (CPPS). CPPS the occurrence of persistent or recurrent, episodic pelvic pain associated with symptoms suggestive of lower urinary tract, sexual, bowel, or gynecological dysfunction. There is no proven infection or other obvious pathology (12). Chronic pain mechanisms are now well described and should be considered as a neurological disease process. The definition of CPPS needs to be altered to reflect this. This has been discussed in several forums, but to date a simple change in the definition to reflect this has not occurred. Perhaps, using the word “local” would do. That is—“. or other local pathology.” Clitoral pain syndrome refers to pain that can be localized by point-pressure mapping to the clitoris (14). Cognitions are thoughts. CRPS currently being redefined by IASP! There are two types: type 1—no obvious nerve injury and type 2—obvious nerve injury precipitating the pain. Salient points include: (i) pain above and beyond what one would expect for the degree of injury, (ii) pain in a regional distribution, e.g., hand and not dermatomal, and (iii) vascular, sensory, and motor dysfunction to varying degrees indicating central nervous system dysfunction. Diaphoresis excessive sweating. Dyschezia difficulty in defecating. Dysesthesia (American)/Dysaesthesia (U.K.) an unpleasant abnormal sensation, whether spontaneous or evoked (2). Paresthesia due to a peripheral neuropathy is an example here. Dorsal root ganglion pathology may cause a running water dysesthesia. Central pathology (within the spinal cord and brain) may cause a burning dysesthesia. Endometriosis-associated pain syndrome chronic or recurrent pelvic pain where endometriosis is present but does not fully explain all the symptoms (14). Many patients have pain above and beyond the endometriosis pathology; this term is used to cover that group of patients. Enthesis the point at which a tendon inserts into bone, where the collagen fibers are mineralized and integrated into bone tissue. Enthesitis inflammation of enthesis. Enthopathy pathology of the enthesis. Epididymal pain syndrome the occurrence of persistent or recurrent episodic pain localized to the epididymis on examination that is associated with symptoms suggestive of urinary tract or sexual dysfunction. There is no proven epididymo-orchitis or other obvious pathology [new and more specific definition than scrotal pain syndrome; (14)]. Chronic pain mechanisms are now well described. The definition needs to be altered to reflect this (see CPPS). This definition could also be subdivided into type 1—no evidence of pathology and type 2—noninfective, inflammatory changes. Excitotoxicity cell toxicity and death due to massive cell stimulation, this may occur when a nerve is cut or damaged or in a disease process such as multiple sclerosis. Fibromyalgia poorly understood, generalized muscle pain associated with tender points. Most definitions expect tender points to be in four quadrants. Some definitions are didactic about the number of tender points that need to be found. The pain is usually associated with sleep disturbance and depression. Generalized vulvar pain syndrome (formally dysesthetic vulvodynia, essential vulvodynia) refers to vulval burning or pain that cannot be consistently and tightly localized by pointpressure “mapping” by probing with a cotton-tipped applicator or similar instrument. The vulvar vestibule may be involved but the discomfort is not limited to the vestibule (14).

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Hematachezia red blood in stools. Hyperalgesia an increased response to a stimulus which is normally painful (2). That is pain above and beyond what you would expect with pin prick examination (Ad mediated sensation) or heat (C fiber mediated sensation); for example, in a patient with vulvar pain syndrome. This may be peripheral or central phenomena. Hyperesthesia (American)/Hyperaesthesia (U.K.) increased sensitivity to stimulation, excluding the special senses (2). Nonpainful, c.f. allodynia. Hyperpathia a painful syndrome characterized by an abnormally painful reaction to a stimulus, especially a repetitive stimulus, as well as an increased threshold (2). This is a very special phenomena, usually associated with a delayed perception of pain, the pain is usually above and beyond what one would expect (hyperalgesia) and continues for a significantly longer time than one would expect. It probably represents a dysfunction of the central nervous system. Hypoalgesia diminished pain in response to a normally painful stimulus (2). Hypoalgesia may be due to a peripheral nerve injury, but may also be due to central (within the spinal cord and brain) phenomena. Hypoesthesia (American)/Hypoaesthesia (U.K.) decreased sensitivity to stimulation, excluding the special senses (2). Hypoesthesia may be due to a peripheral nerve injury, but may also be due to central (within the spinal cord and brain) phenomena. Localized vulvar pain syndrome refers to pain that can be consistently and tightly localized by point-pressure mapping to one or more portions of the vulva. Clinically, the pain usually occurs as a result of provocation [touch, pressure, or friction, (14)]. Long term potentiation the long-lasting enhancement in efficacy of the synapse between two neurons, it is thought to be the basis of learning. Central changes with chronic pain may be similar to the changes with long term potentiation. Maladaptive pain pain that remains long after the injury has gone and is due to central nervous system changes. Neuralgia pain in the distribution of a nerve or nerves (2). Often due to central nervous system responses to the peripheral nerve injury, the pattern is not as clear-cut as one might expect. The pain and sensory dysfunction may thus be outside the expected distribution. For instance, with pudendal neuralgia, pain and sensory disturbances may spread beyond the expected dermatomal distribution of the pudendal nerve. Neuritis inflammation of a nerve or nerves (2). For a true neuritis, inflammation of the nerve is necessary. Neurogenic pain pain initiated or caused by a primary lesion, dysfunction, or transitory perturbation in the peripheral or central nervous system (2) (see neuropathic pain). Transient pain from blunt trauma to a nerve, such as the ulna nerve, where there is no nerve damage would be considered a transitory perturbation. Neuropathic pain pain initiated or caused by a primary lesion or dysfunction in the nervous system (2). There is an overlap with neurogenic pain. Neuropathic pain suggests a greater involvement of the nervous system than neurogenic pain and is associated with nerve damage. It suggests that central sensitization pain mechanisms are involved. Neuropathy a disturbance of function or pathological change in a nerve: in one nerve, mononeuropathy; in several nerves, mononeuropathy multiplex; if diffuse and bilateral, polyneuropathy (2). Nociceptor/nociception a receptor preferentially sensitive to a noxious stimulus or to a stimulus which would become noxious if prolonged (2). Nociception is the “process” responsible for producing pain. Nociception can occur in a decerebrate individual without perception of the sensory stimulus. Pain requires the higher centers. Noxious stimulus is a stimulus that is damaging to normal tissues (2). Damage may be potential. Hot water can activate a nociceptor due to its potential to cause a burn, but if the endangered part is removed quickly no damage may occur. Pain an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage (2). Pain involves the whole of the neuroaxis and is associated with a psychological response, c.f. nociception.

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Pain threshold the least experience of pain which a subject can recognize (2). Pain thresholds may be used to monitor pain mechanisms. Thresholds to different stimuli may be used (e.g., cold, hot, pressure). Quantitative sensory testing involves using a computerized system to obtain accurate sensory perception data. Pain tolerance level the greatest level of pain which a subject is prepared to tolerate (2). Pain tolerance may be used to monitor pain mechanisms. Paresthesia an abnormal sensation, whether spontaneous or evoked (2). If unpleasant, is an example of a dysesthesia. Pelvic floor muscle pain syndrome the occurrence of persistent or recurrent, episodic, pelvic floor pain with associated trigger points that is either related to the micturition cycle or associated with symptoms suggestive of urinary tract or sexual dysfunction. There is no proven infection or other obvious pathology (14). Chronic pain mechanisms are now well described. The definition needs to be altered to reflect this (see CPPS). Penile pain syndrome the occurrence of pain within the penis that is not primarily in the urethra, with the absence of proven infection or other obvious pathology (14). Chronic pain mechanisms are now well described. The definition needs to be altered to reflect this (see CPPS). Perineal pain syndrome the occurrence of persistent or recurrent, episodic, perineal pain that is either related to the micturition cycle or associated with symptoms suggestive of urinary tract or sexual dysfunction. There is no proven infection or other obvious pathology (12). Chronic pain mechanisms are now well described. The definition needs to be altered to reflect this (see CPPS). How this relates to vulvar pain is not clear. Peripheral neurogenic pain pain initiated or caused by a primary lesion or dysfunction or transitory perturbation in the peripheral nervous system (2) (see neurogenic and neuropathic pain). Peripheral neuropathic pain pain initiated or caused by a primary lesion or dysfunction in the peripheral nervous system (2) (see neurogenic and neuropathic pain). Persistent pain equivalent to chronic pain, this is becoming the preferred term, rather than chronic. Post-vasectomy pain syndrome a scrotal pain syndrome that follows vasectomy (14). Post-vasectomy pain may be as frequent as 1%, possibly more. The mechanisms are poorly understood and it is for that reason it is considered a special form of scrotal pain syndrome. Proctalgia fugax refers to severe, brief, episodic pain that seems to arise in the rectum and occurs at irregular intervals (2). This is unrelated to the need to or the process of defecation. How this relates to anorectal pain syndrome is not clear. Prostate pain syndrome the occurrence of persistent or recurrent episodic prostate pain, which is associated with symptoms suggestive of urinary tract and/or sexual dysfunction. There is no proven infection or other obvious pathology (14). Chronic pain mechanisms are now well described. The definition needs to be altered to reflect this (see CPPS). The term prostatitis continues to be used to equate to prostate pain syndrome. In the editors and others opinion, although it is recognized that this term has a long history, its use is often inappropriate (20). The NIH consensus (18) includes infection (types 1 and 2) and should not be considered under prostate pain syndrome. The terminology could be changed to be in line with the ESSIC 2006 recommendations. As well as “prostatitis” the term “prostadynia” has been used in the past. Pudendal neuralgia neuropathic pain in the distribution of the pudendal nerve due to pathology of the pudendal nerve. Pudendal pain syndrome a neuropathic-type pain arising in the distribution of the pudendal nerve with symptoms and signs of rectal, urinary tract, or sexual dysfunction. There is no proven obvious pathology. (14). Chronic pain mechanisms are now well described. The definition needs to be altered to reflect this (see CPPS). This is not the same as pudendal neuralgia. Radicular pain pain in the distribution of a nerve root. Scrotal pain syndrome the occurrence of persistent or recurrent episodic scrotal pain that is associated with symptoms suggestive of urinary tract or sexual dysfunction. There is no proven epididymo-orchitis or other obvious pathology (12). Chronic pain mechanisms are now well

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described. The definition needs to be altered to reflect this (see CPPS). It is a generic term that is subdivided into testicular and epididymal pain syndromes. The term is used when the site of the pain is not clearly testicular or epidydimal. Somatic pain pain perceived or generated in somatic tissues, such as skin and muscles. Sympatho-nociceptor coupling sympathetic nerve fibers coupling with nociceptors. This may be a mechanism by which the sympathetic system may produce/maintain persistent pain. Tender points areas of muscle tenderness, usually associated with fibromyalgia. In contrast to trigger points they are often multiple, diffusely spread throughout the body but well localized. Testicular pain syndrome the occurrence of persistent or recurrent episodic pain localized to the testis on examination that is associated with symptoms suggestive of urinary tract or sexual dysfunction. There is no proven epididymo-orchitis or other obvious pathology (14). Chronic pain mechanisms are now well described. The definition needs to be altered to reflect this (see CPPS). This definition could also be subdivided into type 1—no evidence of pathology and type 2—noninfective, inflammatory changes. Previous terms have included orchitis, orchalgia, and orchidynia. Trigger points hyperirritable areas said to be located in a taut band of skeletal muscle. They tend to be few in number, produce pain locally, but also in a referred pattern. Urethral pain syndrome the occurrence of recurrent episodic urethral pain usually on voiding, with daytime frequency and nocturia, in the absence of proven infection or other obvious pathology (12). Chronic pain mechanisms are now well described. The definition needs to be altered to reflect this (see CPPS). Vaginal pain syndrome the occurrence of persistent or recurrent episodic vaginal pain that is associated with symptoms suggestive of urinary tract or sexual dysfunction. There is no proven vaginal infection or other obvious pathology (12). Chronic pain mechanisms are now well described. The definition needs to be altered to reflect this (see CPPS). Vestibular pain syndrome (formerly vulvar vestibulitis, focal vulvitis) refers to pain that can be localized by point-pressure mapping to one or more portions of the vulvar vestibule (14). Visceral pain pain originating from a visceral organ. Visceral somatic convergence nerves from the viscera and somatic tissues converge (pass) to the same part of the spinal cord. There is some overlap. This may be a mechanism for referred pain. Vulvar pain syndrome the occurrence of persistent or recurrent episodic vulvar pain that is either related to the micturition cycle or associated with symptoms suggestive of urinary tract or sexual dysfunction. There is no proven infection or other obvious pathology (12). Chronic pain mechanisms are now well described. The definition needs to be altered to reflect this (see CPPS). The ISSVD have subdivided vulvar pain syndrome by the results of cutaneous mapping, the EAU have adapted their recommendations. Interestingly, this approach appears to work. Wind up/neural wind up repeated stimulation of the nervous system, which can produce changes within the central nervous system resulting in central sensitization. ACKNOWLEDGMENTS Ursula Wesselmann is supported by NIH grants DK066641 (NIDDK), HD39699 (NICHD, Office of Research for Women’s Health) and the National Vulvodynia Association. REFERENCES 1. Wesselmann U, Burnett AL, Heinberg LJ. The urogenital and rectal pain syndromes. Pain 1997; 73(3):269–94. 2. Merskey H, Bogduk N. Classification of Chronic Pain. Seattle, WA: IASP Press, 1994:163–74. 3. Wesselmann U. Chronic pelvic pain. In: Turk DC, Melzack R, eds. Handbook of Pain Assessment. 2nd ed. New York: Guilford Press, 2001:567–78. 4. Wesselmann U. Guest editorial: pain-the neglected aspect of visceral pain. Eur J Pain 1999; 3:189–91. 5. Zondervan KT, Yudkin PL, Vessey MP, et al. Patterns of diagnosis and referral in women consulting for chronic pelvic pain in U.K. primary care. Br J Obstet Gynaecol 1999; 106(11):1156–61.

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6. Zondervan KT, Yudkin PL, Vessey MP, et al. Prevalence and incidence of chronic pelvic pain in primary care: evidence from a national general practice database. Br J Obstet Gynaecol 1999; 106(11):1149–55. 7. Burnett AL, Wesselmann U. History of the neurobiology of the pelvis. Urology 1999; 53(6):1082–9. 8. Burnett AL, Wesselmann U. Neurobiology of the pelvis and perineum: principles for a practical approach. J Pelvic Surg 1999; 5:224–32. 9. Thomas T. Practical Treatise on the Diseases of Woman. Philadelphia, PA: Henry C. Lea’s Son, 1880. 145–7. 10. Bachmann G, Rosen R, Pinn V, et al. Vulvodynia: definitions, diagnosis and management. A Stateof-the-Art Consensus. J Reprod Med 2006; 51(6):447–56. 11. Moyal-Barracco M, Lynch PJ. 2003 ISSVD terminology and classification of vulvodynia: a historical perspective. J Reprod Med 2004; 49(10):772–7. 12. Abrams P, Cardozo L, Fall M, et al. The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn 2002; 21(2):167–78. 13. ACOG Practice Bulletin No. 51. Chronic pelvic pain. Obstet Gynecol 2004; 103(3):589–605. 14. Fall M, Baranowski AP, Fowler CJ, et al. EAU guidelines on chronic pelvic pain. Eur Urol 2004; 46(6):681–9. 15. Diokno AC, Homma Y, Sekiguchi Y, et al. Interstitial cystitis, gynecologic pelvic pain, prostatitis and their epidemiology. Int J Urol 2003; 10:S3–6. 16. Gillenwater JY, Wein AJ. Summary of the National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases Workshop on Interstitial Cystitis, National Institutes of Health, Bethesda, Maryland, August 28–29, 1987. J Urol 1988; 140(1):203–6. 17. Wein AJ, Hanno PM, Gillenwater JY. Interstitial cystitis: an introduction to the problem. In: Hanno PM, Staskin DR, Krane RJ et al., eds. Interstitial Cystitis. London, U.K.: Springer, 1990:13–4. 18. Krieger JN, Nyberg L, Nickel JC. NIH consensus definition and classification of prostatitis. J Am Med Assoc 1999; 282(3):236–7. 19. Van de Merwe JP, Nordling J. Interstitial cystitis: definitions and confusable diseases. ESSIC meeting 2005 Baden. Eur Urol Today March 2006; 6 (see also 7,16,17). 20. Abrams P, Baranowski A, Berger RE, et al. A new classification is needed for pelvic pain syndromes— are existing terminologies of spurious diagnostic authority bad for patients? J Urol 2006; 175(6):1989–90. 21. Agarwal M, O’Reilly PH, Dixon RA. Interstitial cystitis—a time for revision of name and diagnostic criteria in the new millennium? BJU Int 2001; 88(4):48–50. 22. Simon LJ, Landis JR, Erickson DR, et al. The Interstitial Cystitis Data Base Study: concepts and preliminary baseline descriptive statistics. Urology 1997; 49(Suppl. 5A):64–75. 23. Chung MK, Chung RR, Gordon D, et al. The evil twins of chronic pelvic pain syndrome: endometriosis and interstitial cystitis. J Soc Laparoendosc Surg 2002; 6(4):311–4. 24. Erickson DR, Morgan KC, Ordille S, et al. Nonbladder related symptoms in patients with interstitial cystitis. J Urol 2001; 166(2):557–61 (discussion 561–2). 25. Koziol JA. Epidemiology of interstitial cystitis. Urol Clin North Am 1994; 21(1):7–20. 26. Head H. On the disturbances of sensation with especial reference to the pain of visceral disease. Brain 1893; 16:1–133. 27. Berkley KJ, Hubscher CH. Visceral and somatic sensory tracks through the neuraxis and their relation to pain: lessons from the rat female reproductive system. In: Gebhart GF, ed. Visceral Pain. Progress in Pain Research and Management. Vol. 5. Seattle, WA: IASP Press, 1994:195–216. 28. Bielefeldt K, Gebhart GF. Visceral pain: basic mechanisms. In: McMahon SB, Koltzenburg M, eds. Textbook of Pain. 5th ed. New York: Churchill Livingstone, 2006:721–36. 29. Alagiri M, Chottiner S, Ratner V, et al. Interstitial cystitis: unexplained associations with other chronic disease and pain syndromes. Urology 1997; 49(Suppl. 5A):52–7. 30. Zondervan KT, Yudkin PL, Vessey MP, et al. Chronic pelvic pain in the community—symptoms, investigations, and diagnoses. Am J Obstet Gynecol 2001; 184(6):1149–55. 31. Clauw DJ, Schmidt M, Radulovic D, et al. The relationship between fibromyalgia and interstitial cystitis. J Psychiatr Res 1997; 31(1):125–31.

2

Epidemiology of Urogenital Pain Mary McLoone

St. Michaels’s Hospital, University of Toronto, Toronto, Ontario, Canada

John Lee

Pain Management Centre, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, U.K.

EPIDEMIOLOGY OF CHRONIC UROGENITAL PAIN General Epidemiology of Chronic Pain In order to put into context the incidence and prevalence of chronic or long-term urogenital pain, it is useful to have an overall understanding of long-term pain and the nature of the studies that are conducted to collect this information. The “perfect” study to provide this information does not exist, so a number of different sources provide useful guidance. As with any scientific report, study design and sources of error should be carefully considered. Here are some pertinent questions to consider when assessing people with long-term pain: & & &

How is the pain defined? Is the way this information is gathered from the subjects valid? Is the way that patients are selected likely to be representative of the group being studied?

Some examples of how this might be problematic may be helpful. The data collection tool itself needs to be the subject of rigorous trialing to ensure that it is sufficiently sensitive and specific to give a reproducible answer, so that people with a particular pain can be correctly identified and separated from people with similar complaints. It can often be practical or cost effective to use a predefined group of people, such as those registered with a particular health care provider; however, this will not capture information about those who are not part of this group who may have a particularly high incidence of the type of pain under study. Similarly, although the household under study may have been correctly identified, questionnaires are usually specifically designed for an individual to answer, and the pain sufferer may be assisted in answering by other members of the household, who may provide their own interpretations of the complaint. Therefore, any epidemiological assessment should be approached with caution. As we have discussed, it is often difficult to obtain accurate information within one nation. When different nations are compared, these problems are compounded. It might be assumed that countries with similar social structures are comparable, but simple differences in the way workrelated injury is dealt with, whether compensation is available, or the nature of payment and access to health care can affect not only the way people report pain, but also whether they accept a sick role. Two facts that make this clearer are: (i) people who are self-employed are not absent from work as often as employees who are able to draw sickness benefits and (ii) people who remain working report less pain than those who are absent due to ill health. In 1998, Gureje made some interesting observations about how pain is expressed in different cultures and societies (1). This study collected information from consecutive primary health care attendees between the ages of 18 and 65 years across 15 centers in 14 countries. A total of over 25,000 patients were screened, and a random sample of 5447 patients completed a second assessment. The prevalence rate of chronic pain across all centers was 21.5%. In Europe, Athens (Greece) and Verona (Italy) had 12% and 13%, respectively, but all other centers including Germany, France, the Netherlands, and England were found to have rates in excess of

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20%. Japan and China had low prevalence (12% and 13%, respectively) while South America, Brazil and Chile had relatively high prevalence rates of 31% and 33%. This study also showed that the increased observation of chronic pain in females relative to males is not unique to western societies. Across all centers, persistent pain was associated with psychological disturbance and significant activity limitation. This relationship with psychological comorbidity has been extensively studied and a recent systematic review of neck and back pain suggests that psychological factors not only play an important role in chronic pain, but also in the development of acute pain and its transition to chronic pain (2). In Denmark, a series of health surveys are carried out every six years. The most recent survey, in 2000, consisted of a random sample drawn from the Danish Central Personal Register (3). Ten thousand people, excluding patients with cancer, completed a Short Form-36 general health questionnaire. An overall chronic pain prevalence of 19% was found, 16% for men and 21% for women. In this study, chronic pain was once more associated with limited education. It also identified that divorced or separated individuals had a 1.5 higher odds ratio of having chronic pain compared with married people. Large studies are always compelling, and a study in Australia attempted to assess the prevalence of chronic pain by a computer-assisted telephone interview using randomly selected telephone numbers (4). Seventeen thousand five hundred interviews were carried out, and chronic pain was reported by 17% of males and 20% females. Having chronic pain was also associated with older age, lower levels of completed education, and not having private health insurance. In the U.K., an often-quoted paper by Elliot and colleagues investigated a random sample of 5036 patients from 29 general practices in the primary care setting (5). The subjects were sent out with a self-completion postal questionnaire to assess the prevalence of chronic pain in the community. The response rate was 72%, and 50.4% of these respondents reported that they had chronic pain. Fifteen and four tenths percent said it was severe. Older age, being female, living in a rented accommodation, and the lack of ability to work were all identified as predictors of chronic pain in the community. Arguably the most prevalent long-term pain condition is back pain, and this is often singled out in epidemiological literature. In the U.K., the government conducts regular assessments of different aspects of the makeup of society and the Office of National Statistics has reported the prevalence of back pain in 1993, 1996, and 1999 (6). The latter survey was based on 5500 interviews and showed that 40% of the population had suffered from back pain in the previous 12 months and this had resulted in significant use of primary care services and limitation of work activity. It also showed that there was little difference in the overall prevalence in men and women, but a higher rate in the lower social classes. In summary of this section, it is likely that long-term pain affects around 20% of many societies although there is a good degree of variation. There are differences between the sexes, and also between people who can be grouped with certain psychological and social similarities. Epidemiology of Urogenital Pain As there is limited information available on the overall prevalence of chronic pain, it is not surprising to find that there is even less in the area of urogenital pain. Much of the short fall is due to the difficulty in categorizing such pain. The classification of chronic pelvic pain syndromes by the International Association for the Study of Pain (IASP) into subsets of urological, gynecological, anorectal, neurological, and muscular has done much to improve this. The rest of this chapter will attempt to summarize the currently available epidemiology using this classification. The etiology and definitions of these conditions will be explained in more detail in the subsequent chapters. UROLOGICAL Painful Bladder Syndrome/Interstitial Cystitis There are considerable difficulties in the definition of “interstitial cystitis” (IC), which has been historically thought of as a disease that mainly affects females, but is thought to be

Epidemiology of Urogenital Pain

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under-diagnosed in males as the symptoms are very similar to prostatitis. For this reason the term “painful bladder syndrome” (PBS), which includes classic IC, has been suggested and adopted by several professional organizations. It is, therefore, difficult to estimate the actual prevalence of the condition in males, but it has been noted that there is a particularly high proportion in the American Indians of Cherokee descent, approximately 17% (7). Even though it is more common in women, PBS/IC may still be under diagnosed. In a recent study, 85% of patients with pelvic pain tested positive for intravesical potassium sensitivity (a test for IC) (8). The test detects the presence of abnormal bladder permeability, which is present in most patients with IC. Only 1.6% of these patients had received an initial diagnosis of IC before the test and it is possible that this diagnosis is often confused with other causes of chronic pelvic pain. If this is extrapolated, as many as 7.3 million out of the 9 million women suffering from chronic pelvic pain in the U.S. may have a diagnosis of IC. The most recent estimate of prevalence in females before this study was 750,000 in 1999 (9). Another study indicating that IC is under diagnosed in both men and women was carried out in a managed care population of 10,000 subjects in the North Pacific. The prevalence of IC symptoms was between 6.2% and 11.2% for women, and 2.3% and 4.6% for men when diagnosed from the O’Leary-Sant IC questionnaire mailed to all participants. In a previous study in the same population the prevalence of a physician diagnosis of IC was 0.2% in women and 0.04% in males. Therefore, the prevalence of IC symptoms was 30- to 50-fold higher in women and 60- to 100-fold higher in men compared with the physician diagnosis of IC. The symptoms were long-standing (duration greater than one year) in 80% and bothersome (severity score five or greater) in 50%. The response rate was 35% and so the results of this study may reflect significant nonresponder bias (10). Prostate Pain The epidemiologic literature is limited and definitions similarly difficult to those of PBS/IC, but the worldwide prevalence of “chronic prostatitis” appears to be in the range of 2% to 10% indicating that it is an important international health problem (11). It is difficult to gauge the exact number as most studies are based on physician reported outpatient data and may not be representative of the general population. In the U.S.A., 8% of urology patients and 1% of patients in general are diagnosed with “prostatitis,” giving an annual incidence of almost two million patients (12). Up to 50% of men will suffer from symptoms of prostatitis at some point in their lives (13). Several studies have looked at the demographic distribution of the disease. Chronic prostatitis is a common disease of young men but does affect men of all ages. In one postal study of 3000 Canadian men, the age specific prevalence was highest between ages 20 and 49 years and increased again after age 70 (14). This is compared with benign prostatic hyperplasia and prostate cancer, which are predominantly diseases of older men. More recently, a cross-sectional postal survey of 2987 men aged 20 to 74 years in Canada (with a response rate of 29%) identified 9.7% of subjects as having “chronic prostatitis-like” symptoms according to the National Institutes of Health chronic prostatitis symptom index. The average age of the prostatitis population was 50 years and the prevalence was 11.5% in men younger than 50, and 8.5% in the older men. Although these numbers are more likely to reflect the prevalence of prostatitis in the general population than physician chart reviews or patient surveys, the relatively low response rate raises the issue of nonresponder bias. In this survey younger men were underrepresented and the older age group overrepresented, which also must be taken into account while interpreting the results (15). Scrotal and Testicular Pain Chronic testicular pain or orchalgia is well recognized and seems to be increasing in incidence. The only statistical data available is for the post vasectomy pain syndrome. Most of the studies carried out are retrospective questionnaires and noted the incidence to be 15% to 19% (16). Chronic testicular pain occurs at any age but the majority of the patients are in their mid- to late 1930s (17).

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GYNECOLOGICAL Endometriosis-Associated Pain One-third of patients attending gynecology clinics complain of pelvic pain as their major symptom (18). It is difficult to obtain an overall estimate of prevalence but a systematic review carried out in the U.K. in 1998 suggests an 8% rate of dyspareunia, 45% to 97% rate of dysmenorrhoea and 23% to 29% rate of abdominal pain (19). Also in the U.K., an annual prevalence rate of pelvic pain in primary care of 38/1000, was found in women aged 15 to 73, a rate comparable with that of asthma (20). Studies suggest that a third of chronic pelvic pain is due to endometriosis, a third is due to adhesions and a third of patients have no obvious pathology (21,22). A more recent review of randomized controlled trials indicates that endometriosis appears to be responsible for chronic pelvic pain symptoms in more than half of confirmed cases (23). Vulval Pain Vulval pain encompasses a number of conditions including vulval vestibulitis, where pain is provoked by coitus or dysesthetic vulvodynia, which includes generalized and neuropathic pain. Studies suggest that one in six women may experience vulvodynia, although the magnitude of the problem in the general population is largely unknown. One questionnairebased review of 4915 women estimated that approximately 16% reported vulval pain of more than three months’ duration at some point during their lifetime. Only 54% sought treatment and of those 9% were given a diagnosis of chronic vulval pain (24). Previously, the condition had been thought to be more predominant in Caucasian women but in this study was found to be of similar incidence in white and African American women. Hispanic women were 80% more likely than white women to have experienced chronic vulval pain. SUMMARY Although there is some epidemiological data on the urological conditions discussed, there is a long way to go before confident estimates of the impact of urogenital pain in the population can be provided. There is very little published on conditions of the pelvic musculature and the anorectal area which are becoming more commonly diagnosed. There have been problems using a common language to describe the clinical picture but these are now being addressed by the International Continence Society, European, and IASP systems of classification, which are to be commended to people who work in this field. REFERENCES 1. Gureje O, Von Korff M, Simon G, et al. Persistent pain and well-being: a World Health Organization Study in primary care. J Am Med Assoc 1998; 280(2):147–51. 2. Linton SJ. A review of psychological risk factors in neck and back pain. Spine 2000; 25(9):1148–56. 3. Eriksen J, Jensen MK, Sjogren P, et al. Epidemiology of chronic non-malignant pain in Denmark. Pain 2003; 106(3):221–8. 4. Blyth FM, March LM, Brnabic AJ, et al. Chronic pain in Australia: a prevalence study. Pain 2001; 89(2–3):127–34. 5. Elliott AM, Smith BH, Penny KI, et al. The epidemiology of chronic pain in the community. Lancet 1999; 354(9186):1248–52. 6. The Prevalence of Back Pain in Great Britain in 1998; Department of Health Statistical Bulletin 1998: 1–2. 7. Forrest JB, Schmidt S. Interstitial cystitis, chronic nonbacterial prostatitis and chronic pelvic pain syndrome in men: a common and frequently identical clinical entity. J Urol 2004; 172(6):2561–2. 8. Parsons CL, Bullen M, Kahn BS, et al. Gynaecological presentation of interstitial cystitis as detected by intravesical potassium sensitivity. Obstet Gynecol 2001; 98:127–32. 9. Curhan GC, Speizer FE, Hunter DJ, et al. Epidemiology of interstitial cystitis: a population based study. J Urol 1999; 161:549–52. 10. Clemens JQ, Meenan RT, Richard T, et al. Prevalence of interstitial cystitis symptoms in a managed care population. J Urol 2005; 174(2):576–80.

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11. Krieger JN, Ross SO, Riley DE, et al. Chronic prostatitis: epidemiology and role of infection. Urology 2002; 60(6 Suppl. A):8–13. 12. McNaughton Collins M, Stafford RS, O’Leary MP, et al. How common is prostatitis? A national survey of physician visits. J Urol 1998; 159:1224–8. 13. Stamley TA. Pathogenesis and Treatment of Urinary Tract Infections. Baltimore, MD: Williams and Wilkins Company, 1980:342–429. 14. Roberts RO, Lieber MM, Rhodes T, et al. Prevalence of a physician-assigned diagnosis of prostatitis: the Olmsted County Study of urinary symptoms and health status among men. Urology 1998; 51(4):578–84. 15. Nickel JC, Downey J, Hunter D, et al. Prevalence of prostatitis-like symptoms in a population based study using the National Institutes of Health chronic prostatitis symptom index. J Urol 2001; 165:842–5. 16. Granitsiotis P, Kirk D. Chronic testicular pain: an overview. Eur Urol 2004; 45(4):430–6. 17. Wesselmann U, Burnett AL. The urogenital and rectal pain syndromes. Pain 1997; 73:269–94. 18. Morris N, O’Neil D. Outpatient gynaecology. Br Med J 1958; 14(5078):1038–9. 19. Zondervan KT, Yudkin PL, Vessey MP, et al. The prevalence of chronic pelvic pain in women in the United Kingdom: a systematic review. Br J Obstet Gynaecol 1998; 105(1):93–8. 20. Zondervan K, Barlow DH. Epidemiology of chronic pelvic pain. Baillieres Best Pract Res Clin Obstet Gynaecol 2000; 14(3):403–14. 21. Chamberlain G, Brown JC. Gynaecological Laparoscopy. Report of the Working Party of the Confidential Enquiry into Gynaecological Laparoscopy. London: Royal College of Obstetricians and Gynaecologists, 1978. 22. Howard FM. The role of laparoscopy in chronic pelvic pain: promises and pitfalls. Obstet Gynaecol Surv 1993; 48:357–87. 23. Fauconnier A, Chapron C. Endometriosis and pelvic pain: epidemiological evidence of the relationship and implications. Hum Reprod Update 2005; 11(6):595–606. 24. Harlow BL, Sterwart EG. A population based assessment of chronic unexplained vulval pain: have we underestimated the prevalence of vulvodynia. J Am Med Womens Assoc 2003; 58:82–8.

3

Anatomy of the Urogenital Pain Systems D. Pattern

University of Durham, Durham, U.K.

J. Hughes

The James Cook University Hospital, Middlesbrough, U.K.

INTRODUCTION We consider the anatomy of the urogenital system, along with the rectum and anus. THE URINARY BLADDER The urinary bladder has a strong smooth muscle wall or detrusor muscle. In adults, the empty bladder lies within the true pelvis, but in children, it is predominantly within the abdominal cavity. The bladder has a base, superior, two inferolateral surfaces, and an apex (Fig. 1). The posterior surface is described as the base, about halfway along the base on either side of the midline lie the ureteric openings. The ureters enter the bladder obliquely so that during voiding they are compressed, thus preventing reflux of urine. The superior and inferolateral surfaces unite anteriorly to form the apex of the bladder. The median umbilical ligament, an embryological remnant of the urachus, connects the apex to the umbilicus. The neck of the bladder becomes continuous with the urethra, and the smooth muscle around the neck forms the internal sphincter of the bladder. The mucosal lining of the bladder is thrown into folds or rugae, except in the triangular-shaped region of the trigone between the ureteric and urethral orifices, where it is relatively smooth. Ligaments hold the neck in place in the true pelvis. Anteriorly, in males, the bladder neck is attached to the posterior surface of the pubic symphysis by the puboprostatic ligament and in females, by the pubovesical ligament. Fractures of the pubis in this region may cause trauma to the bladder. The lateral ligaments of the bladder and the tendinous arch of the pelvic fascia also hold the neck of the bladder in place. Peritoneum lines the abdominopelvic cavity and covers the pelvic viscera to different degrees. Anteriorly, the peritoneum covering the superior surface of the bladder is reflected onto the posterior aspect of the anterior abdominal wall. This allows the distended bladder to be drained directly through the anterior abdominal wall without piercing the peritoneum. In females, the peritoneum covering the superior surface of the bladder continues posteriorly to cover the anterior surface of the uterus creating a peritoneal “vesicouterine” pouch between the two viscera (the peritoneal coverings of the female pelvic viscera are discussed in more detail below). In males, however, peritoneum continues posteriorly to cover the anterior surface of the rectum creating a single peritoneal pouch, the rectovesical pouch (Fig. 2). Blood Supply Most of the bladder’s blood supply is from the left and right superior and inferior vesical arteries (Fig. 3, Table 1), the remainder is from small branches of the inferior gluteal and obturator arteries. A venous plexus (vesical plexus) surrounds the bladder in males and females. In males, it unites with the prostatic plexus, which receives blood from the deep dorsal vein of the penis. In females, the deep dorsal vein of the clitoris drains into the vaginal or uterovaginal venous plexus.

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Pattern and Hughes

Superior surface Median umbilical ligamet

Ureters

Urogenital diaphragm

Apex Inferolateral Surfaces

Trigone

Base

Puboprostatic ligament

Prostate gland

Pubovesical ligament

Vaginal opening in urogenital diaphragm

FIGURE 1 Superolateral view of the bladder in the male (left ) and female (right ) showing the bladder surfaces and ligaments associated with the neck of the bladder. Source: Modified from Ref. 1.

Lymphatics Lymphatics from the superolateral bladder drain to the external iliac nodes and from the fundus and neck to the internal iliac nodes (Fig. 4). Innervation The motor innervation of the bladder is via autonomic nerves, mostly from the inferior hypogastric plexus. During storage of urine, sympathetic innervation (T10–L2) causes a reduction in the muscle tone in the body of detrusor and an increase in the muscle tone at the base of the bladder and within the (involuntary) internal sphincter. During micturition, contraction of detrusor and relaxation of the internal sphincter is mediated via parasympathetic pelvic splanchnic nerves (S2–S4). The external urethral sphincter (voluntary), however, is innervated by the pudendal nerve (S2–S4).

THE UTERUS The uterus is a hollow, pear-shaped organ, approximately 7.5 cm long, 5 cm wide, and 2 cm thick. It is described as having a body (the superior two-thirds), a cervix (the inferior third), and two uterine tubes (formerly Fallopian tubes). The body includes the fundus, which is domeshaped and lies superior to the entrance of the uterine tubes. The uterine tubes open into the uterine cavity laterally on each side of the uterus. Inferiorly, the uterine body becomes narrowed at the isthmus, which demarcates the body of the uterus from the cervix. The nongravid uterus usually lies within the true pelvis, overlying the bladder and is normally anteverted and antiflexed. In some women the cervix and uterus are displaced posteriorly and overlie the rectum in a retroverted and retroflexed position. The cervix is cylindrically shaped (approximately 2.5 cm long in a nongravid woman) and projects inferiorly into the vaginal lumen. At the junction of the uterine body and cervix, the lumen is narrowed (the internal os) it also narrows at the external os where the cervix opens into the vaginal lumen. A simple columnar epithelium lines the length of the cervix except at the distal end where the epithelium is stratified squamous nonkeratinizing. The cervix is supported by several fibromuscular ligaments, namely the transverse cervical, pubo-cervical, and sacro-cervical ligaments. These ligaments are subperitoneal condensations of the pelvic fascia associated with the pelvic floor musculature (levator ani). The transverse cervical ligament (or cardinal ligament) anchors the cervix and superior vagina to the lateral

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Anatomy of the Urogenital Pain Systems

Ureter

Inferior epigastric artery

Lateral umbilical fold Small rectovesical fold

Median umbilical fold Medial umbilical fold

Rectovesical pouch

Ureter

Recto-uterine fold Broad ligament Round ligament of uterus Inferior epigastric artery

Lateral umbilical fold

Medial umbilical fold

Recto-uterine pouch

Median umbilical fold Vesico-uterine pouch

FIGURE 2 Peritoneal coverings of the pelvic viscera and associated peritoneal pouches in the male (top) and female (bottom) pelvis. Source: Modified from Ref. 1.

pelvic walls; note that the uterine arteries and ureters lie within this ligament, with the artery superior to the ureter. A single broad ligament and two round ligaments are also associated with the uterus (Fig. 2). The broad ligament is a peritoneal ligament that hangs over and beneath the uterine tubes (see below). The round ligaments are fibrous remnants of the gubernacula and assists in anchoring the uterus in the true pelvis. Each round ligament arises anterior and inferior to the

Deep circumflex iliac vein

External iliac vein

Common iliac vein Internal iliac vein

Middle rectal artery Vaginal artery Rectum Vagina

Uterus Bladder Vesical venous plexus

Inferior Uterine artery epigastric vein Internal pudendal artery Obturator Pudendal nerve veins

Iliolumbar artery Lateral sacral artery Superior Gluteal Inferior arteries

plexus

Deep dorsal vein of penis draining to prostate venous plexus Prostatic Prostate venous plexus

Inferior vesical/ internal pudendal vein

Internal iliac vein Deep circumflex iliac vein

Vagina

Rectum Vaginal venous plexus

Superior gluteal vein Uterine vein Lateral sacral veins Inferior gluteal vein Middle rectal veins Uterine venous plexus (phantom)

Bladder

Rectum

Vesical venous plexus

Middle rectal veins Rectal venous plexus

Inferior gluteal vein

Lateral sacral veins

Superior gluteal vein

Common iliac vein

Superior Gluteal Inferior arteries Inferior vesical Inferior artery epigastric vein Internal pudendal arteryExternal Pudendal nerve iliac vein Middle rectal artery (cut ends) Obturator veins Prostatic branch of inferior vesical artery Vesical venous

Iliolumbar artery Lateral sacral artery

FIGURE 3 (See color insert. ) Branches of the common iliac artery (left ) and common iliac vein (right ) in the male (top ) and female (bottom ) in relation to pelvic viscera.

Medial umbilical ligament (obliterated umbilical artery) Superior vesical arteries Urinary bladder

Internal iliac artery External iliac artery Obturator artery Deep circumflex iliac artery Inferior epigastric artery

Common iliac artery

Urinary bladder prostate

Obliterated umbilical artery (medial umbilical ligament) Superior vesical arteries

Internal iliac artery External iliac artery Obturator artery Deep circumflex iliac artery Inferior epigastric artery

Common iliac artery

26 Pattern and Hughes

27

Anatomy of the Urogenital Pain Systems

TABLE 1 Arteries of the Pelvis Artery Umbilical artery Superior vesical artery Inferior vesical in males; vaginal artery in females Obturator artery

Origin

Distribution in females

Anterior division of internal iliac Superior bladder (sometimes to artery ductus deferens) Umbilical Superior bladder and proximal ureter Anterior division of internal iliac Inferior bladder and ureter, artery vagina

Distribution in males

Inferior bladder and ureter, ductus deferens, prostate, seminal vesicles

Anterior division of internal iliac Pelvic musculature, nutrient artery artery to ilium and femoral head, adductor muscles of the thigh Uterine artery Anterior division of internal iliac Uterus, uterine ligaments, artery uterine tubes Vaginal branch of uterine artery Uterine artery Middle rectal artery Umbilical/anterior division of Inferior rectum, prostate, Inferior rectum internal iliac artery and seminal vesicles Internal pudendal artery Anterior division of internal iliac Main artery to perineum; artery branches to erectile tissue, muscles and skin of anal and urogenital triangles Inferior gluteal artery Anterior division of internal iliac Levator ani, coccygeus, artery pirifoormis, quadratus femoris, superior hamstrings, gluteus maximus, sciatic nerve Superior gluteal artery Posterior division of internal Gluteal muscles, tensor facia lata iliac artery and piriformis Lateral sacral artery Piriformis, erector spinae and overlying skin, contents of sacral canal Iliolumbar artery Psoas major, iliacus, quadratus lumborum, cauda equina Superior rectal artery Inferior mesenteric artery Superior third of rectum Median sacral artery Abdominal aorta Lower lumbar vertebrae, sacrum, coccyx Gonadal artery Abdominal aorta Ovary Testis

uterine tube on each side of the uterus, between the two layers of the broad ligament. They pass anteriorly over the external iliac vessels and exit the abdominopelvic cavity through the inguinal canals before terminating in the subcutaneous fat of the labia majora. The uterine tubes have four parts; the most medial and narrowest is the isthmus, widening into the ampulla before expanding into the wider infundibulum and opening into the peritoneal cavity. Elongated processes, or fimbriae, extend from the infundibulum over the surface of the ovary. Peritoneum covers the anterior surface of the uterus, uterine tubes, fundus, and posterior surface of the uterus to become reflected on the anterior wall of the rectum (Fig. 2). Two peritoneum-lined pouches are thus formed, the vesicouterine pouch (between the urinary bladder and uterus) and the rectouterine pouch (or “pouch of Douglas”), between the rectum, and uterus. Thus, the peritoneum, which “hangs off” the uterine tubes, is known as the broad ligament. Neurovascular structures and lymphatics pass from the posterior abdominal wall to the uterus, uterine tubes, and ovaries between the anterior and posterior layers of the broad ligament. Blood Supply On either side of the uterus, each uterine artery (arising from the anterior division of the internal iliac artery) passes down the lateral pelvic wall to the inferior border of the broad ligament and turns medially towards the cervix before ascending between the layers of the broad ligament

28

Pattern and Hughes

Thoracic duct

Preaortic nodes

L1 Lateral aortic (lumbar) nodes

Lymph from testis External iliac nodes

Inguinal ligament

Deep inguinal nodes Superficial inguinal nodes

Testis

Lymph from glans penis (glans clitoris, labia minora and lower part of vagina in women)

Lymph from superficial tissues of penis and scrotum (clitoris and labia majora in women)

FIGURE 4 Lymphatic drainage of the pelvic viscera and perineum. Source: Modified from Ref. 1.

alongside the uterine body; here the uterine arteries give off branches to the cervix, uterus, and uterine tubes. On each side, the uterine artery overlies the ipsilateral ureter superior to the fornix of the vagina. Branches of the ovarian arteries also supply the uterine tubes and anastomose with the uterine arteries. Venous drainage is firstly to the surrounding venous plexus, then the uterine veins and thence to the internal iliac veins. Venous blood from the uterine tubes also passes into the ovarian veins. Lymphatics Lymph from the fundus, most of the uterine tubes and the ovaries drains to the lateral aortic nodes (part of the para-aortic or lumbar group of nodes), lymph from the body and cervix drains principally to the external and internal iliac nodes. There is also some drainage from the uterus via the round ligament to the superficial inguinal nodes and sometimes the cervix drains towards the sacral nodes. The upper two-thirds of the vagina drains to the internal and external iliac nodes and the lower third drains to the superficial inguinal nodes. Innervation Uterine contractility is largely hormonally mediated and autonomic input from the inferior hypogastric plexus appears to be largely vasomotor via sympathetic motor fibers (T12–L1) and parasympathetics from the pelvic splanchnic nerves (S2–S4). Sensory fibers from the body of the uterus travel with sympathetic nerves (T10–L1), and from the cervix travel with parasympathetic nerves (S2–S4) to the spinal cord.

Anatomy of the Urogenital Pain Systems

29

THE RECTUM AND ANUS The rectum begins at the level of the third sacral vertebra and is continuous with the sigmoid colon. It is approximately 15 cm long becoming continuous with the anal canal at the anorectal junction, which is at the level of the pelvic diaphragm. At this point, the puborectalis muscle (part of levator ani) slings around the rectum forming a sharp bend (the perineal flexure), which assists in maintaining fecal continence. The anal canal is approximately 3.5 cm long and ends at the anus. The rectum is loosely attached to the anterior surface of the sacrum by fascia, allowing for distension of the rectum and fecal storage; only the lateral and anterior superior third of the rectum is covered by peritoneum. The rectum and its contents are predominantly supported by the muscular pelvic floor. The posterior relations of the rectum include the piriformis, coccygeus and levator ani muscles, the sacral, coccygeal, splanchnic and sympathetic nerves, and branches of the internal iliac artery and vein. In males, the rectum is a posterior relation of the base of the bladder, seminal vesicles, prostate, ducti deferentes, and the ureters. In females, the superior two-thirds of the rectum is posterior to the uterus. Blood Supply The rectum is supplied by a single superior rectal artery and paired middle and inferior rectal arteries. The superior rectal artery (a branch of the inferior mesenteric artery) supplies the superior third of the rectum, the left and right middle rectal arteries (if present, are branches of the anterior division of the internal iliac arteries), and the left and right inferior rectal arteries (terminal branches of the internal pudendal arteries) supply the remainder of the rectum. The middle rectal artery may also contribute to the blood supply of the seminal vesicles and the prostate gland in males. Venous blood from the rectum drains into a submucosal venous plexus before draining into the superior, middle, and inferior rectal veins. Blood from the middle and inferior rectal veins drain to the internal iliac veins and from the superior rectal vein to the inferior mesenteric vein and thence to the portal system. The venous plexus around the rectum forms an important anastomosis between the systemic and hepatic portal systems. Lymphatics The lymphatic drainage of the rectum and superior part of the anal canal is to the inferior mesenteric nodes, then to the internal iliac and sacral nodes before entering the pre-aortic nodes. In contrast, lymph from the lower part of the anal canal drains to the superficial inguinal nodes. Innervation The rectum receives only autonomic innervation, but the anal canal receives both autonomic and somatic innervation. Sympathetic nerves from the inferior mesenteric (L1–L2) and superior hypogastric plexus innervate the rectum and superior part of the anal canal. Parasympathetic nerves (from the pelvic splanchnic nerves, S2–S4) within the inferior hypogastric plexus are motor to the rectal muscle and inhibitory to the internal anal sphincter. The inferior part of the anal canal and the external sphincter are innervated by the inferior rectal nerve and perineal branches of S4 and are under voluntary control. Visceral afferent fibers detecting rectal distension travel with parasympathetic fibers, whereas visceral afferents detecting pain travel with both sympathetic and parasympathetic visceral afferent fibers. KIDNEY The kidneys lie obliquely on the posterior abdominal wall and a suprarenal (adrenal) gland is located on the superior pole of each kidney. Each kidney is approximately 10 cm long, 5 cm wide, and 3 cm thick and is described as having a superior and inferior pole, an anterior and

30

Pattern and Hughes

posterior surface, a concave medial border and convex lateral border. The hilum, where vessels, nerves, and lymphatics enter and leave the kidney is found at the level of the transpyloric plane (which crosses the tips of 9th costal cartilages and at the body of L1). The left kidney is located between the inferior border of the 11th rib and the L3/4 intervertebral disc. The right kidney is slightly lower between the 12th rib and the body of the 4th lumbar vertebra (approximately one finger breadth superior to the iliac crest). Each kidney is surrounded by a tough fibrous capsule, which in turn is surrounded by perinephric fat (which assists in anchoring the kidneys in position). A sheath of tough perinephric fascia lies outside the perinephric fat and the suprarenal glands. This fascia is continuous with the fascia of the posterior abdominal wall and limits enlargement of the kidneys, often causing referred pain around the umbilicus (T10–T12). The kidneys are retroperitoneal structures with peritoneum covering the anterior surface of each kidney adjacent to a layer of pararenal fat (which lies outside the perinephric fascia). The diaphragm lies posterior to the superior poles of the kidneys whereas the remainder of the kidneys are related posteriorly to the musculature and associated nerves of the posterior abdominal wall. From medial to lateral these muscles are: quadratus lumborum, psoas major, and transversus abdominis. On each side, the subcostal nerve (ventral ramus of T12) and the ventral ramus of L1 are located between the abdominal wall musculature and the posterior surface of the kidney. Anteriorly, the kidneys are related to gastro-intestinal system. Blood Supply Each kidney is supplied by a single renal artery arising from the abdominal aorta (at the level of L1/2) and entering the hilum anterior to the ureter and posterior to the renal vein. Venous blood drains to the renal veins and thence to the inferior vena cava (IVC). Accessory renal arteries and veins are relatively common (25% of individuals) and normally enter or leave the kidneys at the poles. Lymphatics Lymphatic drainage is to the lateral aortic nodes around the origin of the renal arteries on the abdominal aorta. Innervation The kidneys receive a rich innervation of autonomic nerves from the celiac plexus, the least splanchnic nerve, and the first lumbar splanchnic nerve. Together, these fibers mediate vasomotor effects and unite to form a renal plexus, which is distributed to the kidney parenchyma along the branches of the renal arteries. URETERS The ureters are retroperitoneal muscular tubes about 25 cm in length. Urine passes down the ureters by peristaltic contractions of the ureteric smooth muscle. A single ureter leaves the hilum of each kidney passing inferiorly over the anterior surface of the psoas major muscle before crossing the bifurcation of the common iliac artery. Each ureter continues inferiorly down the lateral pelvic wall, anterior to the internal iliac artery, and towards the ischial spine; at this point, it turns anteriorly to enter obliquely into the posterior surface of the urinary bladder. In males, the ureter is crossed superiorly by the ductus deferens before entering the bladder. The superior part of the seminal vesicle lies posterior and inferior to the distal part of the ureter. In addition, the rectovesical pouch lies posterior to the termination of the ureters as they enter the bladder. In females, the ureter crosses the true pelvis anterior to the internal iliac artery and on reaching the ischial spine, the ureter lies beneath the broad ligament; at this point, it turns anteriomedially and is crossed superiorly by the uterine artery. The ureter then continues anteriorly towards the lateral fornix of the vagina before obliquely entering the posterior surface of the bladder (Fig. 5).

31

Anatomy of the Urogenital Pain Systems Male

Female

Ureter Ureter

Common iliac artery

Internal iliac artery

Uterine artery

Vas deferens

Uterus Pelvic brim (pelvic inlet)

Anterior abdominal wall

FIGURE 5 Structures that cross the ureters in the male (left ) and female (right ) pelvic cavity. Source: Modified from Ref. 1.

The ureters are physically narrowed where they leave the renal pelvis and where they enter the bladder; they are often narrowed where they cross the common iliac arteries. Blood Supply Three arteries supply each ureter, although the pattern of distribution is varied amongst individuals. The superior part is usually supplied by the renal artery; the middle part from either the gonadal artery, the abdominal aorta or common iliac artery, and the inferior part is usually supplied by a branch from the inferior vesical artery. Small blood vessels branch off from these vessels to form a longitudinal anastomosis of vessels along the length of the ureter. Veins from the superior part of the ureters drain into the renal or gonadal veins and from the inferior part of the ureters to the inferior vesical vein and into the internal iliac veins. Lymphatics The lymphatic drainage of the superior portion of the ureters is to the para-aortic and common iliac nodes, the inferior portion is to the common, internal, and external iliac nodes. Innervation The ureters receive sympathetic innervation mainly from T11 and L1 via the renal, testicular/ ovarian or hypogastric plexuses. Parasympathetic fibers arise from S2 to S4. Most nerves to the ureters are sensory, detecting stretch in the ureter walls. Afferent fibers travel with the sympathetic nerves entering the spinal cord at L1 and L2. Therefore, pain arising from renal colic may be referred to the loin and inferiomedially towards the labia majora/scrotum and possibly to the anterior region of the thigh due to its innervation by the femoral branch of the genitofemoral nerve (L1–L2). URETHRA The urethra passes from the internal urethral orifice of the bladder to the external urethral orifice.

32

Pattern and Hughes

In females, the urethra is shorter (4 cm) and more distensible than in males. It opens to the exterior within the vestibule of the vulva anterior to the vaginal orifice. Lying anterior to the vagina, it passes through the pelvic floor musculature and into the urogenital diaphragm where it is surrounded by circular fibers of the sphincter urethrae. Urethral and paraurethral glands open into the urethra just superior to the urethral orifice. The blood supply to the urethra is via the vesical and vaginal arteries with a corresponding venous drainage system. The lymphatic drainage is mainly to the external and internal iliac nodes, although some vessels may drain to the sacral and inguinal nodes. In males, the urethra (18–22 cm) is described in four parts (Fig. 6): 1. Preprostatic (0.5–1.5 cm), from the internal urethral orifice to the superior part of the prostate gland. The musculature of the internal urethral orifice is organized into an internal urethral sphincter in males, but this is not thought to be the case in females. 2. Prostatic (3–4 cm), where the urinary and reproductive tracts merge. It runs through the prostate gland and bears a median ridge (urethral crest), where the ejaculatory ducts open. Within the middle of the crest is an orifice opening into a small blind-ended cavity, the prostatic utricle (an embryonic remnant of the uterovaginal canal). On the either side of the urethral crest is a groove (prostatic sinus) into which the prostatic ducts open. 3. Membranous (1–1.5 cm) is short and narrow traveling within the deep perineal space and passing through the urogenital diaphragm. It is surrounded by circular fibers of the sphincter urethrae. 4. Spongy (or penile) urethra (w15 cm) is the longest and most mobile part of the urethra extending the length of the corpus spongiosum of the penis to open onto the external urethral orifice at the tip of the glans penis. The bulbourethral glands open into the proximal part of the spongy urethra and numerous mucous-secreting glands (of Littre´) open along the length of the spongy urethra. The blood supply to the preprostatic and prostatic urethra is via the prostatic branches of the inferior vesical and middle rectal arteries with venous drainage into the prostatic venous plexus. The membranous and penile urethra is supplied by the urethral artery (a branch of the internal pudendal artery) and the dorsal artery of the penis with drainage into the corresponding veins. The lymphatic drainage from the preprostatic, prostatic, and membranous urethra is mainly to the internal iliac nodes, lymph from the penile urethra drains predominantly to the deep inguinal nodes. Some lymphatic vessels along the length of the urethra may drain to the external iliac nodes. Innervation In the male, the prostate gland, the preprostatic, prostatic, and membranous urethra are innervated by the autonomic prostatic plexus arising from the inferior hypogastric plexus. Sympathetic efferents within this plexus originate in the lumbar splanchnic nerves and parasympathetic efferents originate in the pelvic splanchnic nerves. The dorsal nerve of the penis, a branch of the pudendal nerve, provides somatic innervation to the penile urethra. A similar arrangement exists in the female with the vesical plexus and the pudendal nerve innervating the urethra. Visceral afferents along the length of the urethra run retrogradely with pelvic splanchnic nerves to cell bodies in the spinal ganglia of S2 to S4, somatic afferent fibers also terminate here. PENIS The penis is the male organ of copulation, with the penile urethra serving as a common tract for the passage of urine and semen (Figs. 5 and 6). The penis is described as having a “root” and a “body.” The root is comprised of three cylindrical masses of tissue, a left and right crus, each lying medial to the corresponding ischiopubic ramus, and between the two crura lie the bulb of the penis, which is attached to the perineal membrane. The body of the penis also comprises three cylindrical masses of erectile tissue, the left and right corpus cavernosa (a continuation of each crus) and a median corpus spongiosum (a continuation of the bulb of the penis), which is

Tunica vaginalis

Scrotum

Body of epididymis Testis Tail of epididymis

Head of epididymis

Membranous urethra

Bulbourethral gland in deep perineal pouch

Prostatic urethra

Ejaculatory ducts

Ampulla of vas deferens Seminal vesicle

Urethra

Visceral layer

Cavity

Parietal layer

Capsule (tunica albuginea)

Tunica vaginalis

Seminiferous tubule

Straight tubule

Ligamentus remnant of processus vaginalis

Corpus spongiosum

Corpus cavernosum

Deep dorsal vein

Dorsal penile artery

Vas deferens

Urethral artery

Tail of epididymis

Body of epididymis

Rete testis

Efferent ductules

Head of epididymis

Cavernosal artery

Tunica albuginea

Circumflex vein

Buck's fascia

Dartos fascia

Dorsal nerve of the penis

Superficial dorsal vein

FIGURE 6 Anatomical relations of the male pelvic viscera are shown with the penis in sagittal section to illustrate the component parts of the urethra (left). A crosssection of the penis (top right) is also shown to illustrate the arrangement of penile vasculature and fascia. A cross-section through the testis (bottom right). Source: Modified from Ref. 1.

Penile urethra within the corpus spongiosum

Corpus cavernosus

Vas deferens Musculofascial pouch

Prostate

Spermatic cord

Superficial inguinal ring

Vas deferens

Inguinal canal

Deep inguinal ring

Inferior epigastric artery

External iliac artery

Ureter

Anatomy of the Urogenital Pain Systems

33

34

Pattern and Hughes

expanded at its distal end to form the glans penis. Each mass of erectile tissue is covered individually with a layer of fascia (tunica albuginea) and external to this is the deep fascia of the penis (Buck’s fascia), which binds the three erectile masses together. A pair of ischiocavernosus muscles overlie each crus of the penis and corpora cavernosa and a single bulbospongiosus muscle overlies the bulb and the corpus spongiosum of the penis. These muscles help to maintain erection by restricting venous return from the erectile elements of the penis. In addition, bulbospongiosus helps to support the perineal body and pelvic floor and to expel the last drops of urine or semen from the penile urethra. Blood Supply The arteries of the penis are branches of the internal pudendal arteries (Fig. 6), they are: 1. Deep arteries that provide the main blood supply of the penis. A deep artery pierces each crura and runs deeply within each corpus cavernosum giving off many coiled arteries (helicine arteries), which empty into the corpora cavernosa and are involved in erection. 2. Dorsal arteries supply the penile urethra, the fascial coverings of the cavernous erectile tissue and the penile skin. Both dorsal arteries run in the dorsal groove between the corpus cavernosa, on either side of a single superficial dorsal vein of the penis. 3. Arteries of the bulb of the penis which supply the bulb of the penis, corpus spongiosum, the urethra and the bulbourethral gland within it. The venous plexus draining the cavernous spaces of the glans penis and corpus cavernosa empties into the deep dorsal vein of the penis and then into the prostatic venous plexus. The superficial coverings of the penis drain into the superficial dorsal vein of the penis and into the superficial external pudendal vein and the internal pudendal vein. Lymphatics Lymphatic drainage from the glans and distal urethra is to the deep inguinal and external iliac nodes, the proximal urethral and corpus cavernosa to the internal iliac nodes and from the skin of the penis to the superficial inguinal lymph nodes. Innervation Autonomic efferents and afferents travel to and from the penis with the dorsal nerve, a terminal branch of the pudendal nerve. Pelvic splanchnic nerves (S2–S4) supply vasomotor parasympathetic efferent nerves to the helicine arteries of the cavernous tissue which vasodilate during erection. Sympathetic stimulation to the smooth muscle within the prostate gland and seminal vesicles enables these glands to empty their secretions into the urethra during ejaculation. The skin over the penis has a rich sensory innervation from the dorsal nerve of the penis, especially the glans penis. The skin at the root of the penis is innervated by the ilioinguinal nerve (L1). TESTICLES AND SCROTUM The testes are the paired male gonads, which produce spermatozoa and androgens. Scrotum The scrotum is a sac of skin divided into two compartments by a septum. The superficial fascia of the scrotum contains smooth muscle fibers of the dartos muscle, which are supplied by sympathetic nerves. Blood Supply The blood supply of the scrotum is derived from: the posterior scrotal arteries (perineal branches of the internal pudendal artery), the anterior scrotal branches of the deep external

Anatomy of the Urogenital Pain Systems

35

pudendal artery (a branch of the femoral artery) and the cremasteric arteries (branches of the inferior epigastric artery). The venous drainage corresponds to the scrotal arteries, the anterior scrotal veins drain into the internal iliac vein, the posterior scrotal and cremasteric veins drain into the external iliac veins. Lymphatics The lymphatic drainage of the scrotum is to the superficial inguinal nodes. Innervation The scrotum is innervated from the lumbar and sacral plexuses. The anterior and anterolateral surfaces are supplied by the ilioinguinal and genital branches of the genitofemoral nerves respectively. The posterior surface is supplied by the perineal branches of the pudendal nerve and inferior surface by the posterior femoral cutaneous nerve (Fig. 7). Testis Embryologically, the testes and associated neurovascular structures develop on the posterior abdominal wall and, during development, descend, passing obliquely through the muscle layers of the anterior abdominal wall along the inguinal canal. They complete their descent into the scrotum a few weeks before birth. During development, a pouch of peritoneum (the processus vaginalis) extends into the scrotum and is followed by the testis, thus establishing a continuity of the peritoneal cavity within the scrotum. This continuity is normally lost around the time of birth when the tunica vaginalis forms a double layer of serous membrane around the testis and epididymis. The tunica vaginalis is arranged as though the testis and epididymis have been invaginated into it from behind. Superficial to the tunica vaginalis, the testis and epididymis are covered by three fascial layers, which are continuations of the fascial layer surrounding the spermatic cord. These layers were acquired as the testes descended through the abdominal wall into the scrotum. The outer layer is the external spermatic fascia (from the external oblique aponeurosis), the middle layer is the cremaster muscle and fascia (from the internal oblique and transversus abdominis) and the inner layer is the internal spermatic fascia (from the transversalis fascia). The cremaster muscle is innervated by the genital branch of the genitofemoral nerve. Each testis is ovoid in shape containing numerous coiled seminiferous tubules, which drain, via a series of tubules, into the single duct of the epididymis at its head (Fig. 6). The epididymis lies on the dorsolateral surface of each testis and has an expanded “head” connected to the superior part of the testis. The duct of the epididymis is tightly coiled, but continues as the uncoiled ductus deferens at the inferior pole of the testis before ascending on the medial side of the epididymis. On leaving the testis, the ductus deferens travels within the coverings of the spermatic cord (and therefore through the inguinal canal) on its way to the urethra. Blood Supply The testis receives a testicular (gonadal) artery (at the vertebral level of L1–L2) a direct branch of the aorta. The testicular veins form a convoluted pampiniform plexus, this is replaced by three or four veins which unite into a single testicular (gonadal) vein within the inguinal canal. The gonadal vein on the right drains directly into the IVC, whereas on the left it enters the left renal vein. Lymphatics The lymphatic drainage follows the arteries towards the para-aortic lymph nodes. Innervation A plexus of nerves accompanies the testicular artery containing; sympathetic nerves from the prevertebral plexuses (arising from T10–T11), vagal parasympathetic nerves and visceral afferent fibers that enter the spinal cord via the dorsal roots of the 10th thoracic nerves.

36

Pattern and Hughes Corpora cavernosa Body of penis (cross-section)

Corpus spongiosum containing urethra

Corpus cavernosus Glans penis

Ischiocavernosus muscle External urethral orifice Navicular fossa of urethra Bulbospongiosus muscle

Crus of penis (attached part of corpus cavernosus) Bulbourethral gland within deep pouch

Superficial transverse perineal muscle

Perineal body

Skin

Corpora cavernosa

Body of clitoris (cross-section) Glans clitoris Crus of clitoris (attached part of corpus cavernosus)

Ischiocavernosus muscle

Corpus cavernosus

Bulbospongiosus muscle

Superficial transverse perineal muscle

Bulb of vestibule

Perineal body

Greater vestibular gland in superficial pouch

FIGURE 7 Erectile components of the male (top) and female (bottom). External genitalia attached to the perineal membrane are shown on the right side of the diagrams. The left sides of the diagrams show the location of the overlying perineal muscles, which are located in the superficial perineal pouch.

VULVA AND CLITORIS The vulva or external genitalia of the female comprises the mons pubis, labia majora, labia minora, bulbs of the vestibule, the greater and lesser vestibular glands, the paraurethral glands, and the clitoris. The vulva constitutes the sensory and erectile tissue for sexual arousal; it helps to direct the stream of urine from the urethra and guards the openings of the urogenital tract. The mons pubis is the fatty eminence lying anterior to the pubic bone. Inferior to this are the labia majora, fatty folds of skin surrounding the pudendal cleft. The skin of the labia majora is pigmented and hairy externally; the inner folds (facing the pudendal cleft) are pink and

Anatomy of the Urogenital Pain Systems

37

hairless. Within the pudendal cleft are the labia minora, hairless folds of thin skin surrounding the vestibule where the vaginal and urethral orifices open. The vestibular glands secrete mucous into the vestibule to lubricate the labia and the vestibule. The greater vestibular glands lie within the superficial perineal pouch, inferior to the perineal membrane and on either side of the vestibule. The ducts from these glands open into the vaginal orifice. The lesser vestibular glands are small and also lie on either side of the vestibule and open between the urethral and vaginal orifices. The ducts of the paraurethral glands open on either side of the urethral orifice. The bulbs of the vestibule are paired masses of erectile tissue (homologous to the corpus spongiosum in the male) lying on either side of the vaginal orifice; posterior to each vestibular bulb is a greater vestibular gland. The clitoris is the female organ of sexual arousal. It is formed from two crura and corpora cavernosa, which are attached to the perineal membrane and lie medial to each ischiopubic ramus. The crura unite in the midline anteriorly to form the body and the glans of the clitoris. As in the male, the glans is richly innervated and is covered with a prepuce. A pair of ischiocavernosus muscles overlies each crus of the clitoris and corpora cavernosa, just as in the male. The bulbospongiosus muscles are not fused (as in the male), instead they surround the opening of the vestibule and overlie the bulbs of the vestibule and the greater vestibular glands. These muscles help to maintain erection of the clitoris by minimizing venous return. In addition, bulbospongiosus helps to support the perineal body and pelvic floor. Blood Supply The vulva has a rich blood supply from the external pudendal arteries (supplying the mons pubis and labia majora) and branches of the internal pudendal arteries including the labial arteries and the artery of the clitoris (supplying most of the skin of the vulva and the perineal muscles and clitoris). The venous drainage is predominantly to the internal and external pudendal veins. Lymphatics Lymphatic drainage is mostly to the superficial inguinal lymph nodes. Lymph from the glans of the clitoris, anterior labia majora and minora may drain to the deep inguinal or internal iliac nodes. Innervation The vulva receives both autonomic and somatic innervation. The skin over the mons pubis and anterior labia is innervated by the anterior labial nerves (branches of the ilioinguinal and the genital branch of the genitofemoral nerve). The posteriomedial vulva is innervated by labial branches from the pudendal nerve and the posterolateral area by the posterior cutaneous nerve of the thigh. The clitoris is supplied by the dorsal nerve of the clitoris, a terminal branch of the pudendal nerve. Erection of the clitoris and the bulb of the vestibule is under parasympathetic control via fibers from the uterovaginal plexus of pelvic splanchnic nerves. Control of secretions from the greater vestibular glands is mediated by the pelvic plexuses. THE PELVIS Pelvic Osteology There are structural differences between the anatomy of the male and female pelvis, which relate to the function of the female pelvis in childbirth. Some women have a bony pelvis showing features more characteristic of the male pelvis; this masculinized pelvic structure may be enough to impede the passage of a baby in childbirth. The Coxal Bones Each of the coxal bones of a newborn consists of three irregularly shaped elements which are united by a triradiate-shaped cartilage, they are the ilium, ischium, and the pubis (Fig. 8).

38

Pattern and Hughes

First sacral spine Promontory of sacrum Sacral canal

Sacrotuberous ligament

Sacroiliac joint

Lateral mass of sacrum Ischial spine

Sacrospinous ligament Superior ramus of pubis

Iliopectineal line Acetabulum Obturator foramen

Body of pubis

Pubic crest Pubic tubercle

Ramus of ischium

FIGURE 8 Anterior view of the male pelvic with associated ligaments.

This triradiate-shaped cartilage is found within a cup-shaped cavity on the lateral surface of the coxal bone (the acetabulum) and it begins to ossify during puberty. The acetabulum articulates with the head of the femur. The Sacrum The sacrum is a wedge-shaped bone formed from the fusion of five sacral vertebrae. Anteriorly, the border of the S1 vertebrae is thickened to form the sacral promontory and four anterior sacral foramina are visible on each side allowing the passage of the ventral rami of S1 to S4. Posteriorly, the sacral canal terminates at the sacral hiatus and this is bounded on either side inferiorly by the sacral cornu. The Coccyx The coccyx is formed from the fusion of between three and five rudimentary vertebrae. It articulates with the sacrum at the sacrococcygeal joint. This joint differs in individuals and may be cartilaginous, synovial, an intermediate form or ossified. The Sacroiliac Joints Body weight is transmitted from the lumbar spine to the wedge-shaped sacrum, this does not separate the two hip bones apart because the sacrum is held firmly in place by ligaments at the synovial sacroiliac joint. The adjacent bones fit closely together minimizing movement and there are strong anterior and posterior sacroiliac ligaments and interosseous ligaments stabilizing the joint. With advancing age, the joint cavity is partly obliterated by fibrous bands that further restrict movement. Towards the end of pregnancy, however, under the influence of the hormone, relaxin, the structure of the ligaments change and slight movement may occur at the sacroiliac joints. Ligaments There are several other ligaments associated with the pelvis including the sacrotuberous and sacrospinous ligaments (Fig. 8), which attach from the sacrum to the ischial tuberosity, and from the sacrum to the ischial spine respectively, on each side of the pelvis. These ligaments

39

Anatomy of the Urogenital Pain Systems

help to stabilize the sacroiliac joint as they restrict downward and forward angulation of the upper end of the sacrum. They also define two important exits from the pelvis: The greater sciatic foramen—formed by the sacrospinous ligament and the greater sciatic notch. This provides an exit from the pelvis into the gluteal region. & The lesser sciatic foramen—formed by the sacrotuberous ligament and the lesser sciatic notch enables structures that have left the pelvis through this foramen to enter the perineum.

&

The Pelvic Floor The pelvic floor or diaphragm is formed mainly by a sheet of skeletal muscle (Fig. 9), it supports and maintains the position of pelvic viscera, counteracts increases in intra-abdominal pressure, has an important role in anal continence and defecation, and in women the direction of its slope is a factor in the mechanism of childbirth. The diaphragm is formed by right and left levator ani and coccygeus muscles, which form a gutter-shaped floor, which is lower at the anterior end. An anterior or urogenital hiatus (allows passage of the urethra and in females the vagina) and a posterior or anal hiatus (for passage of the anal canal) are found in the midline. The musculature between the urogenital and anal hiatus is thick and fibrous and known as the perineal body, several perineal muscles are anchored to it. A similar structure, the anococcygeal body, arises between the anal canal and the coccyx.

Superior gluteal nerve

Lumbosacral trunk Nerve to piriformis muscle

Pelvic splanchnic nerves (parasympathetics from S2 to S4)

Perforating cutaneous nerve Posterior femoral cutaneous nerve Inferior gluteal nerve Coccygeal plexus

Sciatic nerve Obturator nerve (from lumbar plexus)

Coccygeus muscle

Nerve to obturator internus and superior gemellus

Anococcygeal nerves

Nerve to quadratus femoris and inferior gemellus

Iliococcygeus muscle

Pudendal nerve

Puborectalis

Nerves to coccygeus, levator ani and external anal sphincter

Pubococcygeus muscle Levator prostate / pubovaginalis

FIGURE 9 (See color insert. ) Musculature of the pelvic floor and its relation to nerves of the sacral and lumbar plexuses.

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Pattern and Hughes

1. Each levator ani muscle is divided into two parts, pubococcygeus and iliococcygeus, according to their attachments. Pubococcygeus arises from the pubis and anterior part of the arcus tendineus (a linear thickening of the fascia of obturator internus) and slopes backwards towards the coccyx. Functionally, it consists of two parts: a. The most anterior fibers attach to the fascial sheath of the prostate and the urethra in the male (levator prostate); or to the vaginal wall in the female (pubovaginalis). b. The more posterior bundle is the puborectalis, with its bilateral origins forming a loop behind the anorectal junction (puborectal sling). This maintains a sharp angulation at the anorectal junction, which is important in maintaining fecal continence. 2. Iliococcygeus arises from the posterior part of the arcus tendineus and the ischial spine. Its fibers insert into the coccyx and meet those from the opposite side to form the anococcygeal raphe or ligament from which the pubococcygeus gains attachment. 3. Coccygeus (or ischiococcygeus) forms the remainder of the pelvic diaphragm posteriorly, attaching to the ischial spine and fanning out medially to attach to the coccyx and lower part of the sacrum. It is applied against the ventral surface of the sacrospinous ligament and its role is to assist the levator ani in supporting the pelvic viscera: it may also flex the coccyx. Levator ani is innervated by the nerve to levator ani (branches of S4) and the inferior rectal nerve, and the coccygeus by branches of S4 and S5 from the coccygeal plexus. Pelvic Innervation Somatic Nerves The somatic innervation of the pelvis is largely from the sacral and coccygeal plexuses with the obturator nerve (lumbar plexus) contributing to pelvic wall innervation (Figs. 9 and 10). Obturator Nerve (Anterior Rami L2–L4)

The obturator nerve courses along the lateral pelvic wall with the obturator vessels and passes through the obturator canal to the medial compartment of the thigh. It is closely related to parts of the bony pelvis and the ovary and may be involved in pelvic fractures or ovarian pathology. Sacral Plexus (Anterior Rami L4–S4)

As mentioned above and described below, the two main nerves arising from the sacral plexus are the sciatic (L4–S3) and pudendal (S2–S4) nerves. The pudendal nerve supplies skin and muscles of the perineum. The pudendal nerve travels with the internal pudendal artery and vein, and leaves the pelvis through the greater sciatic foramen between the piriformis and coccygeus muscles. It then hooks around the ischial spine and sacrospinous ligament prior to entering the perineum via the lesser sciatic foramen (without penetrating the muscle of the pelvic diaphragm). Each pudendal nerve then runs anteriorly in the “pudendal canal” (Alcock’s canal), which lies on the lateral wall of the ischioanal fossa. Coccygeal Plexus (S4–S5)

The coccygeal plexus, overlies the coccygeus muscle of the pelvic floor, is comprised of small nerves from S4 and S5 and the coccygeal nerves. It supplies: coccygeus, part of levator ani and the sacrococcygeal joint and a small region of skin between the coccyx and the anus. Autonomic Nerves The pelvic viscera are innervated via sympathetic nerves from the lumbar splanchnic nerves and parasympathetic nerves from the pelvic splanchnic nerves (Fig.11). These autonomic nerves play an essential role in the control of micturition, defecation, and sexual intercourse. Autonomic nerves enter the pelvic cavity in four ways: 1. Sacral sympathetic trunks: predominantly postganglionic fibers to the sacral plexus (vasomotor, pilomotor, and sudomotor) for innervation of the lower limbs. They meet in the midline ganglion impar on the coccyx.

Anatomy of the Urogenital Pain Systems

L3

41

L1

S2 S3

L2

S4

S5

L3 S3

S2 L2 S3

S3 S4 S4 S5

Iliohypogastric (L1), ilioinguinal (L1) and femoral branch of genitofemoral nerve (L12) Pudendal nerve (S234) Perineal branches of the posterior cutaneous nerve of the thigh (S123)

FIGURE 10 Innervation of the female (top) and male (bottom) perineum. The distribution of dermatomes is shown on the left side of each diagram, and the distribution of cutaneous nerves of the perineum is shown of the right side of each diagram (refer to key).

2. Periarterial plexuses of superior rectal, ovarian, and internal iliac arteries: these are postsynaptic sympathetic vasomotor fibers to the arteries and their branches. 3. Superior and inferior hypogastric plexuses: the major sympathetic supply to the pelvic viscera. The superior hypogastric plexus arises inferior to the bifurcation of the aorta as a continuation of the aortic plexus receiving contributions from lumbar splanchnic nerves (L3–L4). It divides into left and right hypogastric nerves which descend on the anterior surface of the sacrum. The left and right hypogastric nerves are joined by the pelvic splanchnic nerves (parasympathetic; see below) to form the left and right inferior hypogastric plexuses which is therefore a mixed plexus of both sympathetic and parasympathetic fibers and visceral afferents and they form sub-plexuses around the pelvic viscera. 4. Pelvic splanchnic nerves: provide a pathway for parasympathetic nerves (efferent fibers from anterior rami S2–S4 and visceral afferent fibers from the spinal ganglia of the corresponding spinal nerve) to reach pelvic viscera, descending colon and sigmoid colon.

42

Pattern and Hughes Upper lumbar sympathetic trunk

Spinal ganglia or dorsal root ganglia (DRG) T12 L1 L2

L3 Lumbar splanchnic nerves

Prevertebal ganglia

L4 L5 (DRG)

S1

Pelvic splanchnic nerves

S2

Pelvic plexus

S3 S4 S5 Sacral plexus

Para-aortic plexus Superior hypogastric plexus

Uterine plexus

Key (B) Visceral afferents running with parasympathetic fibers Presynaptic Parasympathetic Postsynaptic Presynaptic Sympathetic Postsynaptic Visceral afferents running with sympathetic fibers Somatic motor Somatic afferrent

} }

Pudendal nerve

Inferior hypogastric plexuses

Ovarian plexus

Pelvic plexus Uterovaginal plexus

Pelvic intraperitoneal viscera Peritoneum (lower limit)

Pelvic plexus Pudendal nerve

Pelvic subperitoneal viscera

Perineum

FIGURE 11

Schematic diagram of pelvic innervation.

In the pelvis, sympathetic innervation produces vasomotor effects but inhibits peristaltic contraction of the rectum and stimulates contraction of the internal genital organs during orgasm, producing ejaculation in the male. Parasympathetic innervation causes contraction of the rectum and bladder for defecation, and micturition and erection of the clitoris and penis. Visceral Afferent Fibers Pelvic visceral afferent fibers conducting reflective sensation (information that does not normally reach consciousness) travel with parasympathetic fibers to the spinal ganglia (S2–S4). Nociceptive afferents from viscera that are located below the pelvic peritoneum (e.g., prostate, seminal vesicles, vagina, distal sigmoid colon and rectum, cervix, and vagina, etc.) follow the parasympathetic fibers to the spinal ganglia (S2–S4).

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Nociceptive visceral afferent fibers from viscera located above the inferior limit of the pelvic peritoneum (e.g., bladder, ovaries, uterus, and uterine tubes), travel retrogradely with sympathetic fibers to the inferior thoracic and superior lumbar spinal ganglia. Pelvic Vasculature Arteries The primary arterial supply to the pelvis, perineum and their contents is from the internal iliac arteries (Fig. 3, Table 1). Internal Iliac Artery

The internal iliac artery supplies blood to the pelvic wall, viscera, the perineum and its contents including external genitalia, the gluteal region and hip joint, the upper medial compartment of the thigh, and the iliac fossa. The internal iliac artery is 3 to 4 cm long and divides initially into a large anterior division and a smaller posterior division from which the various branches arise. This branching pattern is variable. In addition, the following arteries provide a significant contribution to the blood supply of the region: 1. Inferior mesenteric artery through its sigmoid and superior branches to the sigmoid colon and rectum respectively. 2. The ovarian/testicular arteries, branches of the abdominal aorta, supply the gonads. They pass inferiorly in front of psoas major to enter the pelvis. The testicular artery passes through the deep inguinal ring as part of the spermatic cord. The ovarian arteries enter the broad ligament laterally and supply the ovaries and the uterine tubes, finally anastomosing with the uterine arteries. 3. The median sacral artery enters the pelvis on the anterior surface of the sacrum and is destined to the pelvic wall. Veins All the branches of the internal iliac artery are accompanied by veins, which drain to an internal iliac vein. The outer walls of internal pelvic organs are surrounded by plexuses of anastomosing veins (e.g., prostatic, vesical, uterovaginal, and rectal) which give rise to the named tributaries of the internal iliac vein. Some exceptions of note are that the right ovarian/testicular vein goes to the IVC, and the left ovarian/testicular vein goes to the left renal vein. The superior rectal vein drains into the inferior mesenteric vein. The small veins in the pelvis have few valves controlling the direction of flow of the blood and the venous plexuses around the rectum constitute one of the main anastomoses between the systemic and hepatic portal venous systems. This arrangement means there is potential for infections and malignancy (e.g., prostate) to spread widely from the pelvis. REFERENCE 1. Richard Drake, Gray’s Anatomy for Students. London: Churchill Livingstone, 2005.

4

Physiology of the Urogenital System Vinay Kalsi, Sohier Elneil, and Clare J. Fowler

Department of Uro-Neurology, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, U.K.

INTRODUCTION The fused somatic and autonomic innervation of the pelvic organs reflects the human need to integrate urogenital functions into our social existence. Proper bladder control is essential for everyday life and sexual behavior is an activity upon which intimate relationships depend, as does the continuation of the species. Thus it is that the physiological functioning of the bladder and sexual organs requires intact innervation that extends from the frontal lobes of the cortex to the distant pelvic plexi. The classic illustrations by F. Netter (Figs. 1 and 2) highlight the complexity of the integration of the sympathetic, parasympathetic, and somatic innervation of the female and male urogenital tract, respectively. The sympathetic innervation arises from the thoracolumbar outflow, whereas the parasympathetic originates from the sacral segments of the spinal cord, as does the somatic innervation. What is not shown in these figures is the parasympathetic innervation that is now thought to reach the pelvis via the vagus nerve, taking an extra spinal course so that its preserved function becomes apparent following high thoracic cord lesions. Afferent nerves travel retrogradely with all three innervating systems. Integration of inputs from the various levels of central and peripheral innervation occurs in plexi, from which nerves arise to innervate pelvic organs. The sacral (predominantly somatic) and the pelvic (predominantly parasympathetic) plexus are intimately linked, with sympathetic connections from the superior and inferior hypogastric plexus. The sacral plexus innervates the perineum, uterus in the female (Fig. 1) and the penis in the male (Fig. 2) through the pudendal nerve. The parasympathetic fibers arise from S2 to S4, to synapse with the ganglia in the pelvic plexus, which is located in the adventitia round the bladder base and in the bladder wall from which visceral innervation to the bladder and the internal genital organs arises. The superior hypogastric plexus (sympathetic), situated at the sacral promontory, is the origin of the left and right hypogastric nerves. PHYSIOLOGY OF THE BLADDER The urinary bladder is a reservoir whose functions are simply that of storage and emptying. These functions are however only accomplished by an extensive and complex innervation which coordinates the activity of the striated muscles of the pelvic floor and the various effector organs making up the lower urinary tract (LUT) (1). Bladder Filling The LUT consists of the urinary bladder and the outflow tract, which in turn is comprised of the bladder neck and the urethra (Fig. 3). The bladder, for the majority of time, is a low-pressure storage system, which accommodates urine entering from the ureters. The walls of the ureters contain smooth muscle arranged in spiral, longitudinal, and circular bundles. Peristaltic contractions of these muscular tubes drain urine from the renal pelvis into the bladder. The ureters pass obliquely through the bladder wall, and although there is no “ureteral” sphincter, the oblique passage forms a valve-like mechanism such that they remain closed

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Innervation of female reproductive organs: schema Sympathetic trunk and ganglion

T5 Celiac ganglia and plexus

T6

Gray ramus communicans

White ramus communicans

Aorticorenal ganglia

Greater splanchnic nerve Superior mesenteric ganglion

Lesser splanchnic nerve Least splanchnic nerve Sympathetic trunk

T11 T11 T12

Intermesenteric (aortic) plexus

L1

L1

Lumbar splanchnic nerves Inferior mesenteric ganglion

L3 spinal nerve L4

L4 Ovarian artery and plexus

Superior hypogastric plexus

Uterine (falloplan) tube

Uterus

Hypogastric nerves Inferior extent of peritoneum Uteruvaginal and inferior hypogastric (pelvic) plexuses

Cervix

Ovary S1

S1

Pelvic splanchnic nerves

S2 S2 S3 S4 S5

S3 S4 S5

Vagina

Sacral plexus

Pudendal nerve Sympathetic fibers

Presynaptic Postsynaptic

Parasympathetic fibers

Presynaptic Postsynaptic

Afferent fibers

FIGURE 1 (See color insert. ) Female pelvic neuroanatomy pain from intraperitoneal pelvic viscera (e.g., uterine contractions) goes via uterovaginal and pelvic plexuses, hypogastric nerves, superior hypogastric plexus, lower aortic plexus, lower lumber splanchnic nerves, and sympathetic trunk from L4 to L5 to spinal nerves T11, 12. Pain from subperitoneal pelvic viscera (e.g., cervical dilation and upper vaginal goes via pelvic splanchnic nerves to S2, 3, 4. Afferent fibers from lower vagina and perineum go via pudendel nerves to S2, 3, 4. Source: Courtesy of F. Netter.

except during peristaltic waves, thereby preventing reflux of urine into the ureters during a bladder contraction. Under normal circumstances, urine entering the bladder does not cause an increase in intravesical pressure. The smooth muscle of the bladder wall (the detrusor muscle) is composed of an interlacing network of fibers running in various directions and as with other types of smooth muscle exhibits plasticity when stretched. The relationship between detrusor pressure and bladder filling can be studied by performing subtracted cystometry, where the pressure

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Physiology of the Urogenital System

Innervation of male reproductive organs: schema Celiac ganglia

Sympathetic trunk and ganglia Greater splanchnic nerve (T5-9) Gray ramus communicans White ramus communicans Lesser splanchnic nerve

T10

Superior mesenteric ganglion

T11 Left aorticorenal ganglion

T12

Least splanchnic nerve

Renal ganglion

L1

Upper lumbar splanchnic nerves

Intermesenteric (aortic) plexus

L2

Inferior mesenteric ganglion

L3 Gray ramus communicans

Testicular artery and plexus

L4

Superior hypogastric plexus

Testicular artery and plexus

Hypogastric nerves

Ductus deferens and plexus Inferior extent of peritoneum Pelvic splanchnic nerves

S2

Pelvic splanchnic nerves

S2

Sacral plexus

S3 S4

Sacral plexus

Ductus deferens and plexus

S1

S1

S3 S4

S5

S5 Pudendal nerve

Pudendal nerve Inferior hypogastric (pelvic) plexus

Dorsal nerves of penis

Vesical plexus

Epididymis

Prostatic plexus

Testis

(Greater and lesser) cavernous nerves of penis Sympathetic fibers

Presynaptic Postsynaptic

Parasympathetic fibers

Presynaptic Postsynaptic

Afferent fibers

FIGURE 2 (See color insert. ) Male pelvic neuroanatomy. Source: Courtesy of F. Netter.

difference between two fluid filled catheters inserted into the bladder and the rectum is determined. A plot of these values against the volume of fluid infused is seen in Figure 4. In health, the detrusor pressure remains almost flat as fluid fills the bladder that can normally accommodate around 500 mL. Detrusor muscle fibers condense in the region of the bladder neck, forming a complete circular collar in the male. In the female, these fibers extend obliquely or longitudinally into the urethral wall do not have the circular orientation. The bladder neck therefore forms a proximal sphincter which is more evident in the male than the female, and thought to be of importance in preventing retrograde ejaculation. Striated muscle comprise the external urethral sphincter, which forms a U-shape around the urethra with some fibers completely encircling it anteriorly, so, that as the muscle contracts, the urethra becomes occluded. During the storage

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Dome of bladder

Ureter

Ureteric orifice Detrusor muscle

Trigone

Bladder neck

Pelvic floor External urethral sphincter

Urethral smooth muscle

FIGURE 3 Effector organs making up the lower urinary tract (LUT). This is a representation of the female LUT; in male the prostate gland will be situated around the external urethral sphincter.

509

Vinfus 100 (ml) 0 20 Pves (cmH2O) 0 20 Pdet (cmH2O) 0 20 Pabd (cmH2O) 0

40s

5 0

0.0 c

FD

ccc cc

ND

FIGURE 4 Subtraction cystometry showing typical bladder function. The detrusor pressure remains less than 10 cmH2O until the first desire to void (FD) is reached, which is accompanied by a small rise in the pressure tracing. There is a concomitant rise in vesical pressure; however, there is no rise in intraabdominal pressure. The pressure rise is due to contraction of the detrusor; however, it is small due to the compliant properties of the bladder. The normal desire to void (ND) is soon accompanied by cystometric capacity (c.500 mL), at which time a void will be initiated. The undulations seen on the traces are a result of interference due to respiration. Note: Pabd, intraabdominal pressure measured with a rectal catheter; Pves, measured intravesical pressure; Pdet, detrusor pressure; PdetZPvesKPabd; Vinfus, infusion volume, 50 mL/min.

Physiology of the Urogenital System

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phase, continence is maintained by the high resistance offered by the bladder neck and urethra, together with the integrity of the external urethral sphincter. Tonic firing of pudendal motor units of the external urethral sphincter and pelvic floor ensure that a higher pressure is maintained within the urethra than within the bladder. Furthermore, dampening of the parasympathetic innervation of the detrusor by the activation of sympathetic efferents via a sacral to thoracolumbar intersegmental reflex pathway (2) prevents the bladder from contracting spontaneously or involuntarily, the so-called “storage reflex.” This reflex not only inhibits the detrusor but also causes contraction of the bladder neck and the proximal urethra. The situation is reversed when micturition is initiated (see below). Afferent Innervation of the Bladder Sensations of bladder fullness are conveyed to the spinal cord in the pelvic and hypogastric nerves (3). The afferent components of these nerves contain myelinated (Ad) and unmyelinated (C) axons. The Ad fibers respond to passive distension and active contraction (3) and thus convey information about bladder filling. The C-fibers, insensitive to bladder filling under physiological conditions (therefore termed “silent” C-fibers) respond primarily to noxious stimuli such as chemical irritation of the urothelium (4) or cooling (5). The cell bodies of both these classes of axons are located in the dorsal root ganglia at the level of S2 to S3 and T11 to L2 spinal segments (Figs. 1 and 2). Bladder afferent activity enters the spinal cord through the dorsal horn and ascends rostrally to higher brain centers involved in bladder control (see below). In the urinary bladder of both humans and animals, sensory nerves have been identified in the suburothelial layer as well as in the detrusor muscle (6–9). These nerves form a plexus in the suburothelium with some terminal fibers possibly projecting into the urothelium (10,11). This suburothelial plexus is particularly prominent at the bladder neck and relatively sparse at the dome of the bladder (12). Afferent fibers also originate from the trigone and urethra, and run in the hypogastric and pudendal nerves respectively. The response of the bladder to stretch has been extensively investigated and recently a population of cells located in the suburothelial layer of the bladder has been identified, with characteristics of both smooth muscle cells and fibroblasts therefore called myofibroblasts (13), which may act as a stretch sensory mechanism. Efferent Innervation of the Bladder The LUT receives innervation from both the parasympathetic and the sympathetic branches of the autonomic nervous system. The pelvic nerves (arising from the parasympathetic pelvic plexus) cause contraction of the detrusor which effects bladder emptying, whereas parasympathetic innervation of the outflow tract exerts an inhibitory effect resulting in relaxation of the bladder neck and urethra (14). The sympathetic fibers are derived from the T11–T12 and L1–L2 in the spinal cord and run either through the inferior mesenteric ganglia and the hypogastric nerve, or pass through the paravertebral chain to enter the pelvic nerves at the base of the bladder and the urethra. The predominant effect of the sympathetic innervation is inhibition of the parasympathetic pathways at local or spinal level and mediation of contraction of the outflow tract. The somatic nerve supply to the pelvic floor musculature and part of the urethra originates at S2 to S4 and is conveyed peripherally by the pudendal nerves. A distinct, medially placed motor nucleus at the same spinal level (Onuf’s nucleus) supplies axons that innervate the external urethral sphincter. Central Control of Micturition Efficient storage and emptying of the bladder requires a coordinated action of the detrusor and the outflow tract. Whilst storage control is achieved in infancy, the decision when to void is determined by the perceived state of bladder fullness and the social environment (15). The spinal reflexes involved in storage and micturition are relatively simple and are controlled by higher brain centers ensuring the sophistication needed for urinary continence in both the

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conscious and unconscious state. Functional brain imaging studies have shown that a wide complex of brain networks control the processes of bladder storage (16,17) and voiding (18,19), that ultimately result in the activation or inhibition of a center in the dorsal tegmentum of the pons, the pontine micturition center. It is from here that direct pathways descend to the S2 to S4 segments of the sacral spinal cord and modulate the parasympathetic outflow to the detrusor and coordinate the somatic innervation to the external urethral sphincter (20). A desire to void is thus generated when the bladder volume reaches capacity, (roughly 500 mL in humans) (21) and but a micturition reflex is only triggered if higher cortical function assesses the situation as appropriate for voiding. The resulting detrusor contraction which is maintained throughout voiding [achieved by the detrusor’s unique ability to sustain near-maximal force generation in the face of significant length change (22)] and concomitant relaxation of the outflow tract ensure complete emptying. PHYSIOLOGY OF THE GENITAL ORGANS Female The female reproductive organs are comprised of the vagina and vulva, important for sexual function, and the ovaries and uterus, necessary for ovulation and reproduction. The uterus is made up of a fibromuscular lower body or cervix and a muscular upper body, which is lined by a hormonally sensitive endometrial layer. The latter responds to the complex monthly hormonal cycle mediated by the hypothalamic-pituitary-ovarian axis acting in tandem with neurological control. Innervation Female reproductive organs are innervated in a topographic fashion by afferents which pass retrogradely to the pelvic or hypogastric plexus (23). The afferent nerves contribute to uterine and vaginal perceptions (nociception) that are modified by reproductive status (24). These plexi communicate with the higher brain centers [the hypothalamus (25), the hippocampus, and the limbic system] via the spinal cord, dorsal column nuclei, and the solitary nucleus. The vagina, a highly expandable fibromuscular tube, receives sensory fibers from the pudendal nerve (the perineal and posterior labial branches) and the ilioinguinal nerve. The blood vessels of the smooth muscle of the vaginal walls are supplied by autonomic fibers from the inferior hypogastric plexuses. The clitoris, which is considered homologous to the penis, is also composed of erectile tissue with two miniature corpora cavernosa. Covered with a prepuce, the free end of the clitoris, the glans, is highly sensitive to sexual stimulation. Sexual excitement induces vascular smooth muscle relaxation (26) mediated by substances such as vasoactive intestinal polypeptide (VIP) (27) and nitric oxide (NO), and resulting in increased pelvic blood flow, clitoral and labial engorgement, and transudative vaginal lubrication. This sexual response is due, as in the male, to parasympathetic activity, and at orgasm there is repeated contraction of the perineal skeletal muscle, supplied by the perineal branch of the pudendal nerve. Women with complete spinal cord injury (SCI) at the mid-thoracic level show perceptual responses to vaginal and/or cervical self-stimulation (for example, pain suppression and sexual response, including orgasm) (28). Animal studies had shown that vagus nerves provide a sensory pathway from the vagina, cervix, and uterus and fMRI studies performed on women with complete SCI showed the importance of preserved sensation via the vagus innervation in humans. Cervical self-stimulation increases activity in the region of the nucleus of the solitary tract, the brainstem projection of the vagus nerve (28). Menstruation Animal studies have shown that the rat uterus is directly innervated by both autonomic and sensory nerves, including adrenergic (29) and cholinergic (30), as well as by different peptidergic fibers containing VIP, substance P (SP), calcitonin-gene-related peptide, and galanin (31,32). Uterine innervation undergoes profound remodeling during puberty, pregnancy, and after delivery. However, the extent to which uterine innervation may change during

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the menstrual cycle is uncertain. Many studies have been carried out looking into nerve fiber density of the rat uterine horn and its alternation during the menstrual cycle (33,34). During the rat oestrus cycle, there is structural remodelling of sympathetic nerves (34), by way of retraction or degeneration of terminal fibers during menstruation. However, no cyclical variation was noted with VIP-immunoreactive parasympathetic nerves fibers (32). The human uterus, which is similarly affected, is under direct control of the hormonal cycle which influences the innervation of the uterine arteries, cholinergic, adrenergic, and peptidergic, and regulates the spontaneous contractile activity of the smooth muscle of vessel walls as well as the motor responses of these tissues to different vasoactive substances (35). A hormonal disturbance may cause dysfunctional bleeding by changing vessel growth as well as vascular and myometrial smooth muscle activity (36). An example of the latter is primary dysmenorrhoea, when there is an increased secretion of vasopressin (35), which acts on type V1 vasopressin receptors of the uterus, causing myometrial hyperactivity and vasoconstriction, with resultant uterine ischemia and pain. Pregnancy and Parturition In the pregnant uterus, the motor and sensory innervation undergoes a profound denervation process, although the changes do not affect all types of nerves. Immunocytochemical studies have indicated that myometrial and perivascular VIP-containing fibers disappear at the end of pregnancy (37). In contrast, SP-containing primary afferent neurons do not degenerate during pregnancy (38). At the end of pregnancy, the numbers of both myometrial and perivascular adrenergic nerves are decreased in the rat (39,40) in the guinea pig (41,42), and in humans (43). The whole autonomic uterine innervation, therefore, undergoes substantial remodeling during pregnancy. Urogenital Pain The innervation of the pelvis shows great convergence and indicates the existence of extensive cross-system, viscero–visceral interactions within the central nervous system that, while organized for coherent bodily functioning, serves as a substrate by which pathophysiology in one organ can influence physiology and responses to pathophysiology in other organs (24). Some cross-system effects that have been observed and reported in the literature include (i) bladder inflammation reducing the rate of uterine contractions and the effects of drugs on the uterus (44) and (ii) colon inflammation producing signs of inflammation in the otherwise healthy bladder and uterus. How pathophysiology of one pelvic organ influences the physiology of another is poorly understood, but knowledge and understanding of the convergence of peripheral and central innervation of the pelvis may have considerable clinical relevance. Male Sexual Function Sexual function in men also involves peripheral nerves, the spinal cord (sacral and thoracolumbar) and higher brain centers (the medial preoptic area, the hypothalamus, the hippocampus and the limbic system). The sexual response in males, like in females, also results from neurotransmitter mediated smooth muscle relaxation (45). Erection and ejaculation have different neural controls; whereas penile erection is due to parasympathetically mediated vasodilatation and veno-occlusion, ejaculation is a result of sympathetic and somatically mediated smooth muscle contraction. The physiological processes involved in erection lead to a common pathway with the key biochemical event being an increase in levels of cyclic guanosine monophosphate (46) mediated by NO and resulting in the relaxation of the smooth muscle of the arterioles of the paired corpora cavernosa and the corpora spongiosum of the penis (47). This erectile tissue becomes engorged with blood and expands becoming rigid when aroused (48). It is now well established that two separate pathways for erection exist, the reflex and the psychogenic erection mechanisms (49). Reflex erection occurs following genital stimulation and

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is mediated by sacral segmental pathways. Impulses in the corporeal branches of the pelvic nerves lead to arteriolar vasodilatation of the penis. This type of erection is short-lived and inadequate for penetration (50). The other type of erection is psychogenically driven in response to visual, auditory, olfactory, and perceived erotic stimuli. Psychogenic erectile activity is mediated by the thoracolumbar sympathetic outflow. The fusion of these two types of responses culminates in an erection which is adequate and well maintained for intercourse (50). During ejaculation the flow of seminal fluid into the prostatic urethra is due to smooth muscle contraction of the epididymis, ductus deferens, seminal vesicle, ejaculatory duct, prostate, superficial trigonal muscle of the bladder neck, facilitated by the sympathetic outflow from segments T11 to L2 (51). Expulsion of the ejaculate is brought about by constriction of the bladder neck eliminating retrograde flow and rhythmic contraction of the bulbospongiosus muscle, supplied by the perineal (pudendal) nerve. Orgasmic sensations are conveyed by the spinothalamic tract and are abolished by spinal cord transection (52), however ejaculation may still be maintained in low thoracic transections.

CONCLUSION The rich and complex innervation of the bladder and genital organs, which enables their physiological function, appears also to be a potential substrate for neural pain. Perhaps it is too simple to surmise that it is the high density of small nerves fibers in the pelvis that poses a particular risk, but the large number of pelvic pain syndromes presumed to be of neurogenic origin do raise the question as to whether, if autonomic innervation “gets muddled,” it can cause pain. REFERENCES 1. de Groat WC, Booth AM. Physiology of the urinary bladder and urethra. Ann Intern Med 1980; 92(Pt 2): 312–5. 2. de Groat WC, Lalley PM. Reflex firing in the lumbar sympathetic outflow to activation of vesical afferent fibres. J Physiol 1972; 226(2):289–309. 3. Janig W, Morrison JF. Functional properties of spinal visceral afferents supplying abdominal and pelvic organs, with special emphasis on visceral nociception. Prog Brain Res 1986; 67:87–114. 4. Habler HJ, Janig W, Koltzenburg M. Activation of unmyelinated afferent fibres by mechanical stimuli and inflammation of the urinary bladder in the cat. J Physiol 1990; 425:545–62. 5. Fall M, Lindstrom S, Mazieres L. A bladder-to-bladder cooling reflex in the cat. J Physiol 1990; 427:281–300. 6. Gosling JA, Dixon JS. Sensory nerves in the mammalian urinary tract. An evaluation using light and electron microscopy. J Anat 1974; 117(Pt 1):133–44. 7. Smet PJ, Moore KH, Jonavicius J. Distribution and colocalization of calcitonin gene-related peptide, tachykinins, and vasoactive intestinal peptide in normal and idiopathic unstable human urinary bladder. Lab Invest 1997; 77:37–49. 8. Avelino A, Cruz C, Nagy I, Cruz F. Vanilloid receptor 1 expression in the rat urinary tract. Neuroscience 2002; 109(4):787–98. 9. Yiangou Y, Facer P, Ford A, et al. Capsaicin receptor VR1 and ATP-gated ion channel P2X3 in human urinary bladder. BJU Int 2001; 87(9):774–9. 10. Birder LA, Kanai AJ, de Groat WC, et al. Vanilloid receptor expression suggests a sensory role for urinary bladder epithelial cells. Proc Natl Acad Sci USA 2001; 98(23):13396–401. 11. Lazzeri M, Vannucchi G, Zardo C, et al. Immunohistochemical evidence of vanilloid receptor 1 in normal human urinary bladder urothelium. Eur Urol 2004; 46:792–9. 12. Gabella G, Davis C. Distribution of afferent axons in the bladders of rats. J Neurocytol 1998; 27:141–55. 13. Wiseman OJ, Fowler CJ, Landon DN. The role of the human bladder lamina propria myofibroblast. BJU Int 2003; 91:89–93. 14. Burnstock G. Innervation of bladder and bowel. Ciba Found Symp 1990; 151:2–18 (discussion 18–26). 15. Kavia RB, Dasgupta R, Fowler CJ. Functional imaging and the central control of the bladder. J Comp Neurol 2005; 493(1):27–32. 16. Athwal BS, Berkley KJ, Hussain I, et al. Brain responses to changes in bladder volume and urge to void in healthy men. Brain 2001; 124(Pt 2):369–77.

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17. Matsuura S, Kakizaki H, Mitsui T, Shiga T, Tamaki N, Koyanagi T. Human brain region response to distention or cold stimulation of the bladder: a positron emission tomography study. J Urol 2002; 168(5):2035–9. 18. Blok BF, Willemsen AT, Holstege G. A PET study on brain control of micturition in humans. Brain 1997; 120(Pt 1):111–21. 19. Blok BF, Sturms LM, Holstege G. Brain activation during micturition in women. Brain 1998; 121(Pt 11): 2033–42. 20. Blok BF. Central pathways controlling micturition and urinary continence. Urology 2002; 59(5 Suppl. 1): 13–7. 21. Wyndaele JJ. Normality in urodynamics studied in healthy adults. J Urol 1999; 161(3):899–902. 22. Uvelius B, Gabella G. Relation between cell length and force production in urinary bladder smooth muscle. Acta Physiol Scand 1980; 110(4):357–65. 23. Anaf V, Simon P, El Nakadi I, et al. Relationship between endometriotic foci and nerves in rectovaginal endometriotic nodules. Hum Reprod 2000; 15(8):1744–50. 24. Berkley KJ. A life of pelvic pain. Physiol Behav 2005; 86(3):272–80. 25. Akaishi T, Robbins A, Sakuma Y, Sato Y. Neural inputs from the uterus to the paraventricular magnocellular neurons in the rat. Neurosci Lett 1988; 84(1):57–62. 26. Berman JR, Adhikari SP, Goldstein I. Anatomy and physiology of female sexual function and dysfunction: classification, evaluation and treatment options. Eur Urol 2000; 38(1):20–9. 27. Levin RJ. VIP, vagina, clitoral and periurethral glans—an update on human female genital arousal. Exp Clin Endocrinol 1991; 98(2):61–9. 28. Whipple B, Komisaruk BR. Brain (PET) responses to vaginal–cervical self-stimulation in women with complete spinal cord injury: preliminary findings. J Sex Marital Ther 2002; 28(1):79–86. 29. Sjoberg NO. Dysmenorrhea and uterine neurotransmitters. Acta Obstet Gynecol Scand Suppl 1979; 87:57–9. 30. Stjernquist M, Owman Ch. Cholinergic and adrenergic neural control of smooth muscle function in the non-pregnant rat uterine cervix. Acta Physiol Scand 1985; 124:429–36. 31. Papka RE, Cotton JP, Traurig HH. Comparative distribution of neuropeptide tyrosine-, vasoactive intestinal polypeptide-, substance P-immunoreactive, acetylcholinesterase-positive and noradrenergic nerves in the reproductive tract of the female rat. Cell Tissue Res 1985; 242(3):475–90. 32. Shew RL, Papka RE, McNeill DL. Galanin and calcitonin gene-related peptide immunoreactivity in nerves of the rat uterus: localization, colocalization, and effects on uterine contractility. Peptides 1992; 13(2):273–9. 33. Sjoberg NO. New considerations on the adrenergic innervation of the cervix and uterus. Acta Obstet Gynecol Scand 1969; 48(Suppl. 3):28–32. 34. Zoubina EV, Fan Q, Smith PG. Variations in uterine innervation during the estrous cycle in rat. J Comp Neurol 1998; 397(4):561–71. 35. Akerlund M. Vascularization of human endometrium. Uterine blood flow in healthy condition and in primary dysmenorrhoea. Ann N Y Acad Sci 1994; 734:47–56. 36. Proctor ML, Latthe PM, Farquhar CM, Khan KS, Johnson NP. Surgical interruption of pelvic nerve pathways for primary and secondary dysmenorrhoea. Cochrane Database Syst Rev 2005; 4:CD001896. 37. Stjernquist M, Alm P, Ekman R, Owman C, Sjoberg NO, Sundler F. Levels of neural vasoactive intestinal polypeptide in rat uterus are markedly changed in association with pregnancy as shown by immunocytochemistry and radioimmunoassay. Biol Reprod 1985; 33(1):157–63. 38. Traurig H, Saria A, Lembeck F. Substance P in primary afferent neurons of the female rat reproductive system. Naunyn Schmiedebergs Arch Pharmacol 1984; 326(4):343–6. 39. Moustafa FA. Changes in cholinergic and noradrenergic nerves in the pregnant and postpartum uterus of the albino rat and guinea pig. Acta Anat (Basel) 1988; 132(4):310–6. 40. Haase EB, Buchman J, Tietz AE, Schramm LP. Pregnancy-induced uterine neuronal degeneration in the rat. Cell Tissue Res 1997; 288(2):293–306. 41. Thorbert G, Alm P, Owman C, Sjoberg NO, Sporrong B. Regional changes in structural and functional integrity of myometrial adrenergic nerves in pregnant guinea-pig, and their relationship to the localization of the conceptus. Acta Physiol Scand 1978; 103(2):120–31. 42. Alm P, Owman C, Sjoberg NO, Thorbert G. Uptake and metabolism of [3H]norepinephrine in uterine nerves of pregnant guinea pig. Am J Physiol 1979; 236(5):C277–85. 43. Wikland M, Lindblom B, Dahlstrom A, Haglid KG. Structural and functional evidence for the denervation of human myometrium during pregnancy. Obstet Gynecol 1984; 64(4):503–9. 44. Dmitrieva N, Johnson OL, Berkley KJ. Bladder inflammation and hypogastric neurectomy influence uterine motility in the rat. Neurosci Lett 2001; 313(1–2):49–52. 45. Levin RJ. The physiology of sexual arousal in the human female: a recreational and procreational synthesis. Arch Sex Behav 2002; 31(5):405–11. 46. Padma-Nathan H, Christ G, Adaikan G, Becher E, Brock G, Carrier S, Carson C, Corbin J, Francis S, DeBusk R, et al. Pharmacotherapy for erectile dysfunction. J Sex Med 2004; 1(2):128–40.

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47. Burnett AL. Nitric oxide in the penis: physiology and pathology. J Urol 1997; 157(1):320–4. 48. Andersson KE. Neurophysiology/pharmacology of erection. Int J Impot Res 2001; 13(Suppl. 3):S8–17. 49. Bernabe J, Rampin O, Sachs BD, Giuliano F. Intracavernous pressure during erection in rats: an integrative approach based on telemetric recording. Am J Physiol 1999; 276(2 Pt 2):R441–9. 50. Schmid DM, Schurch B, Hauri D. Sildenafil in the treatment of sexual dysfunction in spinal cord-injured male patients. Eur Urol 2000; 38(2):184–93. 51. Hendry WF. Disorders of ejaculation. Ann R Coll Surg Engl 1999; 81(5):352–8. 52. Sonksen J, Ohl DA. Penile vibratory stimulation and electroejaculation in the treatment of ejaculatory dysfunction. Int J Androl 2002; 25(6):324–32.

5

Acute and Chronic Pain Mechanisms Sarah Harper

Department of Anaesthesia, Gloucestershire Royal Hospitals, NHS Foundation Trust, Gloucestershire, U.K.

INTRODUCTION The mechanisms of acute nociceptive pain are also covered in detail in Chapter 40. The aim of this chapter is to provide an overview of the changes that may occur in pain processing that lead to chronic pain, even in the absence of ongoing tissue damage. It is recognized that chronic pain states may follow an acutely painful stimulus such as surgery, trauma, or a painful medical condition. A large study of over 5000 patients referred to chronic pain clinics in the United Kingdom revealed that 22.5% had developed their pain after surgery and 18.7% after trauma (1). A significant proportion of patients who complain of chronic pelvic pain recall a specific acute injury or infection that coincided with the onset of the pain for which they are seeking help. In women, this has been found to include surgery, childbirth, infections, complications of early pregnancy, and trauma (2). This observation has stimulated research into the factors associated with the development of chronic pain states and the possible interventions to reduce the rate of transition from acute to chronic pain (3,4). Those patients with chronic pain who do not recall an incident or illness that coincided with its onset may find this in itself to be particularly distressing, and some are very focused on looking for a cause or explanation for the pain’s occurrence. They may incorrectly associate incidental illnesses or accidents with the onset of their pain. A recent survey presented at the Chronic Pelvic Pain Society found that 34% of women with chronic pelvic pain had pain that seemed to them to start “out of the blue” (2).

RISK FACTORS FOR TRANSITION FROM ACUTE TO CHRONIC PAIN STATES The risk of developing a chronic pain condition differs among different surgical procedures and types of trauma. The incidence of persisting pelvic pain after hysterectomy for pain has been found to be 22% (2). The risk of chronic pain following vasectomy has been identified as being as high as 36% (5,6). Technical aspects of many different surgical procedures have been shown to have an impact on the risk of developing chronic pain postoperatively (7). These might reasonably be expected to also apply to surgical procedures in the pelvis. They include: 1. Position of incision: The risk of post thoracotomy pain syndrome (PTPS) is reduced by the use of an anterolateral incision rather than the classical posterolateral incision. The anterolateral incision is associated with a reduced risk of intercostal nerve dysfunction, which has a demonstrated relationship with chronic pain (8,9). Chronic pain following breast surgery has been shown to be more common following breastconserving surgery, extensive axillary dissection or implantation of a prosthesis at the time of primary surgery. Intuitively these techniques may carry a higher risk of (particularly intercostobrachial) nerve damage (10–12). The assumption is that the pain is usually of neuropathic origin (13–15). 2. Use of laparoscopy: Video-assisted thoracoscopic surgery carries a reduced risk of PTPS compared to open thoracotomy (44% vs. 30%) (16). There is also evidence that

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laparoscopic hernia repair leads to a lower incidence of chronic pain than open repair (17,18) although some authors have found no difference (19,20). The putative mechanism is again a reduction in the risk of sensory nerve damage or irritation. 3. Type of intra- and postoperative analgesia used: Use of intraoperative as well as postoperative epidural analgesia has been shown to reduce the risk of PTPS (21). The extent of acute postoperative pain and the number of doses of postoperative analgesia have been shown to be the best predictors of chronic pain after breast cancer surgery (22). The mechanism is likely to be via a reduction in peripheral and central sensitization as discussed later in this chapter. 4. Nerve irritation by adjuvant treatments such as radiotherapy: Adjuvant radiotherapy after breast surgery is a risk factor for chronic pain in both the breast area and the arm (22,23). Most authors attribute this to nerve damage (24–26), and the effect is likely to extrapolate to treatment in other regions of the body. More severe or prolonged acute pain in the pre- and postoperative period as well as postoperative complications, commonly leading to increased nociception, significantly predict the development of chronic pain after surgery (3,4,27). Intense preoperative pain increases the incidence of persisting phantom limb pain following limb amputation (from 33–72%) (28,29). Analogous to this is the risk of ongoing pelvic pain after a hysterectomy performed with the intention of treating pelvic pain. Preoperative risk factors for the development of chronic pain also include “psychological vulnerability,” female gender and long-standing preoperative symptoms (7). There is some evidence for a genetic predisposition to certain chronic pain conditions, especially painful sensory neuropathies. Those identified to date are all rare single-gene disorders. The more common and demographically important multigenic pain conditions which we see in our pain management clinics on a daily basis are proving much more difficult to study using current human genetic techniques. Ongoing study using laboratory animal genetics may be a more efficacious route to the identification of pain-related genes in humans. Epidemiological studies reveal that some families contain several members with either the same or a variety of chronic pain problems. It is difficult to tease out a genetic predisposition from exposure of several members of a family to triggering cultural, environmental and behavioral factors (30). There is excellent research evidence to show that the existence of a chronic pain sufferer in a family has long-lasting effects on the children in that family. Learned behaviors and the effect of modeling may have lifelong consequences that begin even before language development in a child. It has been shown that children in families of chronic pain sufferers experience pain much more intensely in their adult years. Chronic pain sufferers should be aware that their nonverbal reactions to their pain such as writhing, sighing, grimacing, and so on will have long-lasting effects on their children (31). A patient may present with a particular, specific pain problem, which is in fact part of a more generalized pain disorder. Patients with vulvar pain syndrome have been shown to have lower pain thresholds on the upper limb as well as in the vulval vestibule (32,33). It has also been shown that some chronic syndromes, including chronic widespread pain, chronic orofacial pain and chronic fatigue, that are frequently unexplained, co-occur more frequently than would be expected purely by chance. They share common associated demographic and psychosocial factors (34). Patients with certain chronic pain conditions, such as vulvar pain syndrome, seem to have a higher incidence of concomitant psychiatric disorder (35,36). These findings do not however differentiate between cause and effect.

MECHANISMS FOR THE TRANSITION FROM ACUTE TO CHRONIC PAIN The development of chronic pain is based on the phenomenon of central neuroplasticity. Disruption of the normal specialization of the somatosensory system leads to increasing

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mismatch between stimulus and response. The mechanism is not fully elucidated yet, but the following changes in neurophysiology play a role. Detail on the basic science behind these mechanisms is beyond the scope of this chapter but can be found in an excellent review article in Anesthesia and Analgesia (37). Windup A progressive increase in the number of action potentials elicited per stimulus occurs in dorsal and ventral horn neurons when the stimulus exceeds 0.5 Hz. Above this frequency, the postsynaptic depolarizing responses summate to produce a cumulative depolarization resulting in a burst of action potentials, instead of a single action potential in response to each stimulus. It is mediated via N-methyl-D-aspartic acid (NMDA) glutamate receptors and therefore blocked and reversed by NMDA antagonists. Windup lasts for as long as ventral horn cell depolarization, i.e., about 60 seconds. Long-Term Potentiation Repeated episodes of windup may trigger long-term potentiation (LTP). It was first studied in the hippocampus and is now known to occur in visual, sensorimotor and pre-frontal cortex as well as in the spinal cord. Its mechanism is complex (37) but, in essence, high-frequency presynaptic activity causes presynaptic glutamate release, which activates a-amino-3-hydroxy5-methyl-4-isoxazole propionic acid (AMPA) receptors. AMPA receptor activation opens ion channels allowing postsynaptic depolarization. If the depolarization reaches a certain threshold, a magnesium-dependent block of NMDA receptors is released; NMDA receptors are then free to open their associated ion channels. There is an overall influx of calcium ions which triggers additional calcium release from intracellular calcium stores. The intracellular calcium rise triggers a complex chain of events as follows: 1. Release of one or more retrograde factors by the postsynaptic cell, which diffuse back to the presynaptic membrane causing increased transmitter release in response to each presynaptic action potential. The factor is unknown but arachidonic acid, nitric oxide, and carbon monoxide are possible culprits. 2. Calcium-dependent enzymes such as protein kinase C, calcium/calmodulin kinase, and protein kinase A are activated, leading to phosphorylation of membrane proteins including receptors and ion channels. This makes the postsynaptic cell more excitable. 3. Upregulation of AMPA receptors and growth of dendrites/spines on the postsynaptic cell occurs. The overall result is LTP, which can last from one hour to several months. It can be slowed or prevented from occurring in vitro by NMDA antagonists, early cooling or protein kinase C inhibitors but in contrast to windup cannot be reversed. Recruitment Chronic inflammation and nerve injury have an effect on the presence and distribution of voltage-gated sodium channels, which can become concentrated in areas of injury and produce ectopic discharges. Studies have shown that neurone-specific sodium channels become concentrated in neurones proximal to a site of nerve injury and play a role in the hyperalgesia and allodynia of chronic pain states. Not all sensory neurons are active all the time, and this peripheral sensitization will “recruit” dormant nociceptors, thus increasing the receptive fields of dorsal horn neurons and increasing the intensity and area of pain (38). Immediate Early Gene Expression Immediate early genes are a family of genes that share the characteristic of having their expression rapidly and transiently induced upon stimulation of neuronal and nonneuronal cells (39). Damaged sensory neurones may undergo altered gene expression such that they

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release a different type of neurotransmitter. The release of neurotransmitters usually associated with noxious stimuli, such as substance P, may contribute to central sensitization. A change in gene expression can also lead to up- or downregulation of ion channels leading to changes in cellular excitability. Excitotoxicity Excitotoxicity is a phenomenon that was first described by Olney in the seventies (40) It involves the activation of glutamate receptors in the central nervous system. Glutamate, an excitatory amino acid, activates different types of ion channel forming receptors to develop their essential role in the functional activity of the brain. However, high concentrations of glutamate, or neurotoxins acting at the same receptors, cause cell death by apoptosis through the excessive activation of these receptors. The physiological role of the NMDA receptor seems to be related to synaptic plasticity and learning. In addition, working together with G protein-coupled glutamate receptors, it ensures the establishment of the LTP phenomenon described above. Research into the phenomenon has focused on finding clinically useful NMDA receptor antagonists for use in both chronic pain conditions and neurodegenerative disorders in which excitotoxicity play a part such as Parkinson’s disease and Alzheimer’s disease (41). Sympatho-Nociceptive Coupling In a proportion of chronic pain conditions there is involvement of the sympathetic nervous system in maintenance of the pain. Following nerve injury both injured and surrounding uninjured primary afferents may begin to express alpha-2-adrenoceptors on their cell membranes. They therefore become responsive to circulating catecholamines (42,43). Direct coupling also occurs between the sympathetic and peripheral nervous systems. Following nerve injury and cell death in the dorsal root ganglia, sympathetic nerves may sprout axons which take the place of the destroyed primary afferents and form functional synapses with ongoing afferent nociceptive neurones. This sprouting is thought to occur under the influence of nerve growth factor (44). These mechanisms begin to explain why some chronic pain, which is partly or wholly sympathetically maintained, responds to adrenergic blockade. Neurogenic Inflammation There is an interesting evolving school of thought on the role of neurogenic inflammation in chronic pelvic pain conditions (45). Psychological stress alone is capable of producing an acute phase inflammatory response similar to that produced by tissue injury or infection. Black postulates that repeated or chronic episodes of stress may result in inflammatory disease states (46). Many chronic pain conditions including complex regional pain syndrome, painful bladder syndrome (interstitial cystitis), irritable bowel syndrome, prostate pain syndrome and chronic pelvic pain with or without endometriosis exhibit elements of neurogenic inflammation (47–50). CONCLUSIONS These emerging mechanisms imply that chronic pathological pain may persist long after the initial noxious insult has ceased and tissue damage has healed. The process of synaptic plasticity and learning begins early and is difficult to reverse. It seems that untreated acute pain persisting for long periods of time can imprint memory-like processes into the central nervous system (51). It seems intuitive that early intervention, prior to this transition from acute to chronic pain, provides our best opportunity to reduce the burden of chronic pain. This brief overview of current thinking on the mechanisms involved in the chronification of pain aids understanding of the patient with chronic pain, their variable and unpredictable response to treatment and particularly the ongoing variation in severity, nature and treatment

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responsiveness which can prove frustrating to patients, their carers and health care professionals alike. REFERENCES 1. Crombie IK, Davies HT, Macrae WA. Cut and thrust: antecedent surgery and trauma amongst patients attending a chronic pain clinic. Pain 1998; 76:167–71. 2. Royal College of Obstetrians and Gynaecologists. Green-top guidelines: the initial management of chronic pelvic pain 2005 (41). (Accessed September 28, 2007 at www.rcog.org.uk) 3. Katz J, Jackson M, Kavanaugh B, Sandler A. Acute pain after thoracic surgery predicts long-term postthoracotomy pain. Clin J Pain 1996; 12:50–5. 4. Gehling M, Scheidt C-E, Neibergall H, Kocaglu E, Tryba M, Geiger K. Persistant pain after elective trauma surgery. Int J Acute Pain Manag 1999; 2:110–4. 5. Morris C, Mishra K, Kirkman RJ. A study to assess the prevalence of chronic testicular pain in post-vasectomy men compared to non-vasectomised men. J Fam Plann Reprod Health care 2002; 28(3):142–4. 6. Manikandan R, Srirangam SJ, Pearson E, Collins GN. Early and late morbidity after vasectomy: a comparison of chronic scrotal pain at 1 and 10 years. BJU Int 2004; 93(4):571–4. 7. Perkins F M, Kehlet H. Chronic pain as an outcome of surgery—a review of predictive factors. Anaesthesiology 2000; 93:1123–33. 8. Nomori H, Horio H, Fuyuno G, Kobayashi R. Non-serratus-sparing anteroaxillary thoracotomy with disconnection of anterior rib cartilage. Improvement in postoperative pulmonary function and pain in comparison to posterolateral thoracotomy. Chest 1997; 111:572–6. 9. Benedetti F, Vighetti S, Ricco C, et al. Neurophysiologic assessment of nerve impairment in posterolateral and muscle-sparing thoracotomy. J Thorac Cardiovasc Surg 1998; 115:841–7. 10. Tasmuth T, von Smitten K, Kalso E. Pain and other symptoms during the first year after radical and conservative surgery for breast cancer. Br J Cancer 1996; 74:2024–31. 11. Tasmuth T, von Smitten K, Hietanen P, Kataja M, Kalso E. Pain and other symptoms after different treatment modalities of breast cancer. Ann Oncol 1995; 6:453–9. 12. Wallace MS, Wallace AM, Lee J, Dobke MK. Pain after breast surgery: a survey of 282 women. Pain 1996; 66:195–205. 13. Seid AS, Amos E. Entrapment neuropathy in laparoscopic herniorrhaphy. Surg Endosc 1994; 8:1050–3. 14. Starling JR, Harms BA. Diagnosis and treatment of genitofemoral and ilioinguinal neuralgia. World J Surg 1989; 13:586–91. 15. Heise CP, Starling JR. Mesh inguinodynia: a new clinical syndrome after inguinal herniorrhaphy. J Am Coll Surg 1998; 187:514–8. 16. Landreneau RJ, Mack MJ, Hazelrigg SR, et al. Prevalence of chronic pain after pulmonary resection by thoracotomy or video-assisted thoracic surgery. J Thorac Cardiovasc Surg 1994; 107:1079–85. 17. Liem MS, van D, van S, et al. Comparison of conventional anterior surgery and laparoscopic surgery for inguinal-hernia repair. N Engl J Med 1997; 336:1541–7. 18. The MRC Laparoscopic Groin Hernia Trial Group. Laparoscopic versus open repair of groin hernia: a randomised comparison. Lancet 1999; 354:185–90. 19. Dirksen CD, Beets GL, Go PM, Geisler FE, Baeten CG, Kootstra G. Bassini repair compared with laparoscopic repair for primary inguinal hernia: a randomised controlled trial. Eur J Surg 1998; 164:439–47. 20. Gillion JF, Fagniez PL. Chronic pain and cutaneous sensory changes after inguinal hernia repair: comparison between open and laparoscopic techniques. Hernia 1999; 3:75–80. 21. Obata H, Saito S, Fujita N, Fuse Y, Ishizaki K, Goto F. Epidural block with mepivacaine before surgery reduces long-term post-thoracotomy pain. Can J Anaesth 1999; 46:1127–32. 22. Tasmuth T, Kataja M, Blomqvist C, von Smitten K, Kalso E. Treatment-related factors predisposing to chronic pain in patients with breast cancer—a multivariate approach. Acta Oncol 1997; 36:625–30. 23. Keramopoulos A, Tsionou C, Minaretzis D, Michalas S, Aravantinos D. Arm morbidity following treatment of breast cancer with total axillary dissection: a multivariated approach. Oncology 1993; 50:445–9. 24. Tasmuth T, von Smitten K, Hietanen P, Kataja M, Kalso E. Pain and other symptoms after different treatment modalities of breast cancer. Ann Oncol 1995; 6:453–9. 25. Watson CP, Evans RJ, Watt VR. The post-mastectomy pain syndrome and the effect of topical capsaicin. Pain 1989; 38:177–86. 26. Killer HE, Hess K. Natural history of radiation-induced brachial plexopathy compared with surgically treated patients. J Neurol 1990; 237:247–50. 27. Kwekkeboom K. Postmastectomy pain syndromes. Cancer Nurs 1996; 19:37–43.

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28. Nikolajsen L, Ilkjaer S, Kroner K, Christensen JH, Jensen TS. The influence of preamputation pain on postamputation stump and phantom pain. Pain 1997; 72:393–405. 29. Krane EJ, Heller LB. The prevalence of phantom limb sensation and pain in pediatric amputees. J Pain Symptom Manage 1995; 10:21–9. 30. Mogil J, Wilson S, Bon K. Heritability of nociception II. ‘Types’ of nociception revealed by genetic correlation analysis. Pain 1999; 80:83–93. 31. Mailis-Gagnon A, Israelson D. Beyond Pain: Making the Mind-Body Connection. Ann Arbor, MI: University of Michigan Press, 2005 (ISBN 0-472-03082-5). 32. Pukall CF, Binik YM, Khalife S, Amsel R, Abbott FV. Vestibular tactile and pain thresholds in women with vulvar vestibulitis syndrome. Pain 2002; 96:163–75. 33. Granot M, Friedman M, Yarnitsky D, Zimmer EZ. Enhancement of the perception of systemic pain in women with vulvar vestibulitis. Br J Obstet Gynaecol 2002; 109:863–6. 34. Aggarwal VR, Mcbeth J, Zakrzewska JM, Lunt M, Macfarlane GJ. The epidemiology of chronic syndromes that are frequently unexplained: do they have common associated factors? Int J Epidemiol 2006; 35:468–76 (Epub ahead of print 2005). 35. Danielsson I, Sjoberg I, Wikman M. Vulvar vestibulitis: medical, psychosexual and psychosocial aspects, a case control study. Acta Obstet Gynaecol Scand 2000; 79:872–8. 36. Stewart DE, Reicher AE, Gerulath AH, Boydell KM. Vulvodynia and psychological distress. Obstet Gynaecol 1994; 85:587–90. 37. Pockett S. Spinal cord synaptic plasticity and chronic pain. Anesth Analg 1995; 80(1):173–9. 38. Mannion RJ, Woolf CJ. Pain mechanisms and management: a central perspective. Clin J Pain 2000; 16(Suppl. 3):S144–56. 39. Caputto BL, Guido ME. Immediate early gene expression within the visual system: light and circadian regulation in the retina and the suprachiasmatic nucleus. Neurochem Res 2000; 25(1):153–62. 40. Olney JW, Sharpe LG, Feigin RD. Glutamate-induced brain damage in infant primates. J Neuropathol Exp Neurol 1972; 31:464–88. 41. Sureda FX. Excitotoxicity and the NMDA receptor. From EUROSIVA meeting, Vienna, 2000. (www. eurosiva.org/Archive/Vienna/abstracts/Speakers/SUREDA.htm) 42. Mannion RJ, Woolf CJ. Pain mechanisms and management: a central perspective. Clin J Pain 2000; 4(1):5–15. 43. McLachlan EM, Janig W, Devor M, Michaelis M. Peripheral nerve injury triggers noradrenergic sprouting within dorsal root ganglia. Nature 1993; 363(6429):543–6. 44. Janig W, Habler HJ. Sympathetic nervous system: contribution to chronic pain. Prog Brain Res 2000; 129:451–68. 45. Janicki T. Neurogenic inflammation in Chronic Pain Conditions. The International Pelvic Pain Society, 2004; 11(1): 1–4. (Accessed September 20, 2007 at www.pelvicpain.org/VisionNewsletter) 46. Black PH. Stress and the inflammatory response: a review of neurogenic inflammation. Brain Behav Immun 2002; 16(6):622–53. 47. O’Sullivan M, Clayton N, Breslin NP, et al. Increased mast cells in the irritable bowel syndrome. Neurogastroenterol Motil 2000; 12(5):449–57. 48. Pontari MA, Ruggieri MR. Mechanisms in prostatitis/chronic pelvic pain syndrome. J Urol 2004; 172(3):839–45. 49. Wesselmann U. Neurogenic inflammation and chronic pelvic pain. World J Urol 2001; 19(3):180–5. 50. Maier SF. Bi-directional immune-brain communication: implications for understanding stress, pain and cognition. Brain Behav Immune 2003; 17(2):69–85. 51. Schug SA. Acute pain management—its role in the prevention of chronic Pain States. Asian J Anaesthesiol 2004; 5(1):66.

6

Visceral Pain Mechanisms W. Paul Farquhar-Smith

Royal Marsden Hospital, London, U.K.

an Jaggar Si^

Royal Brompton Hospital, London, U.K.

INTRODUCTION The skin is the frontier between self and non-self and the site of impact of extraneous perturbations of environment. There is a clear benefit obtained from “protective reflexes” designed to reduce potential damage, a term coined by Sherrington at the turn of the century [Sherrington, 1906, referenced in (1)]. However, visceral pain comes from within and is more related to disease processes. There is no obvious protective countermeasure that one can make in response to the perception of visceral pain. Indeed, effective stimuli to evoke visceral pain are not always damaging nor necessarily potentially harmful. The assumption has been to infer that the cutaneous and visceral systems share comparable pain mechanisms. However, it is becoming evident that the incongruent clinical features of somatic and visceral pain reflect differences in the neurobiology of these nociceptive systems (1,2).

FEATURES OF VISCERAL COMPARED TO SOMATIC PAIN Effective Painful Stimuli In the skin and deeper somatic tissues, mechanical, thermal, chemical, and even electrical events of sufficient intensity result in the perception of precise local, nonradiating pain. In contrast, effective pain producing traumatic stimuli in the skin often fail to cause pain in the viscera, while some non-damaging stimuli such as distension or stretching provoke intense discomfort (Table 1). Hollow viscera exemplify the response to distension by a diffuse and poorly localized pain sensation. The corollary is also observed: intense smooth muscle contraction is also associated with pain (e.g., pain of uterine contractions in which ischemia may also play a role). Furthermore, some of the viscera (such as the lung) appear to be insensate and unable to signal pain. Pain Summation The total area of tissue stimulated determines pain threshold and intensity of visceral pain. Such summation is not observed with noxious cutaneous stimuli where increasing the area of stimulus leads to a modest increase in perception but has no effect on threshold (3). An intense but localized stimulus fails to achieve the necessary summation to reach pain threshold, explaining the lack of visceral pain from such stimuli. Autonomic Involvement Perception of visceral pain also differs from somatic pain by involvement of autonomic reflexes that cause nausea and sweating and influence the pain experience. It has been suggested that these reflexes are the visceral equivalent to protective reflexes and warn the sufferer to rest for recuperation (4).

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TABLE 1 Comparison of features of visceral and somatic pain Feature Effective stimuli

Character Autonomic symptoms Localization Referred pain?

Visceral

Somatic

Ischemia Contraction Distension Chemical Dull Cramping Often Poor Yes

Noxious mechanical Noxious thermal Noxious chemical Sharp Rare Good No

Referred Pain The localization of pain to distant structures is known as referred pain and is a cardinal sign of visceral pain. Referred pain is usually perceived in superficial structures including the skin and muscle and follows a segmental distribution. The referred pain locates to the superficial area supplied by the same spinal nerve as the affected viscus. The referred pain may also demonstrate a hyperalgesia that is slowly developing and persistent (1). VISCERAL INNERVATION Viscera receive much less innervation than cutaneous structures, estimated to be only 5% of the number of somatic afferents (3). Furthermore, the visceral primary afferents are unmyelinated C-fibers and thinly myelinated Ad fibers with very little representation of faster conducting Ab fibers (4,5). This is reflected in the biochemical classes that make up visceral primary afferent neurons. Visceral primary afferents are predominantly of the nerve growth factor (NGF)dependent peptidergic class. They express substance P and calcitonin gene-related peptide (CGRP) and exhibit significant colocalization with the high-affinity NGF receptor, tyrosine kinase A (trkA) (6). Physiology of Visceral Primary Afferent Neurons The physiological properties of visceral primary afferent neurons differ from their somatic counterparts. Selective activation of a specific set of nerve fibers leads to the activation of a specific group of spinal neurons that communicate with a specific brain site dedicated to pain. These are also called “nociceptor specific” neurons (common in somatic tissues). Although there appear to be few high threshold visceral nociceptor specific neurons that respond to stimuli only in the noxious range (5), specific bladder nociceptors have been identified in animals (5). Nevertheless, in the viscera most primary afferent neurons are not nociceptor specific, but are of low threshold with a firing threshold equivalent to the pressure of human bladder “fullness” sensation. They respond linearly to stimuli from the physiological to the supraphysiological (noxious) range (Fig. 1) (5), consistent with an “intensity coding” role (7). In the rat urinary bladder, 70% of visceral sensory afferent neurons demonstrate such intensity coding and there is evidence for similar populations of receptors in other hollow viscera, including the gut (8). Silent Afferents Perhaps the most significant difference between visceral and somatic processes, involves the recruitment of “silent afferents” (5,7). A proportion of visceral unmyelinated primary afferents are unresponsive to mechanical stimuli. These are estimated to make up between about 50% and 90% urinary bladder primary afferent neurons (7). After inflammation, many of these silent afferents develop a novel mechanosensitivity resulting on an increased afferent barrage into the spinal cord (Fig. 2) (7). Such increased afferent activity contributes to the generation of a central sensitization—evidenced by a slowly developing, and maintained increased excitability

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Mean impulses/s

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FIGURE 1 Graph on left demonstrates a linear response to stimuli encompassing both physiological and nociceptive ranges, consistent with the intensity coding common in visceral sensory afferent fibers. The right hand graph demonstrates the situation in a nociceptive specific afferent found more rarely in visceral tissues no firing occurs until a specific intensity threshold is reached. This is the norm in somatic tissues.

Dmitrieva & McMahon 1996 Pressure mmHg 100

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FIGURE 2 Graphs on the right panel show recordings taken from afferent fibers in the system demonstrated on the left, both before and after inflammation. Following inflammation of the bladder with turpentine, an increase in firing of afferent neurons is observed.

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of central neurons following bladder inflammation. Indeed, the N-methyl-D-aspartate (NMDA) receptor that is involved in the somatic counterpart of central sensitization (9) is implicated in the visceral equivalent since NMDA blockade can interfere with measures of visceral hyperalgesia.

VISCERAL INFLAMMATION Like somatic tissues, viscera respond to chemical stimuli: release of chemical algogens from ischemic tissue is thought to provide the basis of pain induced by this stimulus (10). Thus, inflammation is a clinically relevant trigger to visceral pain, and instigates sensitization in the periphery and subsequently centrally. For example, in human cystitis, the sufferer may feel pain at bladder volumes far lower than in the noninflamed state, and with micturition. These are manifestations of visceral hypersensitivity which may be a recurrent mechanistic theme in different human visceral pain states. As in the somatic domain, inflammation drives alterations in excitation and sensitization of primary afferent neurons that contribute to an equivalent visceral hyperalgesia. Many models of visceral pain display inflammation-induced hyperalgesia, with clinical correlates demonstrated by urinary cystitis and inflammatory bowel syndrome (IBS). Symptoms of urgency (detrusor overactivity and involuntary bladder contraction) and increased frequency of micturition emulate decreased micturition threshold in the turpentine rat urinary bladder model. Patients with IBS are more likely to report pain at a given volume of colonic balloon distension compared to normal subjects (Fig. 3) (8). NGF and Bradykinin The neurotropin, NGF, is a major feature of the inflammatory responses leading to pain (2,11,12). A pivotal role for NGF in the development and maintenance of persistent visceral inflammatory pain is supported by many lines of evidence (1). The majority of visceral primary afferent neurons express the high-affinity receptor for NGF, trkA, and these afferents are excited and sensitized by intravesical inflammation (6). NGF is up-regulated in the inflamed bladder and intravesical application of NGF mimics bladder extravasation after inflammation (13). Exogenous administration of NGF can also reproduce the activation and sensitization of bladder primary afferent neurons, including recruitment of silent afferents. Furthermore, intravesical administration of exogenous NGF reproduces the increased frequency of micturition and referred hyperalgesia to the hind paw analogous to that observed after turpentineinduced bladder inflammation. Finally, administration of the trkA–immunoglobulin G fusion

Proportion reporting pain (%)

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80 60 Normal subjects 40 20 0 0

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FIGURE 3 The graph demonstrates the finding that for a given intracolonic distending pressure, patients with irritable bowel syndrome are more likely to report pain than are normal subjects.

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molecule (which prevents NGF action by sequestration) attenuates the increased frequency of micturition and the referred hyperalgesia associated with this model (13). Bladder primary afferent neurons can be directly or indirectly activated and sensitized by NGF. NGF has been shown to regulate the expression of bradykinin-binding sites in cultured dorsal root ganglia (DRG) neurons. In the bladder, treatment with a selective bradykinin B2 receptor antagonist attenuates cyclophosphamide (CYP)-induced increase in micturition frequency and inhibits the bradykinin-evoked CGRP release from the rat urinary bladder. De novo participation of the inducible bradykinin B1 receptor after inflammation augments the action of a selective B1 agonist on increased frequency of micturition provoked by CYP cystitis. B1 receptor-mediated bladder contraction is not affected by capsaicin pretreatment, implying that this mechanism operates via capsaicin insensitive afferents. The results demonstrate a powerful modulatory role for exogenous and endogenous NGF on primary afferent neuronal sensitivity to bradykinin that may contribute to visceral hyperalgesia. Tachykinins A peripheral action of tachykinins has been implicated in both the normal control of bladder contraction, and in the heightened stimulation and sensitization of the afferent loop of the micturition reflex after inflammation (14). High-affinity binding sites for substance P, (NK1 receptor) are up-regulated in the bladder in interstitial cystitis. NK1 receptor-mediated processes may modulate neurogenic inflammation. Laird et al. discovered the persistence of nonneurogenic visceral inflammation in NK1 receptor knockout mice but capsaicin-induced neurogenic inflammation-induced referred hyperalgesia did not develop (15). However, the situation is complex. Bladder hyperreflexia activated by intravesical capsaicin is only partially inhibited by an NK1 receptor antagonist, but significantly reduced by an NK2 antagonist. Thus, the neurokinin A-selective NK2 receptor is implicated in inflammatory-induced changes in micturition reflexes and mechanosensitive afferent sensitization (14). Furthermore, the neurokinin B-selective NK3 receptor has been implicated in the visceral hyperalgesia following intracolonic zymosan and colorectal distension (16). Therefore, tachykinins may have profound actions on visceral pain in inflamed state via several NK receptors. ATP and NaV1.8 As proposed by Burnstock, ATP may be responsible in part for mediating the pain of visceral distension and therefore noninflamed nociception (17). ATP released when hollow organs such as the bladder are distended acts upon purine P2X3 receptors on visceral afferents and on small diameter DRG neurons. In moderate distension, ATP would mediate normal function such as peristalsis but excessive stimulation would result in an ATP-P2X3-mediated pain (17). P2X3 “knockout” mice show increase in bladder capacity and much reduced distension-evoked micturition contractions, implying this receptor system is involved in visceral pain. In addition to mediators already discussed, the tetrodotoxin-resistant sodium channel, NaV1.8, is involved in the inflammation-induced activation of visceral afferents in the bladder which may provide a novel therapeutic target for visceral pain states (18).

VISCERAL NOCICEPTIVE PROCESSING Numerous illustrations advocate the involvement of excitatory amino acid receptors such as NMDA and alpha-amino-3-hydroxy-5-methyl-4-isoxazoleeproprionic acid (AMPA) in mediating the activity dependent changes in spinal plasticity that contribute to central sensitization—an important feature of pain (9). In visceral systems, there appears to be a contribution of both NMDA and non-NMDA receptors in nociceptive processing in the presence or absence of inflammation.

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Visceral Pain Processing Without Inflammation: NMDA and Non-NMDA (AMPA, Kainite, and Metabotropic Glutamate) Receptor Mechanisms In animal models, in the absence of inflammation, spinal cord neurons that respond to noxious colonic distension are inhibited by a non-NMDA antagonist. The contribution of these receptors to nociceptive visceral processing is demonstrated by inhibition of response to colorectal distension by other non-NMDA receptor antagonists. In addition, NMDA receptors partially mediate visceral nociception (19). Indeed, the NMDA receptor antagonist, ketamine, attenuates the response associated with noxious distension of the ureter, suggesting an NMDA receptor role in normal nociceptive visceral function (19). Furthermore, spinal administration of NMDA leads to a facilitation of the response to colonic distension. Visceral Pain Processing in Inflammation In the gastrointestinal tract, enhanced response to colorectal distension following zymosaninduced inflammation is partly dependent upon NMDA receptor activation, although nonNMDA receptors are also implicated. Similarly, NMDA antagonism attenuates turpentineinduced sensitization to colonic distension. A specific role of spinal NMDA receptors in the development of bladder hyperreflexia in the turpentine inflammation of the rat urinary bladder model has been demonstrated and strengthens the notion that a comparable NMDA-mediated central sensitization is integral to the development of visceral hyperalgesia. Therefore, both NMDA and non-NMDA receptors are involved in visceral nociceptive processing in the resting state and contributing to central sensitization associated with visceral inflammation (Fig. 4). Indeed, the visceral form of inflammation-induced sensory sensitization may be more readily established since Visceral central sensitization 1° Afferent

2° Neuron

Nociceptive response to visceral noxious stimulus AMPA

Glutamate

NMDA

+

mGlu

After inflammation and central sensitization

AMPA

Glutamate

BDNF

+

NMDA

+++

mGlu

FIGURE 4 Cartoon demonstrating the involvement of a range of central glutamate receptors encoding noxious stimuli in both the presence and absence of inflammation.

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1. inflammation-induced recruitment of silent afferents greatly increases total afferent input. In support, after inflammation, the novel activity of previously insensitive afferents contributes more than half of the afferent inflow into the spinal cord; 2. an afferent barrage from visceral C-fibers is a more effective trigger to induce central changes than the cutaneous counterparts (19); 3. NMDA receptors are already involved in nociceptive processing so does not require removal of Mg2C ion for activation; 4. NGF is pivotal to peripheral and central sensitization, and the majority of visceral primary afferents express the NGF receptor, trkA (6).

Referred Pain A classical feature of visceral pain is its localization to distant superficial structures (muscle or skin or both) innervated by the same spinal nerves as the affected viscus. This referred pain may also be associated with hyperalgesia, which develops slowly and may persist after inflammation has resolved. Visceral and somatic primary sensory neurons converge onto common neurons in the deep dorsal horn of the spinal cord. Activity in the ascending projections from these cells could be misconstrued as originating from the somatic structures. Although this “convergence-projection” theory readily explains the segmental nature of referred pain, there is no explicit explanation of referred hyperalgesia. The “convergence-facilitation” theory proposed by Mackenzie states that noxious activity could give rise to an “irritable focus” in the spinal cord [MacKenzie, 1909, referenced in (1)]. Segmentally appropriate somatic inputs would be activated by this irritable focus to produce abnormal referred pain sensations. This theory concurs with the observation of delayed onset of referred pain as the irritable focus is developed. Particularly germane is that this account shares many features of central sensitization, a mechanism of major importance in hyperalgesia and persistent pain (9). Instances of a comparable visceral facilitation are exemplified by the electrophysiology of dorsal horn neurons responding to stimulation of the pelvic nerve after bladder inflammation. Not only do background activity increase, thresholds decrease, and novel mechanosensitivity develop, but the somatic receptive fields enlarge or show reduced thresholds. However, Mackenzie’s theory does not explain all features of referred pain, such as the clinical observation of immediate onset of referred pain before an irritable focus would have time to develop. Clinically relevant symptoms supporting convergence-facilitation is observed in patients with ureteric obstruction. Not only do these patients exhibit a referred hyperalgesia but this hyperalgesia persists after removal of the ureteric stimulus. There is often evidence of a persistent referred hyperalgesia years after stone elimination. An animal model of visceral pain analogous to the clinical scenario demonstrates a novel referred hyperalgesia in a superficial and segmentally appropriate structure (the external oblique muscle of the abdominal wall). A direct linear correlation was found between “pain” experienced (using a behavioral measure) and the degree of referred muscle hyperalgesia. Clinically, the degree of referred hyperalgesia correlates with the number of episodes of colic provoked by upper renal tract stones (20). POTENTIAL NOVEL TREATMENTS Cannabinoids and Visceral Pain Cannabinoid (CB) agonists act via specific G-protein linked receptors. Evidence in animal models and patient populations may support the use of such agents in both inflammatory and neuropathic pain states (21,22). These agents might be useful in visceral pain conditions. In animal models, CB receptors have been demonstrated in both peripheral tissue (including bladder and uterus) and central nervous system sites. Furthermore, administration of specific CB1 and CB2 receptor antagonists is known to inhibit pain-related behavior and features of visceral hyperalgesia in animal models of visceral pain (23). CBs also inhibit mast cell function and reduce release of proinflammatory degrannulation products. These include NGF which in

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turn precipitates further degrannulation, amplifying mechanisms of inflammation-induced peripheral and central sensitization. Clinically, mast cell activation is a key component of pain causes by interstitial cystitis and CBs could be analgesic by mast cell inhibition (12). In humans, CB agonists have been shown to be of use in the treatment of spasticity and neuropathic pain (24), but trials are awaited to demonstrate greater efficacy in the realm of visceral pain. Kappa Opioid Agonists and Visceral Pain Opioid agents act via a variety of cell surface receptors to induce analgesia, with those acting upon the kappa opioid receptor (KOR) potentially having particular use in difficult to control visceral pain. Several lines of evidence in animal models support this, including: 1. KOR deficient mice demonstrate no differences in response to pain in the somatic domain, but are particularly sensitive to that arising in visceral structures. 2. KOR are present on peripheral C-fibers and immune cells, leading to modulation of input to the spinal cord. 3. Agonists at the KOR inhibit visceral pain in animal models and humans (25). Until recently, the dysphoric and sedative central side effects have limited use. Now however, peripherally selective KOR agonists are under development, and may provide a new therapeutic tool for pain arising in the viscera. Many of the unique features of visceral pain can be explained by the anatomy, biochemistry, and physiology of visceral afferents and changes after inflammation. Visceral pain states are often driven by inflammation and the subsequent development of sensitization. Manifest as visceral hypersensitivity, sensitization is a recurrent theme of disparate visceral pain states. Therefore, the myriad components involved in visceral sensitization may offer targets for analgesia. REFERENCES 1. McMahon SB, Dmitrieva N, Koltzenburg M. Visceral pain. Br J Anaesth 1995; 75(2):132–44. 2. McMahon SB. NGF as a mediator of inflammatory pain. Philos Trans R Soc Lond B Biol Sci 1996; 351(1338):431–40. 3. McMahon SB. Are there fundamental differences in the peripheral mechanisms of visceral and somatic pain? Behav Brain Sci 1997; 20(3):381–91. 4. Cervero F, Laird JM. Visceral pain. Lancet 1999; 353(9170):2145–8. 5. Sengupta JN, Gebhart GF. Mechanosensitive properties of pelvic nerve afferent fibers innervating the urinary bladder of the rat. J Neurophysiol 1994; 72(5):2420–30. 6. Bennett DL, Dmietrieva N, Priestley JV, et al. trkA, CGRP and IB4 expression in retrogradely labelled cutaneous and visceral primary sensory neurones in the rat. Neurosci Lett 1996; 206(1):33–6. 7. Koltzenburg M, McMahon SB. Mechanically insensitive primary afferents supplying the bladder. In: Gebhart GF, ed. Visceral Pain. Seattle, WA: IASP Press, 1995. 8. Gebhart GF. Visceral pain-peripheral sensitisation. Gut 2000; 47(Suppl. 4):iv54–5. 9. Coderre TJ, Katz J, Vaccarino AL, et al. Contribution of central neuroplasticity to pathological pain: review of clinical and experimental evidence. Pain 1993; 52(3):259–85. 10. Ness TJ, Gebhart GF. Visceral pain: a review of experimental studies. Pain 1990; 41(2):167–234. 11. Lewin GR, Rueff A, Mendell LM. Peripheral and central mechanisms of NGF-induced hyperalgesia. Eur J Neurosci 1994; 6(12):1903–12. 12. Levi-Montalcini R, Skaper SD, Dal TR, et al. Nerve growth factor: from neurotrophin to neurokine. Trends Neurosci 1996; 19(11):514–20. 13. Dmitrieva N, Shelton D, Rice AS, et al. The role of nerve growth factor in a model of visceral inflammation. Neuroscience 1997; 78(2):449–59. 14. Maggi CA. Tachykinins as peripheral modulators of primary afferent nerves and visceral sensitivity. Pharmacol Res 1997; 36(2):153–69. 15. Laird JM, Olivar T, Roza C, et al. Deficits in visceral pain and hyperalgesia of mice with a disruption of the tachykinin NK1 receptor gene. Neuroscience 2000; 98(2):345–52. 16. Kamp EH, Beck DR, Gebhart GF. Combinations of neurokinin receptor antagonists reduce visceral hyperalgesia. J Pharmacol Exp Ther 2001; 299(1):105–13.

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17. Burnstock G. Purine-mediated signalling in pain and visceral perception. Trends Pharmacol Sci 2001; 22(4):182–8. 18. Yoshimura N, Seki S, Novakovic SD, et al. The involvement of the tetrodotoxin-resistant sodium channel Na(v)1.8 (PN3/SNS) in a rat model of visceral pain. J Neurosci 2001; 21(21):8690–6. 19. Olivar T, Laird JM. Differential effects of N-methyl-D-aspartate receptor blockade on nociceptive somatic and visceral reflexes. Pain 1999; 79(1):67–73. 20. Vecchiet L, Giamberardino MA, Dragani L, Galletti R, Albe-Fessard D. Referred muscular hyperalgesia from viscera: clinical approach. In: Lipton S, ed. The Pain Clinic. New York: Raven, 1990. 21. Pertwee RG. Cannabinoid receptors and pain. Prog Neurobiol 2001; 63(5):569–611. 22. Rice AS, Farquhar-Smith WP, Nagy I. Endocannabinoids and pain: spinal and peripheral analgesia in inflammation and neuropathy. Prostaglandins Leukot Essent Fatty Acids 2002; 66(2–3):243–56. 23. Farquhar-Smith WP, Jaggar SI, Rice AS. Attenuation of nerve growth factor-induced visceral hyperalgesia via cannabinoid CB(1) and CB(2)-like receptors. Pain 2002; 97(1–2):11–21. 24. Farquhar-Smith WP. Cannabinoids and pain: science and evidence. Pain Rev 2002; 9(1):41–67. 25. Riviere PJ. Peripheral kappa-opioid agonists for visceral pain. Br J Pharmacol 2004; 141(8):1331–4.

7

Gender and Pain Pushparaj S. Shetty

Imperial School of Anaesthesia, London, U.K.

Anita Holdcroft

Magill Department of Anaesthesia, Chelsea and Westminster Hospital London, Imperial College London, London, U.K.

Scientific inquiry into sex differences at the system, organ, tissue, cellular, cellular, and genetic levels has the potential to revolutionize the way in which we understand the biology of higher organisms (1).

INTRODUCTION It has become increasingly clear that powerful interactive genetic, physiological, anatomical, neural, humoral, psychological, lifestyle, and sociocultural factors contribute to differences between males and females in pain and its relief. The words “sex” and “gender” have been used to describe these differences, sometimes interchangeably and at other times with a different interpretation. The definitions used in this chapter reflect a North American interpretation based on a consensus document (Level V evidence) (2). Sex is defined as the classification of living things generally as male or female according to reproductive organs and functions assigned by chromosomal complement. Gender is defined as a person’s selfrepresentation as male or female, or how that person is responded to by social institutions on the basis of the individual’s gender presentation. However, this apparent separation of sex and gender is artificial because they interact, influencing each other and changing across the lifespan of an individual. Acknowledging interactive sex-gender differences helps improve our understanding of multiple factors that can contribute to specific circumstances of pain, thereby improving and informing clinical diagnosis and treatment. In experimental studies of normal individuals, women report lower pain thresholds, higher pain intensities, and less pain tolerance (Level III evidence) (3). In epidemiological research, studies describe similar pain reports from women compared with men such that women experience higher pain severity of longer duration, of higher frequency and present in more sites (Level IV evidence) (4). In these population studies the sex prevalence rate of some painful disorders changes with age. Of those with higher female prevalence, abdominal pain had a higher rate in women than men at all ages despite declining steadily over the age of 40 years. This pattern was consistent across countries, towns, and small communities but excluded menstrual pain. Thus if specific gynecological or obstetric problems are included in this rate, female prevalence may be increased further. MECHANISMS Multiple possible mechanisms for the biological-psychosocial model (5) are described. Sex Steroid Hormones Dynamic interactions between the nociceptive and neuroendocrine systems account for many of the differences in pain sensations but these responses have to be interpreted against factors that operate longitudinally throughout a person’s lifetime. For example, developments in reproductive maturation parallel the development of some types of pain, e.g., migraine.

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From fetal life to senescence, sex steroid hormones can influence all major body systems. This concept is illustrated from rodent experiments where testosterone exposure before birth or on the first day after birth is sufficient to enable males to regain their male phenotype as long as they are exposed to testosterone in adulthood whereas exposing females to testosterone soon after birth is insufficient to completely change them into male phenotype in terms of their sensitivity to pain and to morphine-induced analgesia. The testes mainly produce androgens and the ovaries estrogens and progestins, but, since testosterone is aromatized to estrogen, estrogen can be formed in the testes and testosterone is found in the ovary. The adrenal cortex also produces androgens in both sexes which can be aromatized by the liver and other organs. In the fetus, sex hormones have organizational, that is, genomic effects such that they influence not only gonadal development but also morphological and functional brain structure. These long-term effects persist during childhood and adolescence when growth and physical characteristics are dependent on the effects of sex steroids. Epidemiological studies reveal that during this time of puberty, pain disorders start to exhibit sex differences; however, it is also a time for gender-related activities such as psychosocial interactions so that the biological sex type and the behavioral gender type factors for pain coexist. After the menopause, when estrogen levels decrease, some site-specific pain conditions increase, e.g., joint and vaginal pains. Exogenous hormones such as hormone replacement therapy and estrogen creams have been used to treat these conditions. Interestingly, testosterone has been used to treat angina in older men. These effects do not solely depend on one specific hormone but on the duration of exposure or previous fluctuations of that hormone, exposure early in life and its concentration relative to other hormones in the peripheral or central nervous system function as well as lifestyle factors. Sex steroid hormones also have acute nongenomic activity and interact with the cell membrane through neurotransmitters and enzyme synthesis. Neurotransmitter systems that may be influenced by estrogen are reviewed by Aloisi (6) and include the cholinergic, glutamatergic, monoamine, serotonin, and opioid systems. A comprehensive list of those neurotransmitters that are influenced by reproductive status or hormone manipulations has been developed by Holdcroft and Berkley (5) to illustrate that both excitatory and inhibitory nociceptive systems can be activated. Apart from the variability of concentrations of sex steroid hormones in females compared with males that can influence experimental results, another interesting factor is that in females although estrogen levels are higher than in males, testosterone is much higher than estrogen yet at levels below those in males. These relative values in the concentrations of sex steroid hormones may have a functional role in that testosterone in females may be more important than previously considered. This diverse nature of response to gonadal hormones in humans can be illustrated by clinical evidence of androgen levels influencing the incidence of the muscle pains of fibromyalgia in women. It is postulated that the low androgen levels may make women more susceptible to fibromyalgia and modulate behavioral and neuronal responses to pain. Sex-Specific Organization The obvious differences between females and males are the characteristics of their pelvic reproductive structures that are mainly visceral, and their organized central nervous system control. Acute, recurrent, and chronic pains from the reproductive tract appear to be more frequent in women than men and include dysmenorrhea, labor, and postpartum pain, and pelvic inflammatory disease. The higher frequency may lead to sensitization in the nervous system which in turn contributes to the greater co-occurrence in women of other painful conditions, the so-called viscero-visceral and viscero-somatic hyperalgesia. Hyperalgesia is the perception of a painful stimulus as more painful than usual for a given stimulus. Sensitization can occur peripherally, e.g., in response to inflammation, or centrally in the spinal cord or higher centers. It is manifest by increased neuronal activity to a noxious stimulus that can continue long after the pathology has resolved, an expanded receptive field size and spread of hyperexcitability to the spinal cord and onto the thalamus and cerebral cortex. Afferent

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responses from skin, muscles, and viscera converge on spinal cord segments and if sensitization has occurred, there is widespread divergence of neural information from the periphery. The interactions between somatic and/or visceral afferents as a result of pathophysiology in the reproductive organs may influence functions in segments remote from the original site. Hence, in women during menstruation, cyclical muscle hyperalgesia may occur in sites distant from the reproductive tract. In men in a similar age group trauma-induced pain is more common because of gender-related lifestyle differences. In addition to sex organ differences, there are significant physiological distinctions as shown in Table 1. Variations in body composition can alter responses to drugs, and in women, endogenous and exogenous sex hormones induce cyclical fluctuations in protein binding, gastrointestinal transit time, thermoregulation, and creatinine clearance that can influence drug pharmacokinetics and pharmacodynamics. For example, alpha-1-acid glycoprotein levels are under the influence of estrogen such that levels decrease during pregnancy (sex-related) or hormone contraceptive use (gender-related) leading to more free drug availability, e.g., local anesthetics become more toxic. Stress, Anxiety, and Depression In humans, different types of stressors, such as trauma, abuse, and major life events, such as childbearing, influence nociception and pain responses. Stress-induced analgesia can recruit neurochemically distinct mechanisms of which the opioid and N-methyl-D-aspartate (NMDA) systems are predominant. In stress-induced opioid analgesia that has been investigated in rodents, the extent of sex differences in analgesia depends on the pain stimulus and the genotype of the rodent tested. The NMDA system is different in rodents to that of the opioid system such that an NMDA antagonist only blocks stress-induced analgesia in males and not females, yet the stress stimulus produces the same amount of analgesia in males and females despite there being similar NMDA neuronal circuitry. The key to the difference is in the “switch” to activate the system, i.e., estrogen. These findings have led to genetic studies to determine the mechanisms of sex differences. A candidate gene was the melanocortin-1 receptor, and it is homozygous in 60% of red-haired females making population screening relatively easy. The gene is expressed in brain glial cells, the locus coeruleus, and in the midbrain periaqueductal gray, all of which are known functional brain areas in pain modulation. In human experiments, women homozygous for the gene demonstrated greater analgesia to the kappa-opioid pentazocine. However, the linkage with the NMDA system cannot be demonstrated in humans. The locus coeruleus is a brain region that exhibits sexual dimorphism. It integrates sensory impulses from viscera, participates in autonomic nervous system activity, and has a role in pain inhibition. Autonomic nervous system responses are measured through alterations in blood pressure and stress hormones. Other integrative areas include the hypothalamicpituitary-adrenal axis. A directly released stress hormone, vasopressin, demonstrated sex differences in levels in rodents after visceral stimulation, and greater sympathetic responses to somatic pain have been reported in males compared with females and across all age groups (Level IV evidence) (7). Preliminary data in irritable bowel patients (a predominantly female population) suggest an altered stress response that also demonstrates sex differences. Although women are overrepresented in chronic pain disorders where stress and anxiety are factors in etiology, there are few in-depth studies. Psychological factors are well recognized TABLE 1 Physiological Differences Between Males and Females Physiological factor

Males

Females

Effect

Water content Fat content Muscle mass Blood pressure

Higher Lower Higher Higher

Lower Higher Lower Lower

Water-soluble drugs will have a larger Vd Fat-soluble drugs will have a larger Vd Drug distribution may vary Pain responses are inversely proportional to resting blood pressure

Abbreviation: Vd, volume of distribution.

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TABLE 2 Gender-Related Pain Assessment History: Major life events Reproductive status: Number of pregnancies; menstrual history, including menstrual-related pain; menopausal history Chronobiology, e.g., timing of pain complaints in relation to reproductive cycle Symptoms distant to the main site of pain Lifestyle risks Family history Abuse Psychosocial factors: Beliefs, catastrophizing, cognition (including emotion, attention, learning, and memory), coping strategies, cultural expectations, environmental organization, family history/expectations, gender of the interviewer, role obligations (gender identity), self-perceptions, socialization strategies Drug history: Past and present drug history, sex hormones (contraceptives, hormone replacement), dietary preferences (e.g., estrogen-containing foods), and complementary medicines Examination: Physical characteristics (weight/body mass index), signs that are distant to the main area of complaint Assessments: Psychological tests, anxiety, depression

to be associated with pain, but the relationship may not be directly causational. One explanation is socioeconomic because women do not always find well-paid jobs to match their level of education. For women, economic difficulties were highly associated with pain reports, yet unemployment was not a risk factor for pain in women. Table 2 lists a number of gender-related psychosocial factors that influence pain reports. Thoughts, attitudes, and behavior are linked with social constructs that alter responses to stress and may modulate both experimental and clinical pain. Several studies indicate that women are more likely than men to make use of and derive benefit from situational therapies, particularly those with a potential to change cognitive and behavioral aspects of the pain (5). Hence pain management should include an assessment of these features and therapies designed to enhance their positive effect, e.g., by cognitive behavioral therapy. In clinical pain management where females may report higher levels of anxiety and depression than males, a decrease in depression on treatment was associated with a larger social network. This result suggests that passive strategies may not be as successful in reducing symptoms as more active measures in females.

INDIVIDUAL PAIN DYNAMICS AND GENDER From the above conceptualizations of gender-related responses to pain, the net result for an individual is clearly influenced by major life events that are both unique and universally linked with the stages of human development. Body structure and brain functions that are established during fetal life gradually evidence themselves as childhood progresses. These factors, along with family lifestyle and schooling, all influenced by sociocultural sex roles, operate uniquely on each child, gradually producing sex- and gender-specific patterns of processing neural information. During puberty and adolescence, dramatic hormonal alterations exert their activating effects to rapidly produce enormous differences in body structure, physiology, and behavior, which add to childhood lifestyle influences. At this time, personal lifestyle patterns begin to be established, such as risktaking behaviors, occupational goals, social roles, and attitudes, toward injury and disease. Despite changing societal attitudes, it remains the case in nearly all cultures that women still predominate as caregivers and organizers, with wide-ranging obligations and duties spanning family and workplace realms. In contrast, men still predominate in focused, aggressive, and physically demanding occupations and/or leisure activities with a relatively narrower range than women of social obligations. For women, these differences may be exaggerated by repetitive cycles of dysmenorrhea and parturition. The severe dysmenorrhea suffered by a substantial number of women induces a constant and generalized muscle hyperalgesia, and can amplify other painful conditions such as those associated with the gastrointestinal, urinary, or reproductive tracts. Parturition can precipitate or exacerbate painful neuropathies such as carpal tunnel syndrome and repeated parturition is associated with increased severity of postpartum pain.

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Following their fertile years women begin a 5- to 10-year period of gonadal hormonal alterations terminating in a sharp decline, while in men, there is a more complex phase of andropause. The net result is a decrease in many sex-gender differences. However, at all stages an individual’s endogenous hormonal activity can be pathologically or therapeutically altered. GENDER AND PAIN MANAGEMENT It is well documented that women with pain symptoms access the health care system at all levels more than men, consume more analgesic drugs and have a higher incidence of side effects from all types of drugs (Level IV evidence) (8). This epidemiological evidence for gender differences has led to calls for better levels of evidence of gender effects on outcome from drug and interventional clinical trials. It is only recently that strategies and methods for collecting the evidence have been agreed. Incorporation of data collection and analysis for reproductive status, sex hormone milieu, and gender into the design of studies will be a major advance. Clinical Assessment and Diagnosis Gender aspects of pain management may present in the community and into tertiary referrals. At all stages, an individual clinical assessment may identify factors and comorbidity related to gender; in the framework of pelvic pain comorbidity appears to have a greater prevalence in women. Thus the diagnosis of both sexes will be improved by considering not only the patient’s current presenting complaint but also the patient’s lifelong medical history. However, it is in the context of a multidisciplinary environment that specialized diagnostic procedures, such as psychological questionnaires, can be applied. Yet where pain is severe, the interpretation of these tests can be difficult, e.g., cognitive impairment in the context of pain and depression. Therapeutic Interventions The scope of therapeutic interventions relates to the expertise of the health care professionals who are managing the patient and may include psychological as well as physical (e.g., physiotherapy, nerve blocks) and pharmacological treatments if the patient receives multidisciplinary care. The interventions may be selected using gender-based assessments as listed in Table 2. In a randomized clinical trial of multidisciplinary care for back pain, results in women showed more improvement in outcome than men (Level II evidence) (9). This result may indicate that the interventions were more appropriate for women or that to benefit men the barriers which had prevented them from achieving the same outcome needed to be identified and overcome. There is ongoing debate about the choice of strong analgesics based on gender-related research. In animals opioids acting at the mu-opioid receptor are more effective in males than females. This contrasts with prospective studies in humans where postoperatively men consumed more than twice the amount of morphine as women (Level III evidence) (10). However, in other contexts women have been found to consume more than men, e.g., immediately postoperatively and in the community. The factors to consider in the interpretation of these studies are the timing of the therapies, the possible behavioral and side effects of the drugs that may limit patient-controlled drug delivery and differences in pharmacokinetics and pharmacodynamics. Unfortunately evidence from data obtained from opioid studies entered into number needed to treat (or number needed to harm) comparisons does not yet contain enough information to identify gender differences. However, as more data on humans become available and more accurate computer modeling governs drug infusions, adjustments of dosage by sex as well as by weight, and perhaps in future by reproductive status and supplemental hormone use, are likely to improve efficacy for the different classes of analgesics and adjuvants. Differences are likely to be measured for some new drugs if such factors are included in the study design of clinical trials. Finally, where drugs are used to manage pain, their side effects on sexual function may go unrecognized until the patient presents to a urogenital specialist. This aspect of pain

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management is particularly important to males because it is the male sexual performance that is most affected. Opioid drugs induce a state of hypogonadism through the hypothalamicpituitary-gonadal axis with low levels of testosterone that induces a reduction in libido and potency, mood disorders, and muscle wasting. Other analgesics, such as antidepressants and antiepileptic drugs, may inhibit ejaculation. In women, amenorrhea has been reported in association with intrathecal opioid use. REFERENCES 1. Pessin J, Marts SA. Sex, gender, drugs and the brain. Endocrinology 2005; 146(4):1649. 2. Wizemann TM, Pardue M-L, eds. Exploring the biological contributions to human health. Does Sex Matter? Washington, DC: National Academy Press, 2001:13. 3. Fillingim RB, Edwards RR, Powell T. The relationship of sex and clinical pain to experimental pain responses. Pain 1999; 83:419–25. 4. Unruh A. Gender variations in clinical pain experiences. Pain 1996; 65:123–67. 5. Holdcroft A, Berkley KJ. Sex and gender differences in pain and its relief. In: McMahon S, Koltzenburg M, eds. Wall and Melzack’s Textbook of Pain. 5th ed. Edinburgh/Churchill Livingstone: Elsevier, 2006:1181–97. 6. Aloisi AM. Sensory effects of gonadal hormones. In: Fillingim R, ed. Sex, Gender and Pain. Seattle, WA: IASP Press, 2000:7–24. 7. Jensen-Urstad K, Storck N, Bouvier F. Heart rate variability in healthy subjects is related to age and gender. Acta Physiol Scand 1997; 160:235–41. 8. Isacson D, Bingefors K. Epidemiology of analgesics use: a gender perspective. Eur J Anaesthesiol Suppl 2002; 26:5–15. 9. Jensen IB, Bergstom G, Ljungquist T, et al. A randomized controlled component analysis of a behavioral medicine rehabilitation program for chronic spinal pain: are the effects dependent on gender? Pain 2001; 91:65–78. 10. Chia YY, Chow LH, Hung CC, et al. Gender and pain upon movement are associated with the requirements for postoperative patient-controlled iv analgesia: a prospective survey. Can J Anaesth 2002; 49:249–55.

The Multidisciplinary Approach

I

t is well established that pain medicine should involve a multidisciplinary approach to the management of patients. Various models have been used over the past few years, and such models will continue to develop. However, at this point in time the most practical method for helping patients presenting with persistent urogenital pain in secondary care involves two stages. Firstly, good assessment by one or more specialists in the appropriate field (e.g., gynecologists, urologists, or dermatologists) to rule out specific treatable conditions. At this stage, early introduction of pain management strategies needs to be considered if a treatable cause is not likely to be found. This includes the use of appropriate medication as well as psychological techniques. The second stage involves, to a greater extent, the pain management team, with input from pain medicine doctors, psychologists, specialized nurses, physiotherapists, and sexologists, among others. The following section of this book discusses the multidisciplinary nature of pain medicine.

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Multidisciplinary Pain Management Teams Cathy Price

Pain Clinic, Division of Unscheduled Care and Cancer, Southampton University Hospitals NHS Foundation Trust, Southampton, U.K.

Pain that presents to specialist teams is by definition complex and multidimensional. Complex health care is increasingly provided by multidisciplinary teams. Thus, multidisciplinary working should be the norm. Physicians who are unused to working in a team environment may find it challenging. There is a need to respect professional boundaries, to allow each person a voice, and to make consensual, patient-centerd decisions. How does a doctor best contribute to the team? Considerable research has been undertaken in this area, most notably in the field of oncology. This chapter examines 1. strategies that promote collaborative working with patients; 2. strategies that enhance team performance; 3. methods that reduce errors within the team that might otherwise open the team to litigation. Education of teams is essential to achieve these aims (1). A sensible way of describing this issue would be to examine a typical patient journey. Prior to a referral for pain management, the patient usually will have been struggling to cope with high levels of pain, tried multiple attempts at pain relief, and consulted with health-care professionals both in and outside the health-care service for answers. A sense of hopelessness sinks in, with thoughts of a life never pain free being too much to endure. At this stage, it is difficult to concentrate, take in information, and communicate needs effectively. Many patients feel let down by the multiple health-care professionals from whom they have sought answers, and thus approach new faces with some hostility. They may feel bewildered and overwhelmed when encountering a full, multidisciplinary team. Frequently, the doctors in the team are viewed as the “ones with the answers,” and they may face considerable hostility and feel under pressure to provide the answers that patients are looking for. The team tends also to rely heavily on the physician both for explanations of a patient’s pain and to ensure that there are no other medical causes that might explain some, or all, of the patient’s pain. Medical input is usually needed and valued at the following points: & & & & & &

The beginning of the patient’s journey, i.e., the assessment When medicine management is necessary, and, again, medical input plays an important role. (However, pharmacists increasingly play an important role once a clear diagnosis is made.) When evaluating of the contribution of pain from coexisting diseases, e.g., endometriosis, with its multiple pain pathologies When medical reports on patients are necessary usually related to disability or provision of information on diagnosis and prognosis to third parties When referral to other services is made To start a discussion of coping styles

The doctor thus needs to support the team and work to the same model of care. The doctor also needs to have knowledge of the interventions that the team is carrying out so that any difficulties can be put into context for the patient.

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Skills necessary to work as part of a multidisciplinary team include the ability to communicate well and sensitively with the patient and team members. Such teamwork demands respect for nonmedical opinion and flies in the face of paternalistic traditional medicine. Flexibility of thought is required and communication skills are vital. STRATEGIES THAT PROMOTE COLLABORATIVE WORKING WITH PATIENTS A multidisciplinary assessment is increasingly the norm, and the patient will have seen other team members who have formed their own views. The physician is usually the last person to be seen at initial assessment and thus plays an important role at that point to summarize and conclude a management plan. The doctor-patient relationship may be an important influence on patients’ health outcomes and must be taken into account (2). Doctors on the team must therefore reassure both patient and staff that the patient is being treated by the right team and that the principal diagnosis is persistent pain rather than any other diagnosis. They are usually required to at least start trying to make some sense of the pain to the patient, although this may come much later and usually needs to be revisited. Without an explanation of the neurobiological mechanisms underlying persistent pain, and indeed prognosis, from a credible source, the rest of the team would find it difficult to proceed. Effective communication at this point by the doctor is vital to outcome. Frequently, patients are dreading the fact that this pain will be long-term, probably for the rest of their lives. Accordingly, sessions such as these should be viewed as “breaking bad news.” Doctors must therefore be skilled in doing this in a sensitive and effective way. Dealing with dashed expectations can be hard. Table 1 provides some strategies to manage the initial consultation effectively. The development of a trusting relationship with the specialist and the team is an important influence. Patients who feel cared for, understood, listened to, and given enough time are more prepared to accept their doctor’s recommendation (2). Patients frequently give cues that they require further information or wish to discuss relevant emotional issues. However, the cues are often subtle, and patients wait for the doctor to start talking about care before being more explicit about their concerns (3). Anxiety levels rise when patients feel they are not being heard. This anxiety can interfere with decision making and recall of

TABLE 1 Strategies to Manage the Initial Consultation for Someone with Long-Term Pain Manage expectations beforehand: Inform referrers (especially GPs) of the aims and outcomes from a pain service, i.e., management not cure. Provide written information on chronic pain and expected outcomes before the patient books an appointment. Direct them to other sources of information to back up your claims. Ensure that you know as much as possible about the person sitting in front of you beforehand. This includes previous treatments, psychosocial history, and an idea about his/her expectations. This can be done most effectively by asking for standard information from the referrer. Get an idea about their expectations and further information by asking patients to complete questionnaires beforehand. Go over these with another team member; a nurse is usually very helpful in identifying a patient’s concerns and expectations. Streamline bookings ask administration staff to flag potentially difficult consultations in advance; make the process of arriving there parking and so forth smooth. Better to keep the initial appointment to a minimum of difficulties, e.g., consider seeing them in a community setting. First impressions are important. Do you and your staff smile and make eye contact? Is the room well laid out? Is there information available in the waiting area? Are there enough seats for family members? Consider preparing a list of frequently asked questions for patients. Research indicates that question prompt sheets can help patients ask about prognosis, promote recall, reduce anxiety, and shorten consultation time. All of this can be achieved if the clinician proactively addresses the prompt sheet with the patient during the consultation (5). At the beginning of the consultation, acknowledging the fact that it may be difficult and that the team recognize this will save time later. Set the agenda at the beginning and allow patients to be involved. Give permission to interrupt and ask questions. Assess the patient’s coping style if, as is usual, their coping skills are poor, then it is likely that further follow-ups will be necessary to develop a relationship before moving the patient on to treatment. Further assessment from a psychologist may often be necessary if coping skills are very poor. This may take some time. Acknowledging emotion is often very helpful. At the end of the initial consultation, summarize and provide written feedback. Abbreviation: GP, general practitioner.

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important information, lengthen consultations, and increase pain. There are a number of methods by which collaborative relationships can be fostered, patients’ concerns made explicit, anxiety reduced, and decision-making streamlined. Defining clear goals, identifying potentially difficult areas, understanding how pain fits into their life, and managing expectations will often foster a better relationship where information can be shared and outcomes improved. Matching Consultation Styles to Individual Patient Needs One study examined the need to change consultation styles to effectively manage patients who were either “active” or “passive” in presentation style (3). There were distinct differences between active and passive styles. Both tended to be dealt with effectively by the doctor. Allowing the active patient to feel in control was a particularly successful strategy. In the more passive patients checking and rechecking the patient’s understanding, responding to her salient emotional cues, normalizing distress, and discussing coping strategies were particularly effective.

Active Style Let the patient direct most of the consultation interject only at important stages Ask permission to take back control Present choices Give plenty of information Invite feedback

Passive Style Minimize information giving Slow consultation down Check understanding Bring back Normalize distress Discuss coping

There are some strategies that will lead to poor outcomes and should be avoided at all costs! Table 2 summarizes these (4). STRATEGIES THAT ENHANCE TEAM PERFORMANCE Effective pain management is a team game. The power of the team is greater than the power of the individual. Patients often report that the critical factor was that a clear single consistent message was given to the patient. Regular team meetings enhance performance. These should discuss individual patients and overall strategy. The advantages are the following: 1. 2. 3. 4.

Effective treatment approaches are likely to be considered Innovation is more likely to occur Better use of resources—less duplication of effort Improved detection of emotional needs

TABLE 2 Strategies that Lead to Poor Outcomes in a Consultation How to fail in a consultation Not engaging losing eye contact, fiddling and inattention, unnecessary interruptions Using closed or leading questions, e.g., You don’t have any pain, do you? Offering standard explanations these are effective only if chosen well and executed creatively. When you launch into a prepared spiel or diagram of concepts you need to explain often, make sure you slow down and pretend you are thinking it through for the first time. Otherwise it becomes a mechanical move, is hard to follow, and lacks impact (and bores). Make sure this is relevant to the patient (e.g., in your case ) and refer back to his or her particular history. Moving too quickly into advice and reassurance before concerns have been fully expressed and clarified Not sharing a common language jargon obscures meaning, e.g., mechanical back pain implies a problem with anatomical structures to some rather than pain on movement.

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5. Less burnout 6. Fewer complaints The effectiveness of team meetings is enhanced by the layout of the room—circular rather than rows—and effective administrative support. This involves getting notes, notification of meetings, minute taking, and ensuring there are follow-up arrangements in place. Consent should be obtained for case discussion from the patient. A facilitator is usually necessary to ensure that everyone’s view is heard. Recognizing each other’s strengths is just as important as the particular background and expertise of the team member. One study revealed some key differences in the way in which different professionals interacted (5). Occupational therapists, physiotherapists, social workers (SW), and nurses rarely asked for opinions or more patient details. The consultant (the individual in charge of the medical team) tended to have high rates for asking for patient history, giving opinions, and providing direction. It was suggested that therapists, SW, and nurses need to proffer their opinions in teams more effectively if they are to be competent and committed patient-centerd practitioners. The facilitator should be aware of this. Recognizing that patients will need discussion outside these sessions is also important. STRATEGIES THAT REDUCE ERROR It is important that there are clear care pathways. Standard procedures for discharge must be in place. A clear, shared understanding of the patient’s problems needs to be explicit and available to each team member. Analysis of team skills allows clear understandings of the team’s capabilities. Allow for unexpected difficulties with treatment. Team meetings that permit thinking time are extremely important in this regard. It is also vital to record deliberations in these meetings. Recording treatment in shared notes also allows good communication, with clear goals of treatment established at an early stage. CONCLUSIONS Excellent patient outcome is the main goal of treatment by any team. This can only be achieved by appreciating that teamwork in pain management can be difficult and challenging. A harmonious working environment is necessary. This will come from respecting equality in skills and contributions made by all multidisciplinary team members and understanding how doctors fit in. If doctors are prepared to work on collaborative relationships both with patients and teams, better patient outcomes will result. REFERENCES 1. Hall P, Weaver L. Interdisciplinary education and teamwork: a long and winding road. Med Educ 2001; 35:867. 2. Kaplan SH, Greenfield S, Ware JE, Jr. Assessing the effects of physician–patient interactions on the outcomes of chronic disease. Med Care 1989; 27(Suppl. 3):S110–27. 3. Brown RF, Butow PN, Henman M, Dunn SM, Boyle F, Tattersall MHN. Responding to the active and passive patient: flexibility is the key. Health Expect 2002; 5(3):236–45. 4. Boyle F M, Robinson E, Heinrich P, Dunn SM. Cancer: communicating in the team game. Br J Nurs 1997; 6(17):1005–10. 5. Atwal A, Caldwell K. Do all health and social care professionals interact equally: a study of interactions in multidisciplinary teams in the United Kingdom. Scand J Caring Sci 2005; 19:268–73.

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Doctors and the Female Pelvic Pain Patient Ying Cheong

Academic Unit of Reproductive & Developmental Medicine, School of Medicine and Biomedical Sciences, The University of Sheffield, Sheffield, and Princess Anne Hospital, University of Southampton, Southampton, U.K.

R. William Stones

Princess Anne Hospital, University of Southampton, Southampton, U.K.

INTRODUCTION In clinical practice, many women with chronic pelvic pain (CPP) turn out not to have any identifiable pathology despite having undergone multiple investigations. There is no consensus as to the best management for women in this group, and the majority will already have had an invasive procedure such as laparoscopy. When specific pathology is found, there is the further problem that it can often be coincidental. Although a multidisciplinary approach to diagnosis and care has been advocated as best practice, it is costly and not practical in most units in the United Kingdom, and many other countries, owing to a lack of specialists in this area and to resource limitations. As a consequence we see many of these patients undergoing a cycle of repeated consultations over many years with no effective management plan. The outcomes for both patient and medical practitioners in this area are often less than satisfactory. A number of reports have documented the experiences of patients with a range of chronic pain conditions when consulting their doctors, and also the medical perspective. Similar themes can be drawn from these studies: firstly, women with medically unexplained disorders, including women with CPP, have reported negative experiences during medical consultations. Accounts of being met with skepticism, lack of comprehension, feeling rejected, ignored, belittled, or blamed for their condition and assigned psychological explanations are common. Patients with chronic pain syndromes with no identifiable pathology find it “hard work being a credible patient.” As their expectations of a diagnosis and a medical explanation of their pain are not met, there is a vicious cycle of futile attempts to convince the medical practitioner that the pain is real and somatic rather than imagined or psychological. Secondly, many physicians view chronic pain patients as “heart sink patients” and often have a preconceived perception of these patients. There is a lack of time and interests in their conditions and an intense desire to order more investigations to find “something wrong” to help explain the symptoms, which eventually turn out to be unhelpful. In this chapter, we examine some studies that relate to the doctor-patient relationship in women with CPP. We attempt to summarize findings on medical attitudes in relation to chronic pain, CPP, and the influence of the medical consultation on pain outcomes. PHYSICIANS’ ATTITUDES TO CHRONIC PAIN CONDITIONS Attitudes Attitudes are strongly held beliefs that reflect opinions and feelings and can be manifested in behavior, defined as a learned predisposition to respond in a consistently favorable or unfavorable manner with respect to a given object. Attitudes are the enduring positive or negative feeling about some person, object, or issue (1). Attitudes can be expressed verbally or nonverbally in terms of behavior, and are often influenced by people, culture, and society. There is a general acceptance that an individual’s personality makes them susceptible to certain socializing influences and therefore to the development of certain attitudes. Attitudes can change through psychological processes that involve both thought and feeling. In a similar

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vein, doctors acquire attitudes throughout their training from their peers, teachers, and mentors. There are, however, many formal attitudes and behaviors expected of a doctor in general (2). There is, however, no formal learning designed for the formation, development, and change of attitudes in the medical education of doctors. Selfe et al. (3), through focus groups, explored gynecologists’ attitudinal constructs about pelvic pain in women and also tested the interaction among variables such as sex, ethnicity, age, and years from postgraduate training (3). Focus groups are facilitated interactive group discussions designed to tap into collective group experience that relies on group interaction. Themes common to all groups include the need to find a pathological cause for the pain. Time constraints and communication aspects were flagged up, while doctors raised the issues of psychological aspects of pain, patients are more unwilling to directly volunteer information. The themes from the respective focus groups are summarized in Table 1. Selfe et al. (3) also obtained questionnaire responses from 145 gynecologists selected from the register of Fellows and Members of the U.K. Royal College of Obstetricians and Gynaecologists. Five main factors were identified as the main attitudes of doctors towards women with CPP. These were labeled “efficiency” (related to value for money and making best use of resources), “complexity” (related to the idea that CPP is a difficult condition to treat), “socio-cultural liberalism” (related to conservativeness and openness in attitude), “pathology” (related to concern with finding pathology and disease), and lastly “communication.” Age and gender influenced attitudes: younger (!38 years), Caucasian women were more likely to be more open in their attitude and consider alternative therapies while young male gynecologists were more likely to be seeking specific pathology as an explanation for pain. Attitudes—The Impact of Knowledge and Training Attitudes can be influenced by the knowledge and training doctors have on the management of pain. Ponte et al. (2005) sought survey responses from 537 members of the West Virginia chapter of the American Academy of Family Physicians and had 185 questionnaires returned (35% response rate) (4). Respondents were predominantly male and the majority were between 35 and 54 years old. Eighty percent were anxious about prescribing high-dose opioids to patients with chronic nonmalignant pain, and 85% reported frustration when dealing with this group of patients. The feeling that treating patients with chronic nonmalignant pain is time consuming was found to be related to the practice setting: while 13% (nZ62) of solo practice TABLE 1 Themes Derived from Focus Group Meetings Exploring Physicians’ and Patients’ Attitudes and Experiences with Chronic Pelvic Pain Focus groups General practitioners

Hospital doctors

Patients

Themes Frequent mention of diagnosis of exclusion Provisional diagnosis made to justify patients’ symptoms as laparoscopy negative Visit generally too short to develop rapport and effectively communicate Lack of time Statements with negative connotations directed at hospital doctors and patients Importance of referral of patients to the right gynecologist Need to identify pathology, as then pain is real Clear awareness that anxious patients make the diagnosis more difficult Understand that patients do not want to be labeled mad Need to meet GPs expectations of finding some pathology Time constraints Worry of missing pathology Some other coping strategies necessary for the patient Expectations of diagnosis and cure Disappointed no diagnosis is made and feel fobbed off Should be referred directly to specialist by gynecologist rather than wasting time going back to GP to be re-referred Needed time to talk If not given medical explanation, patients imagine what may have happened in their body Feel silly when there is no pain when seeing the doctor

Abbreviation: GP, general practitioner.

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physicians felt that managing chronic nonmalignant pain is not time consuming, only 5.9% (nZ17) of hospital doctors felt the same. The survey also uncovered knowledge gaps in the areas of opioid administration. The majority of respondents felt that their formal medical training did not prepare them to effectively manage pain. Although the above study addressed a specific aspect of pain management in nonmalignant pain, there are many knowledge and training issues arising that are applicable to our discussion of CPP. Traditionally, medical students are taught to focus on the organic aspects of illness, and medical education stresses that “proper” medicine is primarily about objective disease states and organic pathology. The kind of diffuse problems related to chronic pain and chronic unhappiness are frequently troubling to doctors, both in hospital or general practice settings. Salmon, (2000), described this uncertainty of pathology and treatment as troubling for the doctor as it is not clear what, if anything, can be done and because clinical uncertainty about etiology and remedy threatens the authority upon which doctors rely to frame and enact knowledge and practice, and thus its outcomes (5). Bridging the Gap—The Importance of Consultation Styles and Communication The manner in which physicians communicate with their patients has been shown to be of significant importance for the outcome of the consultation. This has been demonstrated most extensively in relation to such measures as recall, satisfaction, and compliance (6–8). Other factors such as race and gender are also known to affect communication style (9,10). An interesting meta-analysis performed by Roter et al. (9) of 29 publications found that, in general, female physicians engaged in more active partnership behaviors, positive talk, psychological counseling, psychosocial question asking, and emotionally focused talk with the exception of obstetrics and gynecology, where they found the opposite (9,10). Male obstetrician and gynecologists were found in two studies in this meta-analysis to demonstrate high levels of emotionally focused talk compared with their female colleagues. They hypothesized that male obstetricians and gynecologists have altered their consultation style due to the increasing preference of women to see female obstetricians and gynecologists. Hence, they extrapolated that communication skills can evidently be improved given the right training and environment. Selfe et al. (3) examined the impact of consultation styles on the outcome in women with CPP in a longitudinal cohort study (3). They followed up 98 women after their initial consultation with the hospital gynecologists after being referred by their general practitioners. In this cohort, 12 (11.4%) had endometriosis, 10 (9.5%) had adhesions, and 15 (14.2%) had other significant pathology. No positive diagnosis could be deduced in 29 (27.6%). Thirty-four doctors undertook the consultations; 54 (52%) of the patients were seen by consultants, 19 (18%) seen by senior registrars, 18 (17%) by registrars, and 14 (13%) by senior house officers. In a multivariate model, they found that the individual doctor undertaking the consultation was shown to influence the severity of pain six months later. The rating of the initial consultation by the patient predicted pain resolution but only in those in who exercise was not impaired. They concluded that where illness is not overwhelming, there is more scope for the establishment of useful therapeutic relationship during consultation; where impairment is more marked, the impact of a positive consultation is not likely to be sustained. Interestingly, in this study, grade or gender of doctor was nonsignificant. Patients’ Expectations Robinson et al. (2005) performed a cross-sectional study on 110 patients referred to the University of Florida and the affiliated pain clinics with the objective of defining treatment success from the patients’ perspective. They found that patients with chronic pain do not always expect complete abatement of pain as successful treatment. They expected residual pain, fatigue, emotional distress, and interference of activity after treatment (15). As we discussed earlier, although physicians’ attitude can affect outcome in general terms, it is not possible to determine what specific attitude provides the best clinical outcome with patients, as patients’ expectations vary and there are uncertain links between attitude and actual behavior in the consultation. Some patients may want to have open, nondirective consultations, some more directive consultation styles. It is therefore essential for physicians to identify patients’

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expectations or preferences and then try to meet them, in order to attain “concordance” in communication. Direct evidence for the importance of meeting expectations came from a follow-up study of women seen in hospital clinics for CPP: the extent to which expectations were met was a prominent determinant of favorable recall of the initial consultation, when women were questioned six months later. The doctor’s affect was also important, but interestingly items related to information provision were nonsignificant (11). CURRENT—CHRONIC PAIN IN TODAY’S U.K. MEDICAL PRACTICE The rapidly evolving target driven context of the National Health Service in the United Kingdom provides limited opportunity for physicians to provide time and make emotional effort in the management of women with CPP and to deal with associated unhappiness. Physicians often find themselves needing to diagnose and manage patients within 10- to 15-minute consultations. Often, patients are brought back to the office or clinic because a single session is not enough to resolve the problem, but the patient often finds herself seeing another doctor at the next visit, thus increasing frustration. By contrast, evidence to show that a multidisciplinary team approach is of benefit in CPP come from Leiden, The Netherlands. Peters and colleagues advocated a multidisciplinary approach in the management of women with CPP (12). Their randomized, controlled trial showed that the multidisciplinary approach was beneficial, compared to a conventional approach, in terms of improvement of quality of life scores [Overall response (OR) 4.15, 95% confidence interval (CI) 1.91–8.99, nZ106] although the McGill pain score were not different in the two approaches (13). The study however also suggested a strong “functional” component in many women with CPP and that this group of women benefited from the “integrated” multidisciplinary treatment including psychotherapy. There are no other randomized controlled trials of treatment examining multidisciplinary care mainly because individual treatment effects would be difficult to dissect. Thus in general, trials for treatment of pelvic pain are conducted aiming at the examination of an individual medical or surgical treatment. The core elements of a multidisciplinary team will include a gynecologist and physician with special interest in pain management, a psychologist, a pain clinic nurse, and a physiotherapist. Figure 1 shows a typical referral and management flow chart for patients referred to our pain team. The multidisciplinary “package” in the United Kingdom, even when available, is quite varied but may include cognitive behavioral psychotherapy, nursing support (such as in between clinic times where medications need readjusting), and the use of complimentary therapy including acupuncture. In our unit, the team includes a gynecologist; a pain physician who is able to offer pain management advice, initiate analgesic and adjunctive medication, and undertake nerve blocks where appropriate; a clinical psychologist focusing on Investigations +/referral to pain team

1. Pain physician 2. Pyschotherapist for cognitive behavioral therapy 3. Specialist pain nurse 4. Physiotherapist

Gynecologist with special interest in pain management

Discharge or shared care with referral GP Chronic or acute admissions General practitioners

FIGURE 1 Flow chart of referral and management of women with chronic pelvic pain within the multidisciplinary team setting. Abbreviation: GP, general practitioner.

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cognitive behavioral aspects and a clinic nurse. Indeed, counseling supported by ultrasound scanning (14) was effective both in terms of pain scores (OR 6.77, 95% CI 2.83–16.19, nZ90) and mood: a negative scan provides much reassurance. There are important questions about the optimal use of this approach as it is time consuming and expensive. Realistically, many cases will continue to be seen by a single specialist. WHAT IS THE FUTURE? Clinicians need to be aware of the importance of medical consultation as a factor influencing patients’ outcome from investigation and treatment. While consulting styles reflect the individual personality of the doctor, we need to be aware of our own underlying attitudes and how these might enter into the dynamics of the consultation. When there is no clear organic cause, patients need to be given clear explanations which do not undermine the legitimacy of their pain or convey a message of dismissal. It is the authors’ view that patient with longstanding problem with pelvic pain requires an extended consultation time, and would benefit from a multidisciplinary style of management. Medical education needs to provide emphasis on personal awareness of attitude and training in communication skills. Consultation style that addresses these needs can be tested in role play scenario as in Objective structured Clinical Examination formats. Feedback can also be provided to students and junior doctors by video-recording and playing back consultations. Perhaps there is a need to integrate these assessments into the current Record of In-Training Assessment system for evaluating progress in training for specialist registrars in the U.K., and corresponding review processes in place in other countries. REFERENCES 1. Fishbein M. Readings in Attitude Theory and Measurement. New York: Wiley, 1967. 2. General Medical Council. Tomorrow’s Doctors: Recommendations on Undergraduate Education. London: GMC, 1993. 3. Selfe SA, Matthews Z, Stones RW. Factors influencing outcome in consultations for chronic pelvic pain. J Womens Health 1998; 7(8):1041–8. 4. Ponte CD, Johnson-Tribino J. Attitudes and knowledge about pain: an assessment of West Virginia family physicians. Fam Med 2005; 37(7):477–80. 5. Salmon P. Patients who present physical symptoms in the absence of physical pathology: a challenge to existing models of doctor–patient interaction. Patient Educ Couns 2000; 39(1):105–13. 6. Bertakis KD, Roter D, Putnam SM. The relationship of physician medical interview style to patient satisfaction. J Fam Pract 1991; 32(2):175–81. 7. DiMatteo MR, et al. Physicians’ characteristics influence patients’ adherence to medical treatment: results from the Medical Outcomes Study. Health Psychol 1993; 12(2):93–102. 8. Hall JA, Horgan TG, Stein TS, Roter D. Liking in the physician–patient relationship. Patient Educ Couns 2002; 48(1):69–77. 9. Roter DL, Hall JA, Aoki Y. Physician gender effects in medical communication: a meta-analytic review. J Am Med Assoc 2002; 288(6):756–64. 10. Roter DL, Geller G, Bernhardt BA, Larson SM, Doksum T. Effects of obstetrician gender on communication and patient satisfaction. Obstet Gynecol 1999; 93(5 Pt 1):635–41. 11. Stones R, Lawrence W, Selfe S. Lasting impressions: influence of the initial hospital consultation for chronic pelvic pain on dimensions of patient satisfaction at follow-up. J Psychosom Res 2006; 60(2): 163–67. 12. Peters A, Van Dorst E, Jellis B, Van Zuuren E, Hermans J, Trimos B. A randomized clinical trial to compare two different approaches in women with chronic pelvic pain. Obstet Gynecol 1991; 77(5):740–4. 13. Stones RW, Cheong YC, Horward F. Interventions for treating chronic pelvic pain in women. Cochrane Database Syst Rev 2005; (3):CD000387. 14. Ghaly A. The psychological and physical benefits of pelvic ultrasonography in patients with chronic pelvic pain and negative laparoscopy. A random allocation trial. J Obstet Gynaecol 1994; 14:269–71. 15. Robinson ME, et al. Multidimensional success criteria and expectations for treatment of chronic pain: the patient perspective. Pain Med 2005; 6(5):336–45.

10

Initial Assessment in the Pain Management Center Natasha Curran

University College London Hospitals NHS Foundation Trust, London, U.K.

Andrew Paul Baranowski

The Centre for Urogenital Pain Medicine, Pain Management Centre, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, U.K.

INTRODUCTION An assessment of urogenital pain often requires the input of an experienced consultant in pain medicine with a special interest in urogenital pain. The basic elements of the assessment are outlined in this chapter. THE REFERRAL LETTER TO THE PAIN MANAGEMENT CENTER The most relevant items of information to include are the following: 1. A brief history of the patient’s complaint 2. Any positive, and significant negative, examination findings 3. Detailed results of all investigations, for instance: cystoscopy findings; urodynamic studies; semen, urine, and vaginal microscopy/cultures; pelvic ultrasound; magnetic resonance imaging (MRI) and computerized tomography scans 4. A list of all physicians and professionals that the patient has already been referred to, with the outcome 5. Previous treatments and results of those treatments The most important, and frequently lacking, information from the referring professional is the results of investigations. Pain management consultants require all investigation results so that they are informed when talking to a patient. A patient who has been through a whole gamete of investigations is likely to feel frustrated and alienated if a new doctor has no idea what they have already been through. They may also question the validity of the consultation, loosing trust at the initial stage. The investigations are also used to aid in diagnosis and guide pain management. One may, for example, conclude that a normal urodynamics study is not noteworthy. However, in a patient with urinary hesitancy and poor flow, such results may suggest pelvic floor dysfunction. This dysfunction may be associated with pelvic floor muscle hyperalgesia and pain. A list of all professionals currently treating or having treated a patient, helps one to understand the types of assessments that have been undertaken. These specialists should also be copied on any future correspondence. All diagnoses should be qualified, such as “This patient has prostatitis, as evidenced by the presence of inflammatory cells in the semen,” or “This patient has a histrionic personality disorder, as diagnosed by Dr Smith based on.” Statements such as “All organic causes have been excluded” or “This patient is mad” (it does happen!) are unhelpful and unprofessional. Finally, it is imperative that a pain consultant have access to the patient’s medical notes for the consultation. A history of multiple unfounded “diagnoses” may suggest a personality disorder requiring further assessment by a psychiatrist.

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CLINICAL SETTING Assessing a patient in the PMC can remove a patient from the more “medical” environment, which may be beneficial (see Chapter 16). It is therefore useful if all investigations have been completed by this stage. However, if a patient has ongoing medical management for a condition such as endometriosis, it may be more appropriate to see them in the gynecological clinic. Whichever environment is chosen, liaison between services is very important. PHYSICAL ENVIRONMENT Ideally this should be a relaxed setting, which has ample space for private communication. A waiting area with reception staff, refreshments, and disabled access can also be helpful in making the patient welcome and relaxed. Such patients are more likely to discuss their problems with the team in an open way. PRIVACY There are clearly times when the presence of a partner or relative may be helpful, or not. There must be opportunity to allow this to change during the consultation. Most pain management consultants have a member of the nursing staff present during the history taking and examination to act not just as a chaperone, but to expand and explain information. It is useful to inform, the patient of this purpose. An additional person such as a pain management trainee may not be welcomed by an embarrassed patient, but if it can be explained sympathetically in writing beforehand that the institution trains experienced doctors in the complex nature of his type of pain, the patient is more likely to accept the trainee. Patients should of course feel under no obligation to do so. PAIN MANAGEMENT HISTORY Some questions may seem irrelevant to a patient, so it is often useful to explain this at the start of a consultation, particularly in potentially delicate areas such as their sex life or abuse, rape, and torture. A previous negative sexual experience may occasionally contribute to but not be the underlying cause of pain: take the case of a woman with pelvic pain who has been raped in the past. The rape may not be the cause of her pain, but if sexual intercourse results in pain, this may evoke unpleasant memories of the rape and contribute to her pain experience and distress. Clearly, there are complex issues in this area, and these are dealt with in detail in Chapter ZZZ by Dr Collett and ZZZ. Date of Onset and Factors Precipitating Pain Here it is useful to dissect the patient’s perceptions of any inciting events, for example, a fall, whether three months or three hours before the onset of pain, has different relevance. Cycles of Pain The pattern of pain may give clues to its origin. Pelvic pain associated with physical activity might suggest pain referred from the spine. Pain associated with the menses may result from endometriosis. Patterns of variation in the pain should be considered. For instance, the relationship to the presence or otherwise of the partner may provide some insight into an underlying problem within the relationship. Aggravating Factors One must ask about the relationship of pain to movement, exercise, posture, temperature, and time of day etc. Urination and sexual intercourse are dealt with specifically below. Factors which exacerbate pain may aide in diagnosis, and must be discerned specifically; for example deep dyspareunia which may indicate pelvic floor pathology is very different from superficial

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dyspareunia with allodynia. Pain exacerbated by sitting may indicate nerve irritation (pudendal nerve) or a prolapsed intervertebral disc. Relieving Factors Again, this can differentiate one condition from another. Patients with pudendal neuralgia obtain relief from their pain while sitting on a toilet seat but not a chair; stretching helps loin muscle pain, but not kidney pain. Associated Factors Factors associated with urogenital pain may suggest specific pathologies. For example, paresthesia (pins and needles), numbness, and increased sensitivity (allodynia or hyperalgesia) suggest a neuropathic cause. Sciatica may be an associated factor in patients with pelvic pain if a spinal problem causes S1 root irritation. On the other hand, sciatica could also be due to piriformis muscle dysfunction with the pelvic pain being muscular. Effect of Pain How does pain affect patient’s ability to work, sleep, look after themselves, and enjoy life? There are specific scales to ascertain if a patient’s anxiety and mood are significant, such as the Beck Depression Inventory and State and Anxiety Inventory (1,2). Previous Investigations and Treatment Received What was the benefit, if any, from each treatment? How much functional improvement was there, and how long did it last? The information gleaned is extremely important, as past treatment and benefit will guide future management. In patients with loin pain, for example, previous treatments aimed at the intercostal nerves may have produced a transient, but not long-term benefit. This suggests a spinal/paraspinal musculoskeletal cause for the pain. Such a response would open the possibility of future treatment with physiotherapy. Urological History In the pain management center (PMC), it is usually assumed that any urological problems have been or are being dealt with, but there remains a need to look at the history from a pain management point of view. Pain management questions asked pertain to these issues: 1. Day and night frequency and small or large volume of urine 2. Hesitancy—may be due to fear of pain on micturition or failure of the sphincters and pelvic floor to relax 3. Poor Flow—in the absence of any structural abnormality, may suggest pelvic floor dysfunction 4. Urgency—may be secondary to sensory hyperesthesia (due to central sensitization), pain, irritation, or fear of incontinence 5. Incontinence 6. Pis a deux—the sensation that the bladder has not emptied at first attempt

Gynecological History Important areas to cover include surgery or trauma to the urogenital system such as clitorectomy or circumcision, endometriosis (sites of lesions, treatment), adhesions (should be noted, but may not be of any significance), and menorrhagia and dysmennorhia [a history of which may affect perception of pain (3)].

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Sexual History This can be a difficult area, but it is important to find out which questions are relevant to the individual, and most patients are relieved to be asked rather than having to volunteer information. One must keep in mind that earlier sexual experience may or may not be important (Chapters 13 and 14), and that any patient may require a formal assessment by a psychologist. Possible areas to explore would be: Sexual orientation, and whether this is known to partner, friends, family Frequency of masturbation, sexual intercourse, masturbation by partner Sex outside of primary relationship Ease of erection, ejaculation, orgasm; impotence, failure to ejaculate, or orgasm How pain is related to sex e.g., on intercourse with partner, but not on masturbation, or different partner & Pain on vaginal (or rectal) insertion of finger, penis, or tampon. After what duration of intercourse (immediate having a very different meaning to after an hour of intercourse associated with delayed ejaculation) and if there is any difference depending on the position adopted during intercourse. & Sexually transmitted diseases: effect on person, family, fertility & Sexual abuse, past history of rape, torture & & & & &

An analytical approach to the sexual history may be necessary to separate the relevance of the response to these questions, and given the initial information it may be necessary to explore some areas in more detail. If a patient describes vulvar pain, for example, can she achieve a clitoral orgasm or not? This may be important for her and her relationship. What an individual patient considers to be normal is what the physician should be sensitive to and also consider normal, although it maybe outside what is generally consider to be so. Impotence and failure to ejaculate or orgasm may be due to a pain problem or an incidental condition that is psychological or secondary to treatment. Past Medical History Ischemic heart disease and diabetes (as well as other rarer conditions) may cause sexual dysfunction. Inflammatory and irritable bowel disease can cause and affect urogenital pain. This is particularly relevant if they have led to fistulas, stomas, or ongoing inflammation. Each condition that a patient has should be considered as a potential culprit or aggravator of pain. Too many conditions, and one must consider the basis of the diagnosis and possibly involve a psychiatrist. Drug History Many drugs will have an effect on the sexual experience (4), including some of those used to treat the pain and hence a good drug history is important (Table 1). Social History It is easy to underestimate the importance of this history, but it is worth spending some time here, as it gives the practitioner a full picture of the patient. Religious beliefs may alter the information offered by an individual and their acceptance of certain treatment options. Alcohol, smoking, and drug use may all affect sexual function. Occupation or hobbies e.g., cycling may be causal, or be affected by pain. Occupational stress may compound a pain problem, particularly if the pain is work related. Psychiatric History Mood and anxiety should always be assessed as mentioned previously. Past history must be elicited. Patients who display depression or other psychiatric illness may require referral to a psychiatrist and or psychologist.

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TABLE 1 Effect of Certain Drugs on Sexual Experience Nature of drug Antihypertensives

Examples Ganglion blockers (e.g., hexamethonium) Adrenergic neurone blocking (e.g., guanethidine) Beta blockers (e.g., propranolol) Alpha blockers Diuretics

Major tranquillizers Antidepressants Anticonvulsants

Phenothiazines and butyrophenones Serertonin reuptake inhibitors tricyclics [e.g., amitriptyline (used for pain)] Carbamazepine, gabapentin

Alcohol Cannabis Opiates

Morphine Tramadol

Effect with approximate incidence Impotence 100%; ejaculatory failure 100% Impotence 40 67%; ejaculatory failure 40 79% Orgasm without ejaculation may occur with guanethidine Impotence 5% Variable effect. Normal erection and orgasm but failure of ejaculation noted Variable effect. Impotence recorded. Menstrual irregularities noted Reduced desire, delayed ejaculation Reduced orgasmic sensation Delayed or inhibited ejaculation May block testosterone with testicular atrophy, gynecomastia, galactorrhea May inhibit ejaculation Increased desire and reduced inhibition at low dose; impotence, delayed ejaculation increasing with increasing doses Increased satisfaction (up to 80%); Impotence 20% Reduced desire Impotence Delayed ejaculation

Family History This may be relevant. For example, a female with interstitial cystitis may have relatives with the same problem. Examination This would include a full neurological examination and structural examination of the spine, pelvis, and hips. The entheses (tendon–muscle attachments) and muscle bodies are examined for tenderness. The entheses are of the: sacroiliac joint with gluteals; greater trochanter with hip abductors; ischial tuberosity with hamstrings; pubic tubercle with adductors, obliques, and rectus abdominus; and ischial spine with sacrospinous ligaments. The external genitalia are examined, and where relevant tested for allodynia. Vulvar pain is currently classified by sensory abnormality (5). Vaginal and/or rectal examinations, although assumed to have already been done by the referring doctor, are repeated, seeking evidence of tenderness around the pudendal nerve and within the pelvic muscles. Pelvic floor muscle function is assessed digitally. The patient’s response to the examination, may also give some understanding of their condition. INVESTIGATIONS The role of further investigation remains unclear. However, tests considered by the PMC could be & & & & &

MRI spine and/or pelvis; specific magnetic resonance pudendal nerve neurography; pelvic floor surface electromyography (EMG) (see Chapter 16); nerve conduction studies (pudendal); pelvic floor needle EMG.

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CONCLUSION The patient’s history will provide the pain management consultant with the best idea of what is causing the pain and the relevance of significant influences such as mood, sexual history etc. It is therefore of utmost importance that time and sensitivity are invested in this area. Further examination and investigation may confirm an initial diagnosis, and indicate how to proceed in the management of the pain. This may include referral to allied professionals. The following chapters will provide further information on specific pain entities. REFERENCES 1. Ku J, Jeon Y, Kim M, et al. Psychological problems in young men with chronic prostatitis-like symptoms. Scand J Urol Nephrol 2002; 36(4):296–301. 2. Ackerman M, Stevens M. Acute and chronic pain: pain dimensions and psychological status. J Clin Psychol 1989; 45(2):223–8. 3. Granot M, Yarnitsky D, Itskovitz-Eldor J, et al. Pain perception in women with dysmenorrhea. Obstet Gynecol 2001; 98(3):407–11. 4. Keene L, Davies P. Drug-related erectile dysfunction. Adverse Drug React Toxicol Rev 1999; 18(1):5–24. 5. Haefner H, Collins M, Davis G, et al. The vulvodynia guideline. J Low Genit Tract Dis 2005; 9(1):40–51.

11

Imaging in Pelvic Pain Chris Hare

Department of Imaging, University College London Hospitals NHS Foundation Trust, London, and Department of Imaging, General Hospital, Jersey, Channel Islands, U.K.

INTRODUCTION Imaging Modalities and Their Utility When imaging patients with pelvic pain, or, indeed, more particularly, suspected pudendal neuralgia, the clinician has a specific goal. Namely, is there a visible pathological abnormality of the nerve, and, if not, is everything else normal? This goal serves the purpose of reassuring the patient, and providing specific anatomical information about pain generators for the pain management specialist. Pelvic pain is a nebulous diagnosis and finding a discreet abnormality, which, if removed, would cure the condition, is rare. Imaging these patients therefore is as much about strategy as it is about making a formal diagnosis. Multiple imaging modalities are available. The cross-sectional ones, magnetic resonance imaging (MRI), computerized tomography (CT), and ultrasound are the most useful. MRI provides the most useful information about muscles, nerves, and soft tissue planes. CT is fast and can provide excellent contrast between bone, soft tissue, calcium, and any structures enhanced with either positive or negative contrast agents. Ultrasound has the highest spatial resolution of all the modalities and can be invaluable in targeting specific areas, i.e., anal sphincter, prostate, uterus, and ovaries. Ultrasound does tend to have the disadvantage that it is invasive, when used for best effect in the pelvis, and hence patients who are already in pain are less likely to accept it. As a single test therefore, MRI has the most to offer, with the added advantage of avoiding irradiating patients who are quite frequently still young and potentially fertile. This last point is important as the gonads are particular radiosensitive and the patient may have had many other scans and X rays already (1). This chapter aims to set guidelines for imaging with more specific detail on the pudendal nerve and the theoretical influences of anatomical variants in its compression. STRATEGY Most patients will have endured pain for some considerable time. They will probably have had multiple scans at other hospitals, perhaps in many institutions and may be even on many continents. The patients are often worn down and depressed and either very cynical about another scan or frightened about the potential findings. The thought of lying in an MRI scanner makes many already anxious people claustrophobic. Each scan should, therefore, start with the most comprehensive history the imaging clinician can obtain and with an explanation. Request forms with “Pelvic pain query cause?” as a clinical detail, while apparently addressing the essence of the problem are utterly useless. It is always the first step to review the old images when available. One may spot undiagnosed abnormalities, get an idea of the conditions chronicity, and decide what there is left to scan. The next step is to plan sufficient scanning time. Even though the yield may be small it is important not to rush. For those working in government hospitals, this will seem an unenviable task. Set aside 20 minutes before the scan to talk to the patient. This gives you an idea of their anxiety level and how much scanning

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they will be able to tolerate. One can then tailor their scans appropriately. Personally I also use this time to try to reduce the expectations of the patient that the “special” MRI scan will be the answer to all their problems; it will not. However, it is important to emphasize that the scan is an effective way of excluding a number of causes of pain, including sinister ones, prior to any trial nerve blocks. It is of great importance not to have this conversation in a busy waiting room, and to allow the patient to as many questions about the scan as makes them feel comfortable. It is also worth noting during this interview time in what position the patient will be able to lie still for the longest amount of time. Movement artifacts during MRI scans not only degrade the quality of the image but also lengthen the time of the whole scan by having to repeat certain segments. A well-informed, cooperative patient tends to provide better pictures.

AIMS OF THE SCAN The basic aim is to exclude any surgically remediable causes of pelvic pain and to help with the diagnosis of those conditions that may be helped by injection-type treatments. Having performed the interview prior to the scan, one should have a fairly good idea as to the type of pain one is likely to be dealing with and therefore to adjust the scan parameters accordingly. A good example is that of pudendal neuralgia. In this particular case, the course of the pudendal nerve is readily identifiable with modern MRI scanning techniques. The pudendal nerve origin is from the sacral plexus nerve roots of S2, 3, and 4 as they coalesce over the piriformis muscle, it then runs between coccygeus and the ischial spine and along the lateral wall of the ischial anal fossa and over obturator internus and can be readily examined by a combination of images in the coronal and axial planes. The aim of scanning this nerve in particular is to ensure that there are no sacral anomalies, masses in the pelvis pressing on the nerve, or abnormalities of the ischial spines compressing the nerve as it runs through the pelvic floor. At the same time it is also important to exclude conditions which may irritate the nerve through inflammation i.e., inflammatory bowel disease, perianal sepsis, prostatitis etc. A list of common causes of pelvic pain is shown in Table 1.

SCAN PROTOCOLS My own personal starting point for these scans is based on prior experience of imaging anal fistulae and perianal sepsis and dealing with pelvic floor problems in women who have had children. I start with a sagittal T2-weighted scan of the whole pelvis incorporating the natal cleft posteriorly to the pubis anteriorly and the bony side walls laterally. This allows a good general over view of pelvic anatomy, obvious large masses, sacral anomalies, pelvic floor weakness, and so on. If everything is normal, I perform coronal and axial T2-weighted scans TABLE 1 Common causes of pelvic pain Gynecological

Gastroenterological

Pelvic inflammatory disease Pelvic venous congestion Endometriosis Pelvic venous congestion syndrome Peritoneal adhesion Ovarian remnant syndrome Ovarian cyst Retroverted uterus

Irritable bowel syndrome Inflammatory bowel disease Malignant bowel disease Pelvic appendicitis Diverticulitis

Urological Urethral syndrome Interstitial cystitis Congenital anomalies Prostatitis

Neurological & musculoskeletal

Nonorganic psychosocial

Nerve entrapment syndromes Myofascial pain Low back pain Tumor infiltration Inflammation e.g. sarcoid

Depression Somatisation disorders Physical and sexual abuse

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along the line of the anal canal. This has a number of advantages. Firstly, one can evaluate the anal canal and the adjacent ischioanal and ischiorectal fossae for fistulae masses and sepsis. Secondly the axial sections tend to be along the line of the pudendal nerve as it courses along the lateral wall of the ischioanal fossa overlying the obturator internus muscle. The coronal sections if extended back to the posterior sacrum will show the proximal pudendal nerve roots as they coalesce from S2, 3, and 4. Extending anteriorly shows the prostate in men, and the vagina and urethra in women. Symmetry of the pelvic floor muscles can be evaluated in this plane. In men it is also important to include the testicles and penis. As a practical point, it helps to make sure the penis is in the midline with the tip pointing towards the umbilicus in order to make interpretation easier. There are specific protocols for penile imaging which are beyond the scope of this chapter. These basic scans should be performed at the best resolution that one can afford, a slice thickness of 5 mm should be the maximum. This takes at least 20 minutes, which may be as much as the patient can tolerate. Additional scans or enhancements to these basic sequences can be tailored to the patient after the initial interview. As an example, excellent rectal views can be obtained by inserting a 100 mL of ultrasound jelly into the rectum with a bladder syringe (2). This also allows for additional MRI proctography to be performed at the end of the study if necessary (Figs. 2 and 4). These scans allow the dynamic evaluation of the pelvic floor muscles in a single plane by utilizing sequences that have high signal to noise ratios, which when combined with a reduced matrix size and a large field of view, allow a movie to be created with frame rates of 1 to 2 per second. These sequences are not available on all scanners, the TRUFISPw from Siemens (Seimans Medical Imaging, Ehrlanger, Germany) is most commonly used and written about. MRI proctograms are an excellent method of looking at pelvic floor movement and excluding the presence of a rectocele or intussusception (3). Contrary to one’s normal instinct, it is possible to defecate supine, babies manage with ease, and all but the smallest rectoceles can be demonstrated (4). In the coronal plane it may also be possible to detect differences in the relative movement and thickness of the levator ani muscles. This may indicate the presence of atrophy or spasm (5). For those interested, an excellent review by Stoker et al. covers the whole area of pelvic floor imaging and evaluation by multiple modalities (6).

THE PUDENDAL NERVE In previously athletic men or women it can be worth performing high resolution, 3 mm or less, T1-weighted scans of the ischial spines in the axial planes to analyze their shape and possibly see the presence of direct pudendal nerve impingement. Numerous authors have proposed an anatomical etiology of pudendal nerve neuralgia (7,8). Briefly, as this is covered elsewhere in the book, one of the common features of pudendal pain is its exacerbation by squatting. This may be due to the remodeling of the ischial spines, which are traction apophyses, by the hypertrophy of the pelvic floor muscles. The ossification center of the ischial spine does note fuse until the mid 20s which is thought to make it more susceptible. It is thought that elongation and posterior rotation of the ischial spine during the athletic period of youth causes distortion of the course of the nerve through the sacrospinous and sacrotuberous ligaments such that the nerve is pinched or sheared at the extremes of movement caused by squatting. Recurrent trauma then acts as pain generator which prolongs the pain after the activity has ceased. One can see from Figures 1 and 2 that all these structures can be visualized. It remains difficult to actually show the nerve being pinched unless there is significant swelling and asymmetry between sides. At the moment I feel that this is at the limit of what is both practically possible, and important, as in the case of pudendal neuralgia, nerve blocks would be most likely to be used regardless of the shape if the history and clinical examination fit, providing the rest of the pelvis is free of other abnormalities. It is worth noting that prone CT scanning is a useful tool for guiding the nerve blocks and sufficient evidence exists that this technique is useful in demonstrating the existence of Alcock’s canal allowing it to be infiltrated with anesthetic (9).

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FIGURE 1 Axial 3mm T1 image of muscular male at level of ischial spines. The right ischial spine is elongated (short white arrow). The pudendal nerve can be seen between the sacrospinous and sacrotuberous ligaments just posterior to the spine (long white arrow). Note the difficulty of assessing the shape to determine compression at this point.

IMPROVING SCAN QUALITY Other general magnetic resonance (MR) techniques can be used to enhance the quality of the scans in the abdomen, namely paralyzing the bowel with Buscopanw (Boehringer Ingelheim, Ltd., Ingelheim, Germany) (hyoscine butylbromide, 20 mg intravenously) which stops the small bowel moving, and allows better analysis of the pelvic cavity. Angiograms can be performed

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FIGURE 2 Coronal 4mm T2 image of female pelvis just behind the ischial spines with aqueous jelly as rectal contrast (thick white arrow). The 10mm roots of the left sciatic nerve with their individual fascicles (three white arrows) are clearly visible in comparison to the 3mm pudendal nerve (small arrow).

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using intravenous contrast, which not only delineate vessels as small as the penile artery, but may also show up arteriovenous malformations, small tumors, and pelvic venous congestion. Scanning the patient with a full bladder facilitates analysis of the bladder wall for the presence of diverticula or bladder tumors. I have deliberately not made any specific recommendations about individual sequences. This is not through idleness but because each radiologist needs to tailor the scan to the machine and what he or she is familiar with looking at. Unlike CT or ultrasound scanners, each manufacturer’s MRI scanner, although working on the same physical principle, has proprietary sequences that are only available on that machine. IMAGE ANALYSIS Rather than provide specific sequences for specific pathologies, it is more useful to structure one’s image analysis. The following list outlines my personal method: Sacrum: asymmetry, anatomical anomalies, distorting masses Piriformis muscle segment: pelvic masses compressing pudendal nerve, asymmetry of pudendal or sciatic nerves, i.e., thickening or change in signal intensity, signs of inflammation in the pelvic cavity (free fluid abscess formation etc.). & Passage through the pelvic floor: compression of nerve by pelvic content, compression of nerve at ischial spine, asymmetry of coccygeus muscle, obturator or perineal hernias & Pudendal nerve canal in lateral wall of ischiorectal fossa: local mass or sepsis

& &

In Males & & & &

Penis: Peyronie’s plaques, fractures or masses Prostate size or inflammation Seminal vesicles: asymmetry absence or inflammation; congenital cysts Testicles: inflammation, hydroceles or masses; inguinal or femoral hernias

Female & & & & & &

Uterine or vaginal prolapse, rectoceles, urethroceles, urethral diverticulae, Gartner cysts Pelvic venous congestion Episiotomy or birth trauma causing a puborectalis muscle tears Endometriosis Ovarian cysts Post surgical complications (Fig. 3)

NB: Many women will have had previous transvaginal ultrasounds that will have excluded most of these abnormalities. LITERATURE-BASED EVIDENCE Due to the rather theoretical nature of the causes of pelvic pain, and the difficulty in defining specific pathology with anatomical abnormalities visible by radiological imaging, finding papers with high-level evidence is very difficult. The appearances of common conditions relating to solid organs are well documented i.e., ovarian masses, endometriosis, cervical cancers, perianal sepsis, rectal cancers etc. A simple Medlinew search for “imaging in pelvic pain” reveals a multitude of review articles. What is more challenging and hence less well covered are specific demonstrable pathologies relating to the compression or entrapment syndromes. Mauillon et al. published a

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FIGURE 3 Axial 5mm T2 image of female pelvis at level of ischial spines. The patient had severe pain following a trans-obturator tape (long white arrow) insertion six months earlier. Of note is the profound increase in the signal from the obturator internus and externus muscles on the left compared to the obturator externus on the right (small white arrow). The pudendal nerves are indicated posterior to the ischial spines (medium white arrows).

series of patients who underwent decompression of the pudendal nerve following trial nerve blocks and steroid injections. Imaging was only used for guiding the blocks and decompression only partially successful (10). Peripheral nerves are very small, and adequately visualizing one of these in vivo with current technology, is no small achievement in itself. One can use specific techniques such as MR neurography, which is in its infancy, to delineate segments of the larger nerves, such as the sciatic, and analyze their dimensions and presence or absence of any inflammation by using the contralateral side as a comparator. MR neurography, although not in common use, has been with us as a technique for several years. Filler, Howe, and Hayes outlined a technique to show an MR neurogram similar to that of a MR angiogram in the Lancet 1993 (11). Several other authors have described different techniques of high-resolution imaging using small field view, prolonged, and extremely localized scans using a combination of T1 and fat-saturated T2 pulse sequences (12). All of these imaging techniques have the common

Rectum Uterus 1 Bladder

FIGURE 4 Sagittal TRUFISP images from a supine female dynamic MR proctogram. The image on the left is at rest, with the white line indicating the level of the pelvic floor. During evacuation an anterior rectocoele (white arrow) forms, with considerable pelvic floor, uterine, and bladder neck descent.

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problem of requiring high-field scanners with phased array coils, and sequences allowing the production of high signal to noise ratio images. In the early 90s, these scanners were relatively few and far between, and hence the technique has been slow to catch on. Even with current machinery, detailed analysis of peripheral nerves can take up to an hour, and hence what could potentially be useful is limited by its impracticality. The majority of articles published on this subject describe imaging of larger nerves. These include the cervical nerve roots, brachial plexus, ulna, and medium nerve in the upper body, and in the lower limbs, the lumbosacral plexus, and sciatic nerve (13–15). Marvilla et al. have written an excellent review of the subject which is a highly recommended starting point for those who wish to know more about the subject (16). Part of the reason there is little literature available is that the actual definitions of the pathologies do not yet exist, i.e., pudendal nerve entrapment is a description of what one group of people thinks is the pain generator in pudendal nerve neuralgia. However, proving this to a level where the imager can say that there is pudendal nerve entrapment, and hence neuralgia, has not yet occurred. The “bottom line” here is that for things that have a high sensitivity and specificity in imaging they have to be rather obvious. CONCLUSIONS In some ways writing a chapter on imaging pelvic pain is simple as it is all rather subjective. In other ways this is rather unsatisfactory, because text book readers like to see lists of facts which can be acknowledged or dismissed by various investigative techniques in order to give a clear answer. Until the specific pathologies are adequately defined, so that imaging techniques can be honed, to categorically indicate whether a pathology is present or absent, then this subject will have to remain slightly vague. For that reason, concentrating on the psychological side of imaging as part of a general approach to the patient is as important as how the imaging itself is performed and what is found. As I have already indicated, the goal of the imager is as much to provide evidence, to enable the pain specialist to reassure the patient that there is nothing drastic going on within the pelvis, which is likely to shorten their life. It must be borne in mind, however, that no test is ever genuinely exclusive of pathologies, only exclusive of ones that can be readily visualized. REFERENCES 1. Hart D, Jones DG, Wall BF. Estimation of Effective Doses in Diagnostic Radiology from Entrance Surface Dose and Dose-Area Product Measurements. London: HMSO, 1994 (NRPB-R262). 2. Hare C, Renfrew I, et al. U.S. Jelly as Rectal Contrast Agent in imaging Rectal carcinoma. United Kingdom Radiology Conference 2002 presentation. 3. Lienemann A, Fischer T. Functional imaging of the pelvic floor. Eur J Radiol 2003; 47(2):117–22 (review). 4. Bertschinger KM, Hetzer FH, Roos JE, et al. Dynamic MR imaging of the pelvic floor performed with patient sitting in an open-magnet unit versus with patient supine in a closed-magnet unit. Radiology 2002; 223(2):501–8. 5. Guaderrama NM, Liu J, Nager CW, et al. Evidence for the innervation of pelvic floor muscles by the pudendal nerve. Obstet Gynecol 2005; 106(4):774–81. 6. Stoker J, Halligan S, Bartram CI. Pelvic floor imaging. Radiology 2001; 218(3):621–41 (review). 7. Robert R, Prat-Pradal D, Labat JJ, et al. Anatomic basis of chronic perianal pain: role of the pudendal nerve. Surg Radiol Anat 1998; 20:93–8. 8. Shafik A, el-Sherif M, Youssef A, et al. Surgical anatomy of the pudendal nerve and its clinical implications. Clin Anat 1995; 8:110–5. 9. Hough DM, Wittenberg KH, Antolak SJ, Jr., et al. Chronic perineal pain caused by pudendal nerve entrapment: anatomy and CT-guided perineural injection technique. AJR Am J Roentgenol 2003; 181(2):561–7. 10. Mauillon J, Thoumas D, Denis P, et al. Results of pudendal nerve neurolysis-transposition in twelve patients suffering from pudendal neuralgia. Dis Colon Rectum 1999; 42:186–92. 11. Filler AG, Howe FA, Hayes CE, et al. Magnetic resonance neurography. Lancet 1993; 341:659–61. 12. Filler AG, Kliot M, Howe FA, et al. Application of magnetic resonance neurography in the evaluation of patients with peripheral nerve pathology. J Neurosurg 1996; 85:299–309.

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13. Moore KR, Tsuruda JS, Dailey AT. The value of MR neurography for evaluating extraspinal neuropathic leg pain: a pictorial essay. AJNR Am J Neuroradiol 2001; 22(4):786–94. 14. Erdem CZ, Erdem LO, Cagavi F, Kalayci M, Gundogdu S. High resolution MR neurography in patients with cervical radiculopathy. Tani Girisim Radyol 2004; 10(1):14–9 (Turkish). 15. Kuntz C, IV, Blake L, Britz G, et al. Magnetic resonance neurography of peripheral nerve lesions in the lower extremity. Neurosurgery 1996; 39:750–7. 16. Maravilla KR, Bowen BC. Imaging of the peripheral nervous system: evaluation of peripheral neuropathy and plexopathy. AJNR Am J Neuroradiol 1998; 19:1011–23.

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Measuring Pain and Disability in Chronic Urogenital Pain Toby R. O. Newton-John

Innervate Pain Management, Hunter Specialist Medical Center, Newcastle, Australia

INTRODUCTION The pain literature is awash with self-report patient questionnaires. A clinician wanting to quantify the effects of a chronic, nonmalignant pain problem on his or her patient now has a vast array of instruments to choose from. These assessment devices range from multiaxial, comprehensive tools such as the Multidimensional Pain Inventory (MPI) (1), and the Profile of Chronic Pain: Extended Assessment Battery (2), to measures of one aspect of the pain experience such as disability [e.g., Pain Disability Index (3)], to syndrome-specific measures [e.g., neuropathic pain assessment tool (4)], to body site-specific measures [e.g., foot pain questionnaire (5)]. Turk and Melzacsk’s (6) excellent textbook on assessment methods in chronic pain lists well over 100 different questionnaires, rating scales, and self-report devices for use in pain assessment. Chronic urogenital pains are common in both men and women. For example, it has been estimated that about 10% of all outpatient gynecological referrals are for chronic pelvic pain (7), while more men were found to consult physicians for chronic prostatitis in one year than for prostate cancer (8). It is therefore surprising that instruments developed for the specific purpose of assessing the effects of chronic urogenital pain are rare. With the exception of the U.S. National Institutes of Health Chronic Prostatitis Symptom Index (9), which has been used in a number of epidemiological studies, researchers and clinicians in this field have needed to draw upon questionnaires and rating scales that were developed using nonchronic urogenital pain populations. Whether or not these assessments are failing to detect important aspects of living with chronic urogenital pain is of course not known, and the appropriateness of using instruments that have not been standardized on the population of interest has been questioned (10). However, qualitative data suggest that chronic urogenital pain can impact upon the sufferer in ways that are very similar to the effects of musculoskeletal pain (11), and information presented here indicates that a considerable amount of valid and reliable data has been gathered about the psychosocial effects of chronic urogenital pain using existing pain measures. In addition to standardized information that might be obtained as part of the clinical interview or examination, there are a number of domains that are routinely assessed psychometrically in chronic pain evaluations—pain intensity, disability and quality of life, and mood. In addition, information will be given regarding the assessment of issues especially pertinent to the chronic urogenital pain patient, namely sexual functioning and the impact of pain on family life. Each of these areas are considered in turn. One caveat to the following discussion applies, however. The term chronic urogenital pain is used to refer to chronic pain syndromes affecting the genitourinary systems. Obviously these systems are different for males and females, and hence the validity of reflecting upon gender differences in the pain experience, as is done with fibromyalgia or in spinal cord injury patients for example, is open to question. This limits to some extent the inferences that can be made regarding the psychosocial effects of chronic urogenital pain conditions. There is also the potential for some inconsistency in the literature, where for example the term “chronic pelvic

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pain” has been used to refer exclusively to women (12) but also exclusively to apply to men (13). In this chapter, sex differences will be made clear when referring to chronic urogenital pain affecting men or women.

PAIN INTENSITY In some ways, the patient’s pain intensity rating is the reference point around which interpretation of the rest of the assessment is based. Pain intensity ratings provide not only an important indicator of treatment success (but by no means the only indicator), but also a context against which the other psychosocial parameters may be evaluated. Pain levels and the effects of pain tend to correlate, such that lower average pain intensity is typically associated with less impairment in daily life due to pain and vice versa. Where there is a marked discrepancy from this, such as very high pain medication consumption with equally extreme pain intensity ratings, or little reported effect of pain on mood or function yet very high reports of pain intensity, the assessor may need to explore this further. For a psychobiological phenomenon as complex as the perception of pain, its assessment can be deceptively simple. Pain intensity can be measured using a visual analog scale (VAS), a numerical rating scale (NRS), or a verbal rating scale (VRS). The VAS consists of a line, usually 10 cm long, anchored at either end with extremes (e.g., “no pain at all” and “pain as bad as it could be”). The patient is asked to place a mark at any point along the scale to indicate his or her pain levels, and the distance from the endpoint to the mark becomes the rating, scored out of 10 or 100. The NRS by contrast involves asking the patient to rate his or her pain on a numbered scale from 0 to 10, 20, or 100, with the endpoints again anchored with the extremes of no pain at all and most severe pain possible. The NRS might be administered with numbers in a sequence, where the patient circles the relevant one, or can be done verbally (e.g., over the telephone) with the patient given just the numerical range and the endpoints. The VRS uses adjectives placed in order of severity (such as none, mild, moderate, severe, and very severe), with a number assigned to each adjective (0–4 in this case) to represent pain intensity levels. There are a number of statistical questions that have been raised over the use of VRS in particular, but also the NRS to some extent, in terms of their ratio-scaling properties. With a VRS, the interval between moderate and severe pain is considered to be the equivalent of the interval between no pain and mild pain—but are these intervals really equivalent in terms of human experience? Probably not. VAS adds a further step in terms of data collection by requiring line measurement and cannot be used over the phone, and the NRS has greater face validity in some cases. Whichever is used, it is important to be aware of the state-dependent nature of pain ratings (14), such that current pain levels greatly influence reports of average pain. A number of ratings over time, for example using a pain diary, offer a more valid overall profile rather than a single estimated average—particularly for pain disorders where the pain is episodic or cyclical. Electronic diary methods are also now available (15). An alternative approach to measuring pain intensity is to measure the qualitative aspects using the McGill Pain Questionnaire (MPQ) (16,17). In addition to the VAS and a 5-item present pain index, which give overall pain intensity ratings, the widely used short form of the questionnaire consists of 15 pain descriptors, such as gnawing, cramping, shooting, and sickening. The patient rates each descriptor from none (0) to severe (3), and a profile emerges of the sensory and affective dimensions of the pain experience. Onwude et al. (18) used the short form of the MPQ to examine pain ratings in 233 women following diagnostic laparoscopy for pelvic pain. The study hypothesis was that viewing a photograph of the pelvic findings at laparoscopy would improve the outcome for patients at six months post-surgery. The hypothesis was disconfirmed, but the sensitivity of the MPQ was demonstrated by its ability to detect changes in pain scores over a six-month period even in the untreated patient group. Yet another approach to pain intensity measurement is embodied by the Graded Chronic Pain Scale (GCPS) (19). This self-report measure is unique in that it samples not only pain intensity but also pain disability—the extent to which pain interferes with daily activities

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and the number of lost activity days such as being unable to attend school or work due to pain—within the one classification. There are four categories into which patients can be placed on the basis of their responses to eight items, from Grade I which is low disability/low pain intensity through to Grade IV, severe disability due to pain. Turner and colleagues (20) showed that approximately 20% of male patients with chronic pelvic pain attending primary care services or urology clinics were classified as having either moderate- or severe pain-related disability on the GCPS. DISABILITY AND QUALITY-OF-LIFE Following on from the above, it is clear that quantifying the effect that the pain has had upon different aspects of the patient’s life is another important dimension of pain assessment. In the musculoskeletal chronic pain literature, disability is typically associated with limitations or restrictions in mobility, i.e., the extent to which pain limits the ability to sit, stand, walk, tie shoelaces, and so on. Administration of a widely used but generic disability measure such as the Disability Questionnaire (21) may not be sufficiently sensitive to detect the limitations associated with chronic urogenital pain, and therefore other options must be sought. Heinberg et al. (22) used two subscales from the MPI (1), a 52-item, multiaxial pain assessment inventory, to assess disability in their mixed sample of chronic urogenital pain patients. The General Activity subscale consists of 30 items measuring the frequency with which a range of routine social, domestic, and recreational activities are carried out. The Interference subscale has 11 items and assesses the degree to which pain compromises performance of and satisfaction with various social and occupational activities. In this study, pain intensity ratings significantly predicted MPI-Interference subscale scores, and were the only significant predictors of MPI General Activity scores, underlining the importance of pain intensity assessment as a context for the evaluation of patient coping. Another type of disability assessment used with chronic urogenital pain conditions is the short-form Medical Outcomes Survey, in both 36-item (SF-36) (23) and 12-item (SF-12) versions (24). These questionnaires contain physical and mental health scales, which separate out the effects of ill health on physical activity levels and emotional functioning over the past month. The SF-36 and SF-12 are often considered to be quality of life measures (20), and their international use with many different illness groups, as well as age- and sex-based norms, means that a significant amount of comparative information can be obtained from them. There is also a free access website (25) where a large amount of data on these measures can be accessed. However, their usefulness as clinical outcome tools, and whether they possess sufficient sensitivity to detect treatment changes, has been questioned (26). FAMILY FACTORS AND SEXUAL FUNCTIONING Quantifying the effects of chronic urogenital pain on function and lifestyle requires a selective approach to the selection of assessment tools. For example, the Family Impact of Pain Scale (FIPS) (27) is a 10-item self-report scale designed to specifically assess changes in family functioning as a result of chronic pain. Exploratory factor analysis in the initial validation study revealed a two-factor solution for the measure: one related to limitations in physical functioning (e.g., “carrying out household tasks,” “participating in leisure activities”) and another related to communication with family members (e.g., “being involved in family decisions,” “communicating with family members”). Although it has not been used with a chronic urogenital pain sample to date, the items appear pertinent to the disability associated with these pain conditions. The FIPS contains one item relating to the effect of pain on sexual activity, and this is an area of assessment that a comprehensive evaluation of the chronic urogenital pain patient should also encompass. There has been much discussion on the association between a history of physical and/or sexual abuse and the development of chronic urogenital pain problems, and Savidge and Slade (7) have summarized much of this literature. Their thoughtful review exposes many of the methodological flaws and weaknesses in the experimental literature

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conducted to date, which has “found” a link between a history of abuse and chronic pelvic pain in men or women. Perhaps the most parsimonious view is that offered by the Royal College of Obstetricians and Gynecologists (28), who state that the relationship between abuse and chronic urogenital pain is a complex one, and that the experience of abuse may be a predisposing factor for the development of chronic pelvic pain in some women but not all. Nevertheless, an assessment of current sexual functioning is an aspect of quality of life evaluation that should be carried out routinely in this population. In female patients, the Female Sexual Function Index (29) is a well-validated, 19-item self-report measure of frequency and discomfort associated with sexual activity. For male patients, there is the Brief Male Sexual Function Inventory (30) which specially assesses erectile function, ejaculatory function, and overall satisfaction with sexual functioning. Considering that prevalence rates of sexual dysfunction in the heterogeneous chronic pain population are already as high as 73%, (31) a high rate of sexual difficulty in the chronic urogenital population is expected. MOOD Given all of the preceding factors, the psychometric assessment of mood is an obvious final aspect of the chronic urogenital pain evaluation. Biopsychosocial models of pain emphasize the reciprocal relationship between depressive mood and the heightened experience of pain (32), and it has been estimated that up to 50% of chronic pain sufferers would also meet the diagnostic criteria for major depressive illness (33). Furthermore, improving mood state in the context of ongoing pain is often a goal for chronic pain management interventions (34). The Beck Depression Inventory (BDI) (35) is the most widely used self-report questionnaire in chronic pain assessment, and its psychometric properties have been extensively tested (36). Its clinical value lies in part in its assessment of cognitions relating to low mood— items include beliefs about worthlessness and the frequency of self-critical thinking, as well as suicidal ideation. Strong endorsement of these items points to areas requiring further assessment. The major limitation of the BDI is the confounding of somatic items of depression with typical symptoms of chronic pain, such as poor sleep, impaired concentration, and lethargy, which can lead to an artificial elevation of the total score. However, recommendations for raising the cutoff score to indicate depression in the assessment of chronic pain patients have been made (37). Savidge and Slade (7) recommend the Hospital Anxiety and Depression Scale (HADS) (38) for use with chronic pelvic pain patients. Because the HADS was developed using medical rather than psychiatric patients, it overcomes the confounding problem inherent in the BDI. It also includes an anxiety subscale, which is valuable as a further dimension in the assessment of affect. The HADS has been rigorously psychometrically validated and used widely over a number of years (39). Finally, a newer mood scale with excellent normative data has begun to be used with increasing frequency in the chronic pain field. The Depression Anxiety Stress Scale (40) is a 42-item self-report questionnaire sampling the three domains of its title, and can be downloaded from the website (41) without charge. Taylor et al. (42) have usefully published means and standard deviations for 419 general population controls, 313 patients attending an outpatient psychology clinic, and 398 patients presenting for treatment of chronic pain, which allow for valid comparisons of scores across different patient groups. A 21-item version is also available which is equally psychometrically robust (43). PAIN BELIEFS Patient beliefs or interpretations of their pain—the ways in which they understand what is happening in their bodies and what the pain represents—are of central importance in understanding the emotional and behavioral consequences of the problem. According to cognitive behavioral theory (34), the cognitive “construction” of a given event will determine the ways in which it is responded to and what is felt about it. As DeGood and Tait (44) have said, “Maladaptive cognitions can lie at the heart of the chronic pain problem” (p. 321).

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One of the most important psychological predictors of pain experience to emerge in the past two decades is that of catastrophizing. This term has been defined as “an exaggerated negative mental set brought to bear during actual or anticipated pain episodes” (p. 53) (45). Factor analytic studies have indicated that catastrophizing is a single construct composed of three dimensions: magnification of the severity of the outcome, rumination upon the negativity of the outcome, and a sense of helplessness to influence the negativity of the outcome. In over 100 research studies, the tendency to think catastrophically about pain has been associated with heightened pain levels, greater disability levels, increased pain behaviors, increased use of health care resources, longer durations of hospital stays, and increased use of analgesic medications (45). Cognitive behavioral interventions that target the reduction of catastrophic thinking about pain are in turn associated with improvements in coping (46). Despite the extensive clinical and experimental investigation of the catastrophizing construct in chronic pain generally, it has not yet attracted much research interest in the chronic urogenital pain literature (47). It is relatively straightforward to assess—most studies use either the 6-item catastrophizing subscale from the Coping Strategies Questionnaire (48), or the 13-item extension of the original measure, the Pain Catastrophizing Questionnaire (49). Respondents rate the frequency with which they experience a range of catastrophic pain-related thoughts, such as “It’s awful and I feel that it overwhelms me” and “I feel I can’t stand it any more.” At the other end of the coping and adjustment continuum is the concept of self-efficacy. Self-efficacy is defined as the personal conviction that one can successfully perform specific behaviors in a specific situation (44). The Pain Self-Efficacy Questionnaire (50) is a 10-item questionnaire asking about the respondent’s confidence to carry out a range of activities (socializing, doing household chores, coping without pain medication) despite ongoing pain. Low self-efficacy has been shown to predict dropout from pain management programs (51), and to be associated with increased pain behavior in pain clinic attendees (52); however, the construct has yet to be explored in the chronic urogenital pain population. CONCLUSION This overview of psychometric assessment in the chronic urogenital pain population is by no means exhaustive. There are areas of assessment such as the use of coping strategies, personality profiles, marital satisfaction, and so on which are often explored in other chronic pain states but which were not presented here due to limitations of space. The material discussed here is intended to offer an outline of the most salient assessment issues pertaining to chronic urogenital pain, with a view to the busy clinician wanting to improve his or her patient evaluation in a standardized way. One aspect of psychometric assessment that is often overlooked is the therapeutic value that completing a concise, relevant set of questionnaires can provide. Given adequate explanation of the purpose and assurances regarding the confidentiality of their responses, patients often comment that reading and completing the measures prompted them to consider issues regarding their pain problem that they had not previously done. This can be an important precursor to a successful intervention. REFERENCES 1. Kerns RD, Turk DC, Rudy TE. The West Haven-Yale Multidimensional Pain Inventory (WHYMPI). Pain 1985; 23:345–56. 2. Ruehlman LS, Karoly P, Newton C, et al. The development and preliminary validation of the profile of chronic pain: extended assessment battery. Pain 2005; 118:380–9. 3. Pollard CA. Preliminary validity study of the pain disability index. Percept Mot Skills 1984; 59:974. 4. Bennett M. The LANSS Pain Scale: the Leeds assessment of neuropathic symptoms and signs. Pain 2001; 92:147–57. 5. Garrow AP, Papageorgiou AC, Silman AJ, et al. Development and validation of a questionnaire to assess disabling foot pain. Pain 2000; 85:107–13. 6. Turk DC, Melzack R. Trends and future directions in human pain assessment. In: Turk DC, Melzack R, eds. Handbook of Pain Assessment. 2nd ed. New York/London: Guilford Press, 2001:707–15. 7. Savidge CJ, Slade P. Psychological aspects of chronic pelvic pain. J Psychosom Res 1997; 42(5):433–44. 8. Luzzi G, O’Leary M. Chronic pelvic pain syndrome. Br Med J 1999; 318:1227–8.

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9. Litwin MS, McNaughton-Collins M, Fowler FJ, et al. The National Institutes of Health chronic prostatitis symptom index: development and validation of a new outcome measure. J Urol 1999; 162:369. 10. Turk DC, Melzack R. The measurement of pain and the assessment of people experiencing pain. In: Turk DC, Melzack R, eds. Handbook of Pain Assessment. 2nd ed. New York/London: Guilford Press, 2001:3–14. 11. Warwick R, Joseph S, Cordle C, et al. Social support for women with chronic pelvic pain: what is helpful from whom? Psychol Health 2004; 19(1):117–34. 12. Wesselmann U. Chronic pelvic pain. In: Turk DC, Melzack R, eds. Handbook of Pain Assessment. 2nd ed. New York/London: Guilford Press, 2001:567–78. 13. Luzzi G. Male genital pain disorder. Sex Relationship Ther 2003; 18(2):225–35. 14. Jensen MP, Karoly P, Huger R. The measurement of clinical pain intensity: a comparison of six methods. Pain 1986; 27:117–26. 15. Turner JA, Mancl L, Aaron LA. Brief cognitive-behavioral therapy for temporomandibular disorder pain: effects on daily electronic outcome and process. Pain 2005; 117(3):377–87. 16. Melzack R. The McGill Pain Questionnaire: major properties and scoring methods. Pain 1975; 1:277–99. 17. Melzack R. The short-form McGill Pain Questionnaire. Pain 1987; 30:191–7. 18. Onwude JL, Thornton JG, Morley S, et al. A randomized trial of photographic reinforcement during postoperative counselling after diagnostic laparoscopy for pelvic pain. Eur J Obstet Gynecol Reprod Biol 2004; 112:89–94. 19. Von Korff M, Ormel J, Keefe FJ, et al. Grading the severity of chronic pain. Pain 1992; 50:133–49. 20. Turner JA, Hauge S, Von Korff M, et al. Primary care and urology patients with the male pelvic pain syndrome: symptoms and quality of life. J Urol 2002; 167:1768–73. 21. Roland M, Morris R. A study of a natural history of the back pain, part 1: development of a reliable and sensitive measure of disability in low back pain. Spine 1983; 8:141–4. 22. Heinberg LJ, Fisher BJ, Wesselmann U, et al. Psychological factors in pelvic/urogenital pain: the influence of site of pain versus sex. Pain 2004; 108:88–94. 23. Ware JE, Sherbourne CD. The MOS 36 item short-form health survey. Med Care 1992; 30:473–83. 24. Ware JE, Kosinski M, Keller SD. A 12-item short-form health survey: construction of scales and preliminary tests of reliability and validity. Med Care 1996; 34:220–33. 25. http://www.sf-36.org (Accessed September 14, 2007). 26. Battie MC, May L. Physical and occupational therapy assessment approaches. In: Turk DC, Melzack R, eds. Handbook of Pain Assessment. 2ne ed. New York/London: Guilford Press, 2001:204–24. 27. Newton-John TR. The family impact of pain scale: preliminary validation. J Clin Psychol Med Set 2005; 12(4):349–58. 28. Royal College of Obstetricians and Gynaecologists. The initial management of chronic pelvic pain. Guideline No. 41, April 2005. 29. Rosen R, Brown C, Heiman J, et al. The Female Sexual Function Index (FSFI): a multidimensional selfreport instrument for the assessment of female sexual function. J Sex Marital Ther 2000; 26:191–208. 30. O’Leary MP, Fowler FJ, Lenderking WR, et al. A brief male sexual function inventory for urology. Urology 1995; 46:697. 31. Ambler N, Williams AC, Hill P, et al. Sexual difficulties of chronic pain patients. Clin J Pain 2001; 17(2):138–45. 32. Gamsa A. The role of psychological factors in chronic pain I. A half century of study. Pain 1994; 57:5–15. 33. Banks SM, Kerns RD. Explaining high rates of depression in chronic pain: a diathesis-stress framework. Psychol Bull 1996; 119:95–110. 34. Turk DC. A cognitive-behavioral perspective on treatment of chronic pain patients. In: Turk DC, Gatchel RJ, eds. Psychological Approaches to Pain Management: A Practitioners Handbook. New York: Guilford Press, 2002:138–58. 35. Beck AT, Ward CH, Mendelson M, et al. An inventory for measuring depression. Arch Gen Psychiatry 1961; 4:561–71. 36. Beck AT, Steer RA, Garbin MG. Psychometric properties of the Beck Depression Inventory: twentyfive years of evaluation. Clin Psychol Rev 1988; 8:77–100. 37. Geisser ME, Roth RS, Robinson ME. Assessing depression among persons with chronic pain using the Center for Epidemiological Studies-Depression Scale and the Beck Depression Inventory: a comparative analysis. Clin J Pain 1997; 13:163–70. 38. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand 1983; 67:361–70. 39. Jensen MP, Karoly P. Self-report scales and procedures for assessing pain in adults. In: Turk DC, Melzack R, eds. Handbook of Pain Assessment. 2nd ed. New York/London: Guilford Press, 2001:15–34.

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40. Lovibond PF, Lovibond SH. The structure of negative emotional states: comparison of the Depression. Anxiety and Stress Scales (DASS) with the Beck Depression and Anxiety Inventories. Behav Res Ther 1995; 33:335–43. 41. http://www.psy.unsw.edu.au/groups/DASS (Accessed September 14, 2007). 42. Taylor R, Lovibond PF, Nicholas MK, et al. The utility of somatic items in the assessment of depression in patients with chronic pain: a comparison of the Zung Self-Rating Depression Scale and the Depression Anxiety Stress Scales in chronic pain and clinical and community samples. Clin J Pain 2005; 21(1):91–100. 43. Henry JD, Crawford JR. The short-form version of the Depression Anxiety Stress Scales (DASS-21): construct validity and normative data in a large non-clinical sample. Br J Clin Psychol 2005; 44(2):227–39. 44. De Good DE, Tait RC. Assessment of pain beliefs and pain coping. In: Turk DC, Melzack R, eds. Handbook of Pain Assessment. 2nd ed. New York/London: Guilford Press, 2001:320–45. 45. Sullivan MJ, Thorn B, Haythornthwaite J, et al. Theoretical perspectives on the relation between catastrophizing and pain. Clin J Pain 2001; 17:52–64. 46. Vlaeyen JW, Morley S. Cognitive-behavioral treatments for chronic pain: what works for whom? Clin J Pain 2005; 21(1):1–8. 47. Masheb RM, Nash JM, Brondolo E, et al. Vulvodynia: an introduction and critical review of a chronic pain condition. Pain 2000; 86:3–10. 48. Rosensteil AK, Keefe FJ. The use of coping strategies in low back pain patients: relationship to patient characteristics and current adjustment. Pain 1983; 17:33–40. 49. Sullivan MJL, Bishop SR, Pivik J. The pain catastrophising scale: development and validation. Psychol Assess 1995; 7:33–44. 50. Asghari A, Nicholas MK. Pain self-efficacy beliefs and pain behaviour: a prospective study. Pain 2001; 94:85–100. 51. Coughlan GM, Ridout KL, Williams AC, Richardson PH. Attrition from a pain management programme. Br J Clin Psychol 1995; 34:471–9. 52. McCahon S, Strong J, Sharry R, et al. Self-report and pain behavior among patients with chronic pain. Clin J Pain 2005; 21(3):223–31.

13

Men and Urogenital Pain Andrew Paul Baranowski

The Centre for Urogenital Pain Medicine, Pain Management Centre, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, U.K.

INTRODUCTION The aim of this chapter is to look at men’s sexual health and its relationship to chronic pain of the urogenital system. To a certain extent this is a taboo area, often causing patients significant embarrassment. However, there is a strong suggestion that urogenital pain (UGP) affects sexual activity and therefore produces increased distress and increased psychological and sexual disability. To manage these problems clinicians must be aware of what is normal so that they can hold discussions with the patient in an informed manner. There is a significant amount of misinformation circulated within the popular press and during informal discussions, and this may be compounded by limited sexual experience of the patient and his partner. As a part of the process of managing the sexual problems, normalizing this information is important. Referral by a clinician to the appropriate specialist (psychologist, sexologist, or counsellor) must also be considered. DEFINITIONS In this chapter the following terms are used: Gender: the psychological perspective of sex difference and masculinity versus femininity Male sex: chromosomal gender with associated development of the classical male genitalia, both internal and external organs. MEN’S HEALTH—THE EFFECT OF SEX AND GENDER ON ILLNESS Men suffer premature death compared to women (1). It is suggested that the projected life expectancy for men in 2020 will be less than it was for women in the 1980s. This appears to be irrespective of race and country of abode (2). As one might expect, in certain countries over others men have a higher mortality risk. Being disadvantaged is certainly a predisposing factor with educational factors also being important—the less well educated are more likely to suffer illness. Being of the male sex (genetics and genitalia) will result in specific illness, such as prostate cancer (which has a lifetime risk of one in 13 in the United Kingdom). Gender (the psychological perspective of sex difference and masculinity versus femininity) not only has an effect on how and when the male seeks medical help but also on how the man sees himself in the light of his illness; those with a masculine outlook appear not only at greater risk of illness related to their lifestyles but are less likely to seek medical help when problems arise (3). MEN’S HEALTH—THE EFFECT OF ILLNESS ON GENDER IDENTITY In their paper, Kiss and Meryn (4) not only talk about the effect of gender on illness and illness behavior but also discuss the effect of illness on gender identity. Despite the subject matter being of significance to our patients, there is a limited amount of research available in this field. There is an even less literature on the effect of chronic UGP on male psychology, and this is

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despite the fact that UGP is not uncommon (the primary reason for attending an urology clinic when under the age of 50 years is for urogenital pain). There is good evidence that chronic pain affects sexual function (5). However, there is little research on the effect of chronic UGP on sexual function. Despite there not being much published data, many men in the UGP clinic will admit to avoiding sex due to lack of desire, arousability, potency, or sexual satisfaction as a result of pain. Others avoid sex because sexual activity results in increased pain. The importance of sexual avoidance is medically significant to these males as it is enforced celibacy and not through choice. Patients avoid seeking new relationships so that they do not have to face, among other things, the embarrassment of having to discuss the problem. Established relationships break down as a consequence of what must be multiple factors, the sexual dysfunction contributing. Sexual dysfunction heightens anger, frustration, and depression, all of which will place a strain upon a relationship. Interestingly, the important paper by Heinberg et al. (6) indicates that with symptoms such as depression, physical disability, and catastrophizing it is pain severity and site that explains variance in these more than patient’s genetic sex. Irrespective of the site of the pain (pelvis or back) or genetic sex, patients were depressed equally, with higher pain scores being associated with greater depression. Difficulty with coping (catastrophizing) and disability were greater with back pain. THE EFFECT OF NONCONSENSUAL SEX ON UGP The prevalence of childhood sexual abuse depends on country and culture but is thought to be between 3% and 16% (7). In the United Kingdom approximately 5% of males have been exposed to nonconsensual sex as children (less than 16 years of age) and approximately 3% of men have had similar experience as adults. Coxell et al.’s paper (8) indicates that nonconsensual sex acts are associated with a greater prevalence of psychological problems, alcohol misuse, and self-harm. Similar results were found in Canada (9). As one might expect, a wide range of other psychological consequences have also been recorded with an increase in antisocial behavior (10). Whether such nonconsensual acts predispose to chronic pelvic pain is unclear from the literature; however, the prevalence of nonconsensual sex in our UGP clinic, University College London Hospitals, is probably no greater than in the general population. As a consequence, we assume that there are many more significant mechanisms, other than abuse, producing UGP. Further evidence against abuse being a prime association with UGP can be gleamed from our psychologists. All patients with a history of a nonconsensual sex act considered by a patient to be an abuse are encouraged to discuss the matter with our psychologists. Of those where some form of nonconsensual sexual abuse has occurred, it very rarely appears to have been the trigger factor for the UGP. On the other hand, the pain can significantly stir up memories of the abuse causing significant psychological distress; patients often question the relationship of the pain to the abuse and may not be able to separate the two out. As a consequence, a history of abuse must always be considered (see Chapter 10). Victims of torture are frequently subjected to sexual abuse (11). These patients often represent a very complex group of people with multiple psychological and physical problems. To help these patients requires the support of many specialties. Often, psychologists have to “team up” to deal with both the issues of pain management and posttraumatic stress related to their torture. NORMAL SEXUAL ACTIVITY FOR THE MALE This section attempts to clarify what is normal sexual activity for the male. This area is a minefield! Much research has been undertaken, but much of it also has been criticized for not taking into account multiple confounding factors that will skew the results and may lead to misinterpretation of the data. The book Human Sexuality and Its Problems (12) interprets much of the data collected up till 1989 and it still serves as a good reference book. By understanding the normal, we can place into a population context the patient’s sexual history. “Neurosexology: guidelines for neurologists” by Lundberg et al. is another general review worth reading (13).

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Prior to the onset of the painful event the patient will have a past sexual history that will affect their perspective of their current sexual activity. That past history is important so that we can place the patient’s current sexual activity in the context of what the patient considers normal, hence the significance of taking a detailed past sexual history as well as current. The patient’s past sexual activity may have been outside of what is mainstream for the population but still within the rich variability of normal sexual activity. For the clinic setting what the patient tells you must be the starting point for what is considered to be the patient’s normal; for the medical establishment to vary from that “norm” may cause difficulties for all those involved in the patient care. Confrontation with facts from the literature often does not help. When change in a patient’s normal sexual function has occurred, there are two ways of managing it: 1. Return the changed current sexual function to the patient’s past normal. This is often what the patient is looking for. The patient often considers that the main problem is the pain, and if the pain is resolved sexual function will automatically return to the patient’s norm. There are two problems with this approach. First, resolving the pain may not be possible, and second, there is evidence that unless efforts are made to maintain normal sexual function during the presence of the pain, even if the pain is resolved, sexual function does not return to normal. 2. To work with the new level of sexual function. This is where a knowledge of what is normal in the general population may help. “Sexual behaviour and its medicalization: in sickness and in health” (14) is one of several important papers looking at how medical practice can generate sexually related problems when none exist. The paper serves to remind us to take care how we interpret the information on sexual function provided to us by our patients. When compared with population data and used appropriately, patients may be relieved to discover that they fall within a set of collective norms. On the other hand, some patients may be made to feel inadequate, or even deviant, despite there being no evidence for this. What is considered as socially acceptable sexual behavior can be published in the popular press as normal despite little evidence that it is normal. As a result sexual behavior outside the norm may be expected. When such responses fail, this may result in sexual dissatisfaction. There are large variations among cultures and countries (15). There is a strong association between sexual dysfunction and unsatisfying personal experiences and relationships. These factors must also be taken into account (16). Desire Desire refers to sexual interest or appetite. The term is descriptive similar to hunger. It refers to the amount of interest that a person has in sex and is a complex interaction between cognitive and affective processes, as well as neurophysiological mechanisms. Desire is probably a psychological domain in its own right, similar to mood. It is important to be able to interpret the information presented to the brain for desire to occur. Sexual desire will be affected by external parameters (social, environmental, and sensory cues) as well as intrinsic physiology (hormones) and psychological processing. As a consequence of the importance of psychological processing, mood, anxiety, cognition, and many other psychological conditions will affect desire. Pain interacts with all of these but probably also has a direct effect, itself reducing desire. UGP may have an even more negative effect on sexual desire than pain at other sites. What is normal desire is not clearly defined. There are three dimensions of the experience and each of these dimensions may be interpreted differently and weighted differently: cognitive desire (thoughts and internal imagery); affective desire (mood and emotion); and neurophysiological (which overlaps with arousability). These dimensions are complex in their own right. For instance, the cognitive dimension processes are subject to sociopsychological influences, the affective to psychological and biochemical factors, and the neurophysiological to biochemical, neurophysiological, and hormonal factors. In the United Kingdom, Mercer et al. (17) presented data on the self-reported prevalence of sexual function problems of heterosexuals. Approximately, 17% of men reported a lack of interest in sex that lasted at least one month in the past year. 1.8% reported a lack of desire that

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lasted for more than six months. The mean age was 33 (range 16–44) years. The group looked at a range of sexual dysfunctions: of relevance in this normal sample is that 32% avoided sex because of their problems. In another smaller study in the United Kingdom (nZ447 men, mean age 33 years), 6.7% reported lack of sexual desire (18). Nicolosi et al., collected data from 27,500 men and women from 29 countries. They concentrated on those of age 40 years and over. There was a country-by-country difference in the lack of interest in sex. In the Southeast Asia, 20% of men lacked interest compared with approximately 13% in the Middle East and Asia. In Europe and the Americas, lack of interest was 6% to 9%. There are many questions relating to the true representation of the sample questioned in this study. But it does illustrate that there may be country and cultural differences. Opposite to desire is sexual aversion. In the Nazareth et al. study, 2.5% men admitted to this problem. Desire is about appetite and does not always and in fact probably frequently does not lead to arousal. Desire is not a prerequisite to arousal. Arousability Is the state of heightened sexual awareness and finely tuned sexual physiological response that enables normal physical sexual activity to occur (12,13)? Arousal has both a central component and a peripheral component. It usually follows desire. However, a person may become aroused due to an increase in central information being perceived, despite not having had the desire. In the aroused male, the general peripheral responses include cardiovascular changes (raised blood pressure, raised pulse, raised skin temperature, and skin flushing), respiratory changes (increased tidal volume and rate), and pupilary dilatation. These sorts of changes are signs of alertness and not especially of sex-specific arousal. Penile erection normally should occur. However, there are degrees of arousability when a full erection may not occur. It is well recognized that men can be extremely aroused but without an erection. Also, erections may occur in the otherwise unaroused male. Arousal problems in male UGP patients may be central, peripheral, or both. There is not much information relating to this in the literature as most studies equate potency/erection to arousal and do not separate out the issues despite the obvious differences. Arousal to the pain scientist is interesting as it probably shares some of the neurophysiological changes also associated with central sensitization seen in a number of pain conditions. Potency Potency refers to the penile erection due to increased intravascular pressure within the penis (see Chapter 9). The ICD-10 classification defines male erectile dysfunction as “no erection or penis too soft for penetration.” According to this definition and the study of Nazareth et al. 8.8% of men mean aged 33 years are impotent (18). The Mercer et al. study (17) looking at selfreport in “sexually active men” of a similar age placed the figure at 5.8% and the Nicolosi study (15) a range of 8% to 22%. Erection may fail for many reasons. The common medical reasons include disease/ damage of the relevant peripheral nerves to the penile vasculature, diseases of the central nervous system, and vascular problems. The older male may require more tactile stimulation with erectile dysfunction increasing with aging (10% at 55 years, 20% at 60 years, 30% at 70 years, 80% at 80 years with complete failure). The turgidity is less with age, the refractory period increases, and it becomes easier to loose the erection. Alcohol and drugs may also affect the turgidity. Obesity and smoking are also related to impotence. Separating out the various causes of impotence is a complex issue made even more complicated by a patient suffering with UGP. To many men (and women) the erection is a sign of masculinity. Several papers have been published on the role of sildenafil and other similar drugs in the management of erectile dysfunction. These papers note a high incidence of: emasculation, depression, and lack of selfesteem associated with the impotence despite it being a common problem. Interestingly in the paper by Tomlinson and White (19), only 6 of 20 patients when treated successfully felt a return of their manhood and only 10 of 20 were happy, whereas 19 of 20 when sildenafil did not work

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suffered severe disappointment. To me this illustrates that the erection is only a part of the problem and that the psychological issues must be addressed. This again is important when managing the male UGP and no UGP clinic can function without a good team of psychologists. Sexual Satisfaction In the context of this chapter refers to the sexual ability, performance, and outcome (12). Usually sexual satisfaction is about the ability to achieve successful arousal and potency with the male obtaining sexual satisfaction for both himself and his sexual partner by psychological and/or physical stimulation, raising the arousal levels to the point of inevitability and orgasm resulting in a state of complete physical and psychological relaxation. Sexual satisfaction is complex as different persons have different expectations of the sexual act and at any one time even the same individuals will have different needs. It is often easier to define abnormalities of sexual satisfaction, such as inability to achieve orgasm and premature ejaculation (see below) than to define satisfaction itself. However, such an approach often oversimplifies the matter and a more comprehensive psychological approach may be more appropriate. Refractory Time Refractory time refers to the duration that has to elapse prior to arousal occurring following orgasm and the possibility of a further erection allowing penetrative sex (12). In young males this period may be a matter of tens of minutes whereas in the older male it may be many hours. The exact mechanism of the refractory period is not clear. Sexual arousal appears to be the psychophysiological correlate of windup and central sensitization. The sensory changes that occur in this physiological process appear similar to the pathophysiological processes associated with allodynia and hyperalgesia. The refractory period may thus be due to a loss of facilitatory neuromodulators and neurotransmitters. Another possibility may be that inhibitory pathways are activated to reduce the chances of multiple ejaculations reducing fertility. Like all sexual norms the refractory period can be very variable between individuals and even within individuals depending upon circumstances. What some patients consider abnormal may be normal for some men. Patients have attended the clinic where an increase in the refractory period has been a major concern; for instance, some male patients have found the loss of their ability to achieve orgasm several times a night distressing. In view of the refractory period, premature ejaculation may be a more significant problem for the male than delayed orgasm. Orgasm The mechanism of the orgasm is not clear (12). However, modern understanding of arousal as being related to central sensitization phenomena may give us a clue. Windup neurofacilitation appears to be important in generating this central sensitization and hence the importance of repeated stimuli (physical, auditory, visual, taste, and olfactory) in most cases of sexual arousal leading to orgasm. Normal touch sensations become more acute and pleasurable with increased neurofacilitation within the nervous system until the orgasm. Following orgasm and as a part of the orgasmic experience, the lack of inhibitory neuromodulation and the presence of the central sensitization results in light touch being perceived as a mixed sensation of sexual pleasure and pain. A part of the orgasmic sensation is thus due to the heightened perception generated by the central sensitization. This can be clearly linked to the penile (clitoral) and other cutaneous aspects of the orgasm. Certain other factors also need to be considered & &

The male can ejaculate without orgasm and He can have an orgasm without ejaculation. This may lead us to believe that the emission of semen is not the important factor (smooth muscle); on the other hand, some patients do

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complain of a “loss of quality” with dry orgasms, and thus emission is a component of the experience. & Progressive stimulation may produce increased arousal and central sensitization; however, when the reflex for ejaculation occurs (a separate neuropathway but linked to the arousal pathway) contraction of both smooth and striated muscles occurs. Ejaculation is achieved, and the sensory information from the pelvis is sent to the spinal cord where the process of central sensitization magnifies it, so the brain perceives an explosive force. In the presence of central sensitization, pelvic floor muscle contraction is probably responsible for a part of the orgasmic experience. This component is well described in women but less well recognized in men. Whereas the above may be perceived as purely academic, it does have significant consequences for the male with UGP. Firstly, for normal sexual function everything must click into place (12,13), the central sensitization must occur and the various physical responses must fire off in an appropriate order. In a pain patient this may not occur. Secondly, the multiple mechanisms at play mean that there are multiple factors that can go wrong (12,13). Explaining these points will help the pain patient regain some control over their sexual activity. Thirdly, the multiple mechanisms can be manipulated by a range of different physical and psychological techniques and the treating doctor needs to be aware of these. Work aimed at improving the facilitatory mechanisms and reducing the inhibitory mechanisms may provide the patient with improved sexual function. The doctor assessing the patient must be able to discuss these sorts of issues so that the patient can progress seamlessly from the pain medicine consultant to other members of staff for appropriate interventions. Premature Ejaculation Premature ejaculation is defined as ejaculation sooner than desired rather than ejaculation prior to an arbitrary time. It affects around 10% of the male population. There is an association with impotence, with the longer and more difficulty it takes to achieve an erection, the more likely premature ejaculation is. Satisfaction with intercourse is less likely if ejaculation occurs before 2.5 minutes of intercourse, the average time to ejaculation from the start of intercourse in normal males was around 5.6 (SD 0.9) minutes in the Rolanda et al. study (20). Other studies have placed the latency at three to five minutes (21). In a paper, retrospective postal questionnaire, the time was eight minutes. Fifteen percent of men with a latency of four minutes considered themselves to have a problem compared to 42% of men with a latency of two minutes. As well as latency, perceived control over the time of ejaculation and concern around the timing are issues that need to be taken into account. Therefore, individuals with a latency of eight minutes, but who feel a lack of control that concerns them, may consider themselves to have a premature ejaculation problem. There are age differences as one may expect. Treatment with phosphodiesterase inhibitors such as sildenafil (to encourage an erection with minimal stimulation) and an antidepressant such as clomipramine or paroxetine are said to be effective in the management of premature ejaculation. Psychosexual management may also be important. Inability to Achieve Orgasm It is considered a sexual dysfunction and can be more difficult to treat than premature ejaculation. Its management requires specialist psychological and sex therapy interventions in many cases. It affects 2.5% to 5.8% of the normal male population. One reason for mentioning it in this chapter is because of the relevance to women with chronic pelvic pain with dyspareunia (see Chapter 16). In women with dyspareunia, prolonged intercourse is more likely to increase the pain, methods of reducing the time to ejaculation are therefore important. One may speculate that men who take 20 minutes or longer to ejaculate with a regular stimulation may be predisposed to pelvic floor muscle dysfunction and pain as they strain to achieve an orgasm, though this is not supported by any evidence in the literature.

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TABLE 1 The Kinsey Report Survey of Penis Size in White College Males in the 1950s Length (in.) !4.00 4.01 4.50 4.51 5.00 5.01 5.50 5.51 6.00 6.01 6.50 6.51 7.00 7.01 7.50

Percent of men (%)

Cumulative percentage (%)

Girth (in.)

Percent of men (%)

Cumulative percentage (%)

0.5 1.9 2.8 15.1 31.9 23.1 15.2 4.7

0.5 2.4 5.2 20.3 52.2a 75.3 90.5 95.2

!3.00 3.01 3.50 3.51 4.00 4.01 4.50 4.51 5.00 5.01 5.50 5.51 6.00 O6.00

3.3 1.3 7.4 23.4 35.8 21.4 6.9 0.5

3.3 4.6 12.0 35.4 71.2 92.6 99.5 100

Note: The foreskin was retracted for uncircumcised men. The girth was measured midway along the shaft. Note that 52% of men more than half had a penis 6 inches or less when erect.

a

Normal Foreplay and the Use of Sex Toys Surveys suggest that foreplay (for around 20 minutes, depending on country) is ubiquitous and the use of sex toys (such as the use of vibrators) is normal for between 10% and 50% of a country’s sexually active population. The proportion using “toys” will depend upon relative wealth, social, education, and religious factors. This is important, when intercourse is not possible because of pain, patients must be aware that there are other methods that are normal, which can be used to maintain the physical relationship. Also, where pain reduces desire, there are a range of approaches that are used within the normal population, which can be used to improve the patient’s sex life. Anxiety The average penis size, while this may appear irrelevant, many patients do have concerns, and these concerns can result in psychological issues that compound the UGP situation (Table 1). Many male patients seen in our clinic have also had concerns about their genital anatomy and possible relationship with pain. Some of these concerns are obviously not relevant to the informed clinician, e.g., it is well accepted that one testis hangs lower than another, but in some patients this has been brought to our attention as a sign of a disease process. However, the relevance of hyper-retractile testis, varicoceles, and anatomical variations, such as with peyronie’s disease are more debatable. CONCLUSION An understanding of what is normal is an important prerequisite to understanding the person who presents as a patient with UGP. Appreciating that there is a wide variation in normality of sexual activity and response is equally important as is not having preconceived ideas (22). Failing to take onboard the sex side of a patient with UGP is failing to provide the patient with holistic care. Whereas specialist management may be required of sexually related symptoms (by a psychologist, sex therapist, or counsellor) the physicians and nurses involved in the patient’s care must be able to appreciate the concerns of the UGP patient relating to their sex, gender, and sexual activity; enabling a good rapport to develop is essential for a smooth transition of management between the specialists in the team helping the patient. Many, even quite senior, UGP medicine specialists avoid these issues relating to sex due to embarrassment, whereas most patients are only too pleased to be given the opportunity to discuss their concerns. REFERENCES 1. McKee M, Shkolnikov V. Understanding the toll of premature death among men in eastern Europe. Br Med J 2001; 323:1051–5. 2. White A, Cash K. The State of Men’s Health across Seventeen European Countries. The European Men’s Health Forum, 2003. (Accessed September 18, 2003 at http://www.emhf.org/index.ccm/ item_id/97)

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3. Banks I. No man’s land: men, illness, and the NHS. Br Med J 2001; 323:1058–60. 4. Kiss A, Meryn S. Effect of sex and gender on psychosocial aspects of prostate and breast cancer. Br Med J 2001; 323:1055–8. 5. Kwan KS, Roberts LJ, Swalm DM. Sexual dysfunction and chronic pain: the role of psychological variables and impact on quality of life. Eur J Pain 2005; 9:643–52. 6. Heinberg LJ, Fisher BJ, Wesselmann U, et al. Psychological factors in pelvic/urogenital pain: the influence of site of pain versus sex. Pain 2004; 108:88–94. 7. Johnson CF. Child sexual abuse. Lancet 2004; 364:462–70. 8. Coxell A, King M, Mezey G, et al. Lifetime prevalence, characteristics, and associated problems of nonconsensual sex in men: cross sectional survey. Br Med J 1999; 318:846–50. 9. Ratner PA, Johnson JL, Shoveller JA, et al. Nonconsensual sex experienced by men who have sex with men: prevalence and association with mental health. Patient Educ Couns 2002; 49:67–74. 10. Davies M. Male sexual assult victims: a selective review of the literature and implications for support services. Aggress Violent Behav 2002; 7:203–14. 11. Moisander PA, Edston E. Torture and its sequel—a comparison between victims from six countries. Forensic Sci Int 2003; 137:133–40. 12. Bancroft J. Human Sexuality and Its Problems. 2nd ed. London: Churchill Livingstone, 2002. 13. Lundberg PO, Ertekin C, Ggezzi A, et al. Neurosexology, guidelines for neurologists. Eur J Neurol 2001; 8(Suppl. 3):2–24. 14. Hart G, Wellings K. Sexual behaviour and its medicalisation: in sickness and in health. Br Med J 2002; 324:896–900. 15. Nicolosi A, Laumann EO, Glasser DB, et al. Sexual behaviour and sexual dysfuncions after age 40: the global study of sexual attitudes and behaviours. Urology 2004; 64(5):991–7. 16. Lauman E, Paik A, Rosen RC. Sexual dysfunction in the U.S.: prevalence and predictors. J Am Med Assoc 1999; 281:537–44. 17. Mercer CH, Fenton KA, Johnson AM, et al. Sexual function problems and help seeking behaviour in Britain: national probability sample survey. Br Med J 2003; 327:426–7. 18. Nazareth I, Boynton P, King M. Problems with sexual function in people attending London general practitioners: cross sectional study. Br Med J 2003; 327:426–7. 19. Tomlinson JM, Wright D. Impact of erectile dysfunction and its subsequent treatment with sildenafil: qualitative study. Br Med J 2004; 328:1037 (doi:10.1136/bmj.38044.662176.EE). 20. Rowland DL, Strassberg DS, de Gouveia Brazo CA, et al. Ejaculatory latency and control in men with premature ejaculation: an analysis across sexual activities using multiple sources of information. J Psychosom Res 2000; 48:69–77. 21. Kreutzer N, Sommer F, Klotz T, et al. Premature ejaculation—a study of average ejaculation time and overview of the literature. Aktuelle Urol 2001; 32(7):435–8. 22. Ramage M. Management of sexual problems. Br Med J 1998; 317:1509–12.

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Women and Urogenital Pain Caroline F. Pukall, Kelly B. Smith, and Katherine S. Sutton

Department of Psychology, Queen’s University, Kingston, Ontario, Canada

INTRODUCTION This chapter examines three common types of urogenital pain in women, vestibular pain syndrome (VPS), generalized vulvar pain syndrome (GVPS), and bladder pain syndrome/interstitial cystitis (BPS/IC), using a biopsychosocial model of chronic pain. The term biopsychosocial implies that the successful understanding and management of a health condition requires consideration of the biological, psychological, and social factors involved in disease and illness (1). According to this model, various physical, psychological, and interpersonal variables interact to influence one’s experience with chronic pain. In turn, one’s pain and related disability impact a patient’s psychosocial and physical well-being. In this chapter, the biopsychosocial model is used to highlight the various components of women’s experiences with urogenital pain. Diagnostic and assessment considerations of VPS, GVPS, and BPS/IC are presented; sexual, relationship, and psychological concerns are also highlighted. The chapter concludes with common difficulties encountered in clinical practice and guidelines on how to manage them.

UROGENITAL PAIN CONDITIONS: DIAGNOSIS Vestibular Pain Syndrome Vestibular pain syndrome (VPS) is the most common form of dyspareunia (i.e., painful intercourse) in premenopausal women (2), affecting 12% in the general population (3). Typically, women with VPS present with provoked, superficial dyspareunia. They report experiencing intense, burning/sharp pain in response to pressure localized to the vaginal entrance [i.e., the vulvar vestibule; (4)]. Although the most frequent complaint of a woman with VPS is that of dyspareunia, the pain can also be elicited by nonsexual situations, such as gynecological examinations and tampon insertion. Investigations of possible conditions leading to the pain (e.g., infections, dermatological conditions) are often negative, and even when conditions believed to cause the pain are treated, the pain may remain. Clinically, the diagnosis of VPS is based on a woman’s report of dyspareunia and is confirmed with the cotton-swab test, the standard gynecological tool for diagnosing VPS (5). The cotton-swab test consists of the application of a cotton-swab to various areas of the genital region; if pain is elicited during palpation of the vulvar vestibule, then the diagnosis of VPS is made. Generalized Vulvar Pain Syndrome A recent epidemiological study estimated that GVPS affects 6% to 7% of women in the general population, with a higher prevalence in women over the age of 30 (3). The diagnosis of GVPS is based on the description, quality, and location of the pain. GVPS is a noncyclic, chronic vulvar pain that may extend to the perineal, urethral, and rectal areas, typically characterized by the patient’s complaint of a burning sensation (6). The pain of GVPS occurs independently of stimulation, although light touch may exacerbate the pain. Some women with GVPS may also have VPS, but estimates of comorbidity have yet to be reported. McKay (6) recommends examining the skin for dermatoses and searching for infectious agents likely to

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cause inflammation. Assessing nerve function and the anatomical distribution of the affected area is also an important part of the evaluation. Bladder Pain Syndrome/Interstitial Cystitis The prevalence of BPS/IC is estimated to be 10 to 500 per 100,000 (7). BPS/IC affects women disproportionately: over 90% of cases affect females (8). It is a chronic condition of the bladder characterized by a high-voiding frequency and pain (9). Pain in the urogenital and pelvic areas is often intense and unremitting, and many women report experiencing dyspareunia (8). Although BPS/IC symptoms often vary, flare-ups are common and unpredictable, and can be so extreme that a woman may urinate 30 to 60 times within a 24-hour period (10). The level of pain reported during these flare-ups matches or exceeds that experienced in other chronic pain conditions, such as fibromyalgia and rheumatoid arthritis (10). The diagnosis is based on patient-reported symptoms, a sterile urine culture, and positive findings at cystoscopic examination of the bladder under anesthesia to assess for Hunner’s lesions (i.e., large reddened wedge-shaped lesions) or, more commonly, glomerulations [i.e., small petechial hemorrhages of the bladder wall; (8,11)]. UROGENITAL PAIN CONDITIONS: ASSESSMENT When assessing urogenital pain, the pain needs to be carefully characterized. Questions about the location, quality, onset, intensity, unpleasantness, and pattern of the pain are necessary to obtain comprehensive information about pain characteristics, and may serve as valuable factors for differential diagnosis and important indicators regarding outcome. It is also important to recognize that many women have limited knowledge of their genital/pelvic anatomy; a diagram is often helpful for localizing the pain. Pain location may also aid in differential diagnosis. For example, a woman with VPS can often be distinguished from a woman with GVPS based on the highly localized nature of the pain in VPS. The quality of the pain is an important differentiator as well: despite the fact that both pruritis vulvae (PV) and GVPS affect the same area, the “itching” quality of PV sets it apart from GVPS. In addition, asking about pain onset can reveal whether the pain is primary (i.e., lifelong) or secondary (i.e., acquired). This information may have implications for treatment outcome; it has been shown that women with primary VPS do not benefit as much from surgical intervention as those with secondary VPS (12). Obtaining information about levels of pain intensity may also have implications for treatment outcome. Chronic pain patients with higher pain intensity ratings benefit less from treatment when compared with patients with lower ratings (13,14). In addition to pain intensity levels, which serve as an indicator of the sensory aspect of pain (i.e., how strong is the pain?), it is important to gauge the level of unpleasantness resulting from the pain. Assessing unpleasantness can provide information about the affective component of pain (i.e., how much the pain bothers the patient) and may account for differences in the clinical presentation of some women. For example, some women with VPS may vocalize and move away from the painful cotton-swab palpation, whereas others may tolerate it despite high-reported pain intensity. Pain intensity and unpleasantness ratings are most commonly assessed on scale from 0 (no pain at all; not at all unpleasant) to 10 (worst pain ever; most unpleasant ever). It is also crucial to understand the patterns of the pain. For example: What makes the pain worse? What makes it better? Does the pain vary with the menstrual cycle? In which situations does the pain occur? Questions about specific activities that elicit the pain can be useful in determining if the pain is situational (i.e., occurs in one specific context) or generalized (i.e., occurs in all contexts). In order to investigate these patterns, a pain diary is useful for both the physician and the patient. Asking about pain characteristics not only provides useful diagnostic information, but it is also therapeutically beneficial because it validates the patient’s experience. Often, the pain is the last symptom that health professionals inquire about, if at all. Questions about past treatments, previous diagnoses, and remedies that helped or worsened the pain are also key in obtaining a complete picture of the problem. Furthermore, careful questioning about how the

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pain has affected the patient’s sexuality, relationships, psychological well-being, and overall quality-of-life will provide a more thorough understanding of the pain and may clarify potential treatment options.

PSYCHOSOCIAL ISSUES INVOLVED IN UROGENITAL PAIN Sexual Functioning The sexual consequences of urogenital pain cannot be ignored. The expectation or experience of repeated pain during penetrative sexual activity can affect all components of the sexual response cycle, leading to diminished desire, reduced arousal, orgasmic difficulties, and decreased frequency of partnered and solitary sexual activity (15). Pain during intercourse may lead to the avoidance of all sexual activities, even those that are not painful. This generalized avoidance may be due to fear that sexual activity will lead to penetrative activity and, therefore, to pain. Given that the patient’s goals for treatment often involve the reduction of pain and reestablishment of sexual functioning, it is important to target both of these components. Many clinicians erroneously assume that focusing only on decreasing the pain will reverse the sexual dysfunction; however, this is not necessarily the case. For example, women with VPS who underwent successful pain treatment reported lower levels of sexual functioning when compared with similar-aged women (16). In addition to pain, sexual functioning must be addressed, as it is difficult for the patient to break the long-existing, negative association between sex and pain. One way to address this issue in therapy is to encourage the patient to engage in nonpainful forms of partnered and solitary sexual activity. This suggestion may allow her to, over time, reconnect with the pleasure involved in sexual activity, without the fear of pain. Relationship Functioning Chronic pain conditions have a significant impact on interpersonal functioning and intimate relationships. Given the location and the chronic nature of the pain and associated sexual dysfunction, many women with urogenital pain present with decreased relationship adjustment (17–19). For example, patients may feel that they are less sexually desirable to, and less able to sexually satisfy, their partners (19,20). As well, patients may experience decreased relationship satisfaction as a result of engaging in painful sexual activity out of the fear that their relationship might end (19,21). Relationship factors also affect pain and treatment outcomes, thus, the inclusion of partners in the management of urogenital pain may be beneficial. Obtaining information about women’s relationships may help inform treatment options, clarify the impact of pain in patients’ lives, and increase understanding of the broader psychosocial context in which the pain exists. For example: In what ways has the pain changed the relationship? How does a woman’s partner respond to her when she is in pain? How are she and her partner coping with the pain and relationship changes? Such questions provide a sense of how pain impacts the relationship and vice versa, and helps determine the feasibility and potential value of certain treatments (e.g., sex and couple therapy). Clinicians may also want to inquire into any fertility and pregnancy issues that couples are experiencing. For example, is the pain interfering with attempts to get pregnant? Many women with urogenital pain are of childbearing age, and may struggle between wanting to become pregnant and avoiding painful intercourse. Patients may also be concerned about having children in the context of a strained relationship, or may worry about the impact of pain on their ability to function as parents (8). Inquiring about relationship issues helps clinicians conceptualize the patient’s pain and related experiences. It also offers patients an opportunity to share and validate their experiences, and can lead to addressing negative relationship issues or capitalizing on the support offered by an intimate partnership.

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Psychological Functioning Chronic pain disorders, including urogenital pain, are commonly associated with psychosocial difficulties, such as depression, anxiety, and decreased body image (18,22,23). For example, patients suffering from BPS/IC report levels of depression exceeding those of the general population and chronic pain populations (10). As well, anxiety has been found to predict pain ratings in women with VPS (24). Further, research has shown that health and well-being are important for positive body image, sexual functioning, and intimacy. The experience of pain has a profound effect on body image and self-esteem. For example, people who view their bodies negatively are more likely to experience disruptions in sexual functioning (25). Likewise, women who experience difficulties in sexual functioning may develop a negative sexual self-concept. Consistent with this literature, Reed et al. (26) found that women with VPS had a decreased self-concept when compared with control women. It is important to assess the impact of the urogenital pain on the patient’s self-view, as this information may prove valuable in guiding the focus of treatment. CLINICAL ISSUES RELATED TO TREATING UROGENITAL PAIN IN WOMEN Many health professionals find it difficult to deal with patients suffering from urogenital pain. In addition to the general difficulty inherent in treating chronic pain, the health professional is faced with a patient who is likely suffering from comorbid sexual, relationship, and psychological difficulties. These comorbid problems add to the complexity of the presenting condition and lead to challenges in treatment. Further, there is no simple answer regarding what causes urogenital pain in women, and certainly no simple and effective treatment to “cure” the pain and its associated difficulties. Current treatment options are largely based on trial and error, with little empirical outcome data to guide appropriate treatment plans. Certainly, health professionals are challenged on many levels when dealing with patients suffering from urogenital pain. However, the patients themselves are in a more disadvantageous position. Although urogenital pain is common, many sufferers do not present to clinics. Reasons may include the embarrassment associated with talking about urogenital pain, lack of access to services, or the poor diagnostic and treatment capabilities of the health care system. One recent study reported that approximately 50% of women with vulvar pain did not seek treatment. Of those who consulted health professionals, 40% did not receive a diagnosis even after multiple consultations (3). Given the multitude of factors involved in urogenital pain, diagnosis, assessment, and treatment should be conducted in a multidisciplinary fashion (23,27). For example, gynecologists or urologists can aid in establishing a medical diagnosis, and psychologists or sexologists can contribute by assessing the cognitive, affective, and behavioral dimensions of the pain. The team can integrate their expertise in an effort to target the various factors involved in the maintenance of the pain. The importance of this team is made clear by the findings of a randomized treatment outcome study of women with VPS (16). This study demonstrated that pain reduction did not necessarily lead to improved sexual functioning, and suggested that psychosexual factors, in addition to the pain, be targeted through treatment. A multimodal approach to urogenital pain is currently the gold standard in the treatment of other pain problems and has proven successful in reducing pain and disability (28). There are multiple advantages of working within such a conceptual framework: First, it is likely the only model that can address the many problem areas typically presented by women with urogenital pain; it holds the potential to accelerate patient recovery, as it targets multiple symptoms simultaneously and early in the treatment process; and it allows patients access to all relevant health professionals from the beginning of treatment. As well, in line with the biopsychosocial model of pain, a multimodal approach emphasizes the interdependent roles of biological, cognitive, affective, behavioral, and interpersonal factors in contributing to the development and maintenance of urogenital pain (29). Second, this approach acknowledges that no single discipline has all the answers; in order to successfully treat a woman with urogenital pain, it is necessary to collaborate with colleagues from other health care specializations.

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REFERENCES 1. Schmaling KB, Sher TG. Physical health and relationships. In: Halford WK, Markman HJ, eds. Clinical Handbook of Marriage and Couples Intervention. New York: Wiley, 1997:323–45. 2. Meana M, Binik YM, Khalife S, et al. Biopsychosocial profile of women with dyspareunia. Obstet Gynecol 1997; 90(4 Pt 1):583–9. 3. Harlow BL, Wise LA, Stewart EG. Prevalence and predictors of chronic lower genital tract discomfort. Am J Obstet Gynecol 2001; 185(3):545–50. 4. Bergeron S, Binik YM, Khalife´ S, et al. Reliability and validity of the diagnosis of vulvar vestibulitis syndrome. Obstet Gynecol 2001; 98:45–51. 5. Friedrich EG, Jr. Vulvar vestibulitis syndrome. J Reprod Med 1987; 32(2):110–4. 6. McKay M. Vulvodynia: diagnostic patterns. Dermatol Clin 1992; 10:423–33. 7. Moore J, Kennedy S. Causes of chronic pelvic pain. Baillieres Clin Obstet Gynaecol 2000; 3:389–402. 8. McCormick NB. When pleasure causes pain: living with interstitial cystitis. Sex Disabil 1999; 17:7–17. 9. Nordling J. Interstitial cystitis: how should we diagnose it and treat it in ? Curr Opin Urol 2004; 14:323–7. 10. Rabin C, O’Leary A, Neighbors C, et al. Pain and depression experienced by women with interstitial cystitis. Women Health 2000; 31:67–81. 11. Sant GR, Hanno PM. Interstitial cystitis: current issues and controversies in diagnosis. Urology 2001; 57(Suppl. 6-A):82–8. 12. Bergeron S, Binik YM, Khalife´ S, et al. Facteurs associe´s au succe`s the´rapeutique dans le traitement de la vestibulite vulvaire. In: Levy J, Maisonneuve DH, Bilodeau C et al, eds. Enjeux Psychosociaux de la Sante´. Montreal: Presses de l’Universite´ du Que´bec, 2003:135–49. 13. Block AR. Presurgical psychological screening in chronic pain syndromes: psychosocial risk factors for poor surgical results. In: Gatchel RJ, Turk DC, eds. Psychosocial Factors in Pain: Critical Perspectives. New York: Guilford Press, 1999:390–400. 14. Gatchel RJ, Epker J. Psychosocial predictors of chronic pain and response to treatment. In: Gatchel RJ, Turk DC, eds. Psychosocial Factors in Pain: Critical Perspectives. New York: Guilford Press, 1999:412– 34. 15. Binik I. Bergeron S. Chronic vulvar pain and sexual functioning. National Vulvodynia Association (NVA) News. Spring 2001:5–7. 16. Bergeron S, Binik YM, Khalife´ S, et al. A randomized comparison of group cognitive-behavioral therapy, surface electromyographic biofeedback, and vestibulectomy in the treatment of dyspareunia resulting from vulvar vestibulitis. Pain 2001; 91(3):297–306. 17. Bergeron S, Bouchard C, Fortier M, et al. The surgical treatment of vulvar vestibulitis syndrome: a follow-up study. J Sex Marital Ther 1997; 23:317–25. 18. Gates EA, Galask RP. Psychological and sexual functioning in women with vulvar vestibulitis. J Psychosom Obstet Gynaecol 2001; 22:221–8. 19. Danielsson I, Sjoberg I, Wikman M. Vulvar vestibulitis: medical, psychosexual, and psychosocial aspects, a case-control study. Acta Obstet Gynecol Scand 2000; 79:872–8. 20. Sackett S, Gates E, Heckman-Stone C, et al. Psychosexual aspects of vulvar vestibulitis. J Reprod Med 2001; 46:593–8. 21. Gordon A, Panahian-Jand M, McComb F, et al. Characteristics of women with vulvar pain disorders: responses to a web-based survey. J Sex Marital Ther 2003; 29(Suppl. 1):45–58. 22. Schover LR, Youngs DD, Cannata R. Psychosexual aspects of the evaluation and management of vulvar vestibulitis. Am J Obstet Gynecol 1992; 167:630–6. 23. Pukall CF, Payne KA, Kao A. Dyspareunia. In: Balon R, Segraves RT, eds. Handbook of Sexual Dysfunction. New York: Taylor & Francis, 2005:249–72. 24. Wylie K, Hallam-Jones R, Harrington C. Psychological difficulties within a group of patients with vulvodynia. J Psychosom Obstet Gynaecol 2004; 25:257–65. 25. White G, Jantos M. Sexual behaviour changes with vulvar vestibulitis syndrome. J Reprod Med 1998; 43:783–9. 26. Reed BD, Advincula AP, Fonde KR, et al. Sexual activities and attitudes of women with vulvar dysesthesia. Obstet Gynecol 2003; 102:325–31. 27. Pukall CF, Lahaie M-A, Binik YM. Sexual pain disorders: pathophysiological factors. In: Goldstein I, Meston CM, Davis S et al, eds. Women’s Sexual Function and Dysfunction: Study, Diagnosis, and Treatment. London: Taylor & Francis, 2005:237–43. 28. Flor H, Fydrich T, Turk DC. Efficacy of multidisciplinary pain treatment centers: a meta-analytic review. Pain 1992; 49:221–30. 29. Melzack R, Wall PD. The Challenge of Pain. 2nd ed. London: Penguin, 1996.

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Lower Urogenital Tract Pain and Sexuality Howard I. Glazer

Department of Psychiatry, Weill Cornell Medical College, New York Presbyterian Hospital, New York, New York, U.S.A.

DYSPAREUNIA DEFINITION, DIAGNOSIS, AND PREVALENCE Dyspareunia literally means “bad or difficult mating,” and it is manifest as persistent painful intercourse which can occur at any age, in both sexes. The pain can begin at penetration, during thrusting, at the time of orgasm or postcoital. Dyspareunia is characterized by location, onset, and frequency. Pain can be located at the vaginal entry, known as “introital,” “entry,” or “superficial” dyspareunia, or pain can occur after penetration localized at the cervix or lower abdominal area, known as “deep” dyspareunia. Introital dyspareunia is usually described as sharp burning or pinching and most commonly occurs with vulvar disorders and with vaginismus. Deep dyspareunia is often described as burning, fullness, or something being bumped, and is most often associated with abdominal, uterine, cervical, ovarian, and vaginal disorders. Primary dyspareunia is present if intercourse has always been accompanied by pain. Symptoms may be dated from initial tampon use or initiation of attempted vaginal insertion, associated with the use of a speculum on gynecological examination, or with initial digital or penile insertion. Primary dyspareunia is often associated with vulvar disorders, structural abnormalities, and psychosocial factors. Secondary dyspareunia onsets follow a period of painfree vaginal penetration and sexual functioning and are often associated with a specific event, such as an infection, or a condition, such as atrophic changes with menopause or endometriosis. Dyspareunia frequency may occur on all occasions of penetration, with all partners, positions, and situations, or be situational, occurring only with specific conditions such as size of object inserted, depth of insertion, a specific partner, or only when premenstrual. The diagnosis of dyspareunia appears in both the Diagnostic and Statistical Manual of the American Psychiatric Association, Fourth Edition, Text Revision (DSM IV) (1) and in The International Classification of Diseases, Ninth Revision, Clinical Modification Volumes 1 and 2 (ICD 9) (2). The diagnostic codes include 625.0 “Dyspareunia, difficult or painful sexual intercourse, excluding psychogenic dyspareunia,” and 302.76 “Psychosexual or functional dyspareunia, difficult or painful sex due to psychosomatic states.” Two additional relevant diagnostic codes are 306.51 “Psychogenic or functional vaginismus, a psychogenic response resulting in painful contractions of vaginal canal muscles which can be severe enough to prevent sexual intercourse,” and 608.89 “Other specified disorders of male genital organs,” which is the coding typically used for the diagnosis of male dyspareunia. In a recent study of 3017 women aged 20 to 60 years, the prevalence rate of severe and prolonged dyspareunia is reported as 9.3% for the entire group studied and 13% for women aged 20 to 29 years. In this study, for those women who reported ever having experienced severe dyspareunia, only 28% had consulted a physician for their symptoms; 20% recovered after treatment, while 31% recovered spontaneously (3). In a recent epidemiological survey of 3358 women aged 18 to 64 years, 12.4% reported vulvar pain on contact, lasting three months or longer at some point in their life. Of these, 39.6% never sought treatment and of those who did seek treatment, 57% report visits to three or more practitioners and 39.1% remained undiagnosed (4). A study using a meta-analysis of the dyspareunia literature reported an incidence rate ranging from 8% to 23% across the studies reviewed (5). In a survey of 105 women on sexual experience and dyspareunia, 21% of participants reported dyspareunia as rare, 55% reported occasional, and 24% reported frequent or constant dyspareunia (6). These studies clearly suggest that

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dyspareunia occurs in a significant portion of the female population is greatly underreported by patients despite a low rate of spontaneous resolution, and when reported is poorly diagnosed and treated. There are no reports in the literature of prevalence of male dyspareunia. DYSPAREUNIA CAUSES Dyspareunia is a symptom of many different conditions. Multiple etiological and maintaining factors, including both organic and psychosocial, are common. Causes of dyspareunia are shown in Table 1 (7–15). HISTORY AND PHYSICAL EXAMINATION The purpose of the history and physical examination is to confirm the complaint of sexual pain and to identify contributory factors to be addressed with treatment. An additional goal is patient education on anatomy and sexual functioning. Patients often deny or fail to report lower urogenital tract sexual pain due to embarrassment or false beliefs about such pain. This is often exacerbated by either very few or generalized sexual questions, or none at all, as many physicians are either uncomfortable asking sexually explicit questions or are uncertain of what to ask. Questions such as, “Are you experiencing any sexual difficulties?” will rarely elicit specific reports of dyspareunia. Even, “Do you experience pain with intercourse?” may not elicit an accurate report from a patient suffering mild-to-moderate or occasional dyspareunia. The investigation may begin with the question, “Have you ever experienced any genital pain associated with sexual activity?” A positive response to this type of question is much more likely and can then be followed up with a detailed sexual history and specific questions concerning pain location, onset, frequency, duration, sensory quality, exacerbating and ameliorating factors, associated physical and psychosocial components, and previous evaluation and treatment. Details of sexual activity must also be noted, including orgasmic status, masturbatory preferences and history, use of sexual devices, sexual orientation, positional preferences, oral and anal sexual activities, and previous sexual partner experiences. In some cases, with permission of the patient, the presence of the sexual partner for all or part of the history-taking process may yield further information. An alternative approach to the evaluation of dyspareunia is the use of a standardized scale such as The Female Sexual Distress Scale (16) as the starting point for a discussion with the patient. A complete systems review and physical examination are necessary to determine possible contribution to dyspareunia from factors such as infectious diseases, dermatological, musculoskeletal, neurological, urological, gastrointestinal, hormonal, immunological, surgical/ traumatic, and psychosocial sources. The pelvic examination may be deferred rather than conducted immediately after the history taking if the patient appears apprehensive or unprepared to continue. Since many women have little or no knowledge of their genital anatomy and physiology, it is best to start the pelvic examination with some education by having the patient use a mirror to view her genitals (10). Before initiating the examination, the patient should be encouraged to provide feedback on any sensory experience so that she feels a sense of control over the situation. If the patient reports any discomfort, the physician can determine whether this replicates the dyspareunia. The examination starts with a visual vulvar inspection. The examiner should note erythema, lesions, or leukoplakia. A moistened cotton tipped applicator can be used to examine the urethral meatus, Skene’s glands, and Bartholin’s glands and to localize areas of focal tenderness in the vestibule. A colposcopic inspection (17) of the vulva, or vulvar biopsy (18), may follow based on findings of the visual inspection. Before the bimanual or speculum examination, a vaginal examination with one finger is recommended. Pelvic muscles can be assessed with the introital insertion of one finger as the patient performs a series of contractions and relaxations. This may help ascertain the presence of vaginismus, but one-fourth of all women who tolerate pelvic examination and tampon insertion are reported to have involuntary pelvic muscle spasms during intercourse (1). The lateral walls of the vagina, the bladder and

Congenital factors vaginal agenesis, duplication, septation Structural abnormalities arising from surgery or radiation Pelvic organ prolapse cystocele, rectocele, enterocele Atrophic vaginitis Vaginitis Vaginismus Infections Tumors or masses Inflammatory or allergic reaction

Vaginal disorders Hysterectomy Adenomyosis of uterus Ovarian pathology Prolapsed adnexa Leiomyoma or benign tumors of the uterus Salpingitis Pelvic inflammatory disease Endometriosis Pelvic adhesions Pelvic floor muscle dysfunction Pelvic venous congestion Neuropathies nerve entrapment

Disorders of pelvic structures

Abbreviation: SSRI, serotonin-specific reuptake inhibitor. Source: From Refs. 7 15.

Infections bacterial, viral, fungal Irritation mechanical, chemical Dermatoses Vulvar papillomatosis Hymenal stenosis Adhesions Trauma Episiotomy scars Decreased lubrication Peri/postmenopausal or lactation atrophy Estrogen deficiency Inflammatory or allergic reaction Vulvar pain syndrome and its localized subtypes, e.g., clitoral pain syndrome Postpartum dyspareunia lactation, episiotomy Cancer radiation

Disorders of the vulva and vaginal outlet

TABLE 1 Causes of Dyspareunia

Acute and chronic cystitis Painful bladder syndrome (interstitial cystitis) Urethral lesions Urethral diverticulum Urethritis Fistulas

Urinary tract disorders Inflammatory bowel disease Diverticulitis Hemorrhoids Constipation Fistulas Crohn’s disease

Gastrointestinal tract disorders Anxiety Depression Phobias Conversion or somatization reactions Posttraumatic stress disorders Anger towards partner Arousal disorders Childhood or adult physical or sexual abuse Substance use disorders

Psychological factors Medications Progesterone contraception by reducing cervical mucous and causing vaginal atrophy due to estrogen deficiency Bromocriptine mesylate causing clitoral vasocongestion Desipramine hydrochloride leading to painful orgasm SSRIs which can reduce libido, delay orgasm and lead to dyspareunia

Male dyspareunia Infection of seminal vesicles Infection of prostate Prostatitis of all types, infective inflammatory or noninflammatory (prostate pain syndrome) Urethritis Infection of penile skin Penile cancer Testicular cancer and other disease Penile anatomy diseases Torsion of spermatic cord Musculoskeletal disorders of pelvis and lower back.

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urethra anteriorly, and the wall and fornices posteriorly should be palpated. The position of the uterus should be noted. The vagina should then be evaluated with the use of a speculum. The speculum should be chosen and well lubricated with the patients’ comfort in mind. Vaginal and cervical mucosa should be inspected for lesions, infection, atrophy, congenital abnormalities, and trauma. Assessment of vaginal atrophy should include skin elasticity, pubic hair, labial fullness, and evaluation of the introital and vaginal depth (19). Endocervical cultures, Papanicolaou’s smear, or wet mounts may be obtained if suggested by history or visual inspection. A bimanual examination is then performed to assess the uterus, adnexae, and posterior cul-de-sac. Finally, a rectovaginal examination is conducted to assess perirectal and rectal disorders. TREATMENT Overlapping organic system involvement and frequent multiple pathophysiology, as well as psychosocial and sexual aspects of lower urogenital tract pain, demand an integrated multidisciplinary approach to the diagnosis and treatment of this disorder. Figure 1 is an example of an integrated biopsychosocial model of lower urogenital tract pain disorders. In this model recognition is given to both organic and psychosocial predisposing factors. Provocative factors, individually or in consort, may cause the onset of discomfort. In the absence of predisposition and with the resolution of provocative factors, the discomfort is acute

IDIOPATHIC LOWER UROGENITAL TRACT PAIN DISORDERS MODEL Organic Predisposition

[e.g., IL 1-ra gene/vestibulitis, Witkin & Ledger (20)]

Chronic Pain Non-self-resolving with resolution of provocation

Provocation

(mechanical, chemical, hormonal, infectious, dermatological, neuromuscular, traumatic)

Acute Pain

Self-resolving with resolution of provocation and restoration of tissue integrity

Acute Localized Tissue Reactions with Nociceptive Pain Neurological central representation with resulting neuropathic + nociceptive pain elements

(inflammation, sensitization, vascular neuromuscular, cytokines/neurokines)

Psychosomatic

Psychophysiology / Pain Perception Psychological Depression Anxiety Loss of self-esteem

Psychological/Sexual/Functional Psychosexual Libido Arousal Orgasm

Functional Occupational Familial Social Sexual

Psychological Predisposition History (e.g., abuse/neglect) Personality (e.g., depression/anxiety) Pain tolerance Etc.

A wide variety of provocative events can lead to localized, acute tissue reactions with resulting nociceptive pain. This acute pain most often resolves on resolution of the provocative factors. In the presence of an organic and/or psychological predisposition, this pain may become chronic pain with the addition of neuropathic elements to the nociceptive factors. With urogenital pain psychological, sexual and functional states are adversely affected adding a psychophysiological element to the chronic pain.

FIGURE 1 A biopsychosocial approach to lower urogenital tract and sexual pain.

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and self-resolving. Chronic unresolved provocative factors or acute factors acting upon predisposition can lead to chronic pain with the addition of neuropathic pain elements to the original nociceptive pain elements. As with all chronic pain disorders, resulting psychological dysfunction and functional limitations are common. In the case of lower urogenital tract chronic pain in particular, psychological, sexual, and functional consequences are almost always present (21). These factors act upon the psychophysiology of pain perception to further perpetuate the pain cycle. Treatment of dyspareunia must be directed at all the underlying causes. For example, a perimenopausal patient with endometriosis, chronic vaginal yeast infection, vulvar dermatoses, chronic vulvar burning, vulvar dryness, and a limited sexual repertoire may require antifungals for persistent vaginal yeast, corticosteroids for vulvar dermatoses, hormone replacement therapy for atrophic changes, surgical therapy for endometriosis, neuropathic pain medications such as tricyclics or anticonvulsants, and use of vaginal lubricants, dilators, pelvic floor muscle rehabilitation and modification of foreplay, and sexual techniques to decrease pain on penile insertion. No specific pharmacological therapy has demonstrated efficacy in dyspareunia but pharmacological agents that improve vascular flow, relax smooth or striate muscles, or increase vaginal lubrication may be useful as part of an integrated therapy plan. The author’s clinical practice is one example of an integrated biopsychosocial approach to dyspareunia combining intravaginal pelvic floor muscle surface electromyography (biological) with cognitive behavioral pain management techniques and sexual dysfunction therapy (psychosocial). Glazer has proposed that essential vulvar pain disorders are a type of complex regional pain syndrome in which electrophysiological changes in the motor unit action potentials of the pubococcygeus muscle are an integral part of the physiology, perpetuating altered sensation of the local soft tissue (22). Using this approach, Glazer and his colleagues have demonstrated diagnostic validity (23,24) and therapeutic efficacy (22,25) of pelvic floor muscle surface electromyography and biofeedback for both vulvar pain syndrome and vestibular pain syndrome. In addition, this technique serves to (i) introduce the patient to the concept of self regulation of pain and (ii) enlist the partner to participate in increased communication of the sensory, emotional, and sexual experience of the patient. CONCLUSION Dyspareunia is a heterogeneous symptom with potentially multiple overlapping etiological factors. The treating physician must take great care to obtain a complete history and systems review including a detailed sexual history. A comprehensive physical examination with vulvar inspection, single digit and bimanual palpation, and speculum and rectal evaluation are necessary. Psychological, sexual, social, and life-functioning elements must all be assessed. Treatment should follow the integrated biopsychosocial model and must incorporate interventions for all positive historical and examination findings. REFERENCES 1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed-TR. Washington, DC: American Psychiatric Association, 2000:511–8. 2. Hart AG, Hopkins CA. ICD-9-CM Professional for Physicians 2005, Volumes 1 and 2 (paperback). Ingenix, 2004. 3. Danielsson I, Sjoberg I, Stenlund H, Wikman M. Prevalence and incidence of prolonged and severe dyspareunia in women: results from a population study. Scand J Public Health 2003; 31(2):113–8. 4. Harlow BL, Stewart EG. A population-based assessment of chronic unexplained vulvar pain: have we underestimated the prevalence of vulvodynia? J Am Med Womens Assoc 2003; 58:82–8. 5. Spector IP, Carey MP. Incidence and prevalence of the sexual dysfunctions: a critical review of the empirical literature. Arch Sex Behav 1990; 19(4):389–408 (Review). 6. Glatt AE, Zinner SH, McCormack WM. The prevalence of dyspareunia. Obstet Gynecol 1990; 75(3 Pt 1):433–6. 7. Smith RP. Gynecology in Primary Care. Baltimore, MD: Williams & Wilkins, 1997. 537–48. 8. Meana M, Binik YM, Khalife S, Cohen DR. Biopsychosocial profile of women with dyspareunia. Obstet Gynecol 1997; 90(4 Pt 1):583–9.

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9. Meana M, Binik YM, Khalife S, Cohen DR. Dyspareunia: sexual dysfunction or pain syndrome? J Nerv Ment Dis 1997; 185(9):561–9. 10. Steege J. Dyspareunia and vaginismus. Clin Obstet Gynecol 1984; 27:750–9. 11. Halvorsen JG, Metz ME. Sexual dysfunction, part I: classification, etiology, and pathogenesis. J Am Board Fam Pract 1992; 5:51–61. 12. Reamy KJ, White SE. Sexuality in the puerperium: a review. Arch Sex Behav 1987; 16(2):165–86. 13. Attico NB, Billy MH. A clinical guidde to using DMPA. Fam Pract Recertif 1996; 18(11):53–65. 14. Rhodes JC, Kjerulff KH, Langenburg PW, et al. Hysterectomy and sexual functioning. J Am Med Assoc 1999; 282(20):1934–41. 15. American Collee of Obstetricians and Gynecologists. Sexual Dysfunction, ACOG Tech Bull 1995, No. 211. Washington, DC: American College of Obstetricians and Gynecologists, 1995. 16. Derogatos LR, Rosen R, Leiblum S, Burnett A, Heiman J. The Female Sexual Distress Scale (FSDS): initial validation of a standardized scale for assessment of sexually related personal disteess in women. J Sex Marital Ther 2002; 28(4):317–30. 17. Noller K, Wagner A, Jr. Colposcopy. In: Sciarra JL, ed. Gynecology and Obstetrics. Vol. 1. Philadelphia, PA: Lippincott/Williams & Wilkins, 2000:21–9. 18. Chaim W, Meriwether C, Gonik B, Qureshi F, Sobel JD. Vulvar vestibulitis subjects undergoing surgical intervention: a descriptive analysis and histopathological correlates. Eur J Obstet Gynecol Reprod Biol 1996; 68(1–2):165–8. 19. Phillips N. The clinical evaluation of dyspareunia. Int J Impot Res 1998; 10(Suppl. 2):S117–20. 20. Jeremiaj J, Ledger J, Witkin SS. Interleukin 1 receptor antagonist gene polymorphism in women with vulvar vestibulitis. Am J Obstet Gynecol 2000; 182:283–5. 21. Meana M, Binik YM, Khalife S, Cohen D. Dyspareunia: sexual dysfunction or pain syndrome? Nerv Ment Dis 1997; 185:561–9. 22. Glazer HI, Rodke G, Swencionis C, Hertz R, Young AW. Treatment of vulvar vestibulitis syndrome with electromyographic biofeedback of pelvic floor musculature. J Reprod Med 1995; 40:283–90. 23. Glazer HI, Jantos MA, Hartmann EH, Swencionis C. Electromyographic comparisons of the pelvic floor in women with dysesthetic vulvodynia and asymptomatic women. J Reprod Med 1998; 43:959–62. 24. White G, Jantos M, Glazer HI. Establishing the diagnosis of vulvar vestibulitis. J Reprod Med 1997; 42:157–60. 25. Glazer HI. Long term follow-up of dysesthetic vulvodynia patients after completion of successful treatment by surface electromyography assisted pelvic floor muscle rehabilitation. J Reprod Med 2000; 45:798–801.

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Training in Urogenital Pain Management Florella Magora

Department of Anesthesiology/Intensive Care, Hadassah Medical Center, Ein Kerem, Jerusalem, Israel

INTRODUCTION The field of pain medicine has been in a constant state of development since 1946, when Dr. Bonica introduced the concept that only a team of multidisciplinary specialists could effectively control the manifestations of chronic pain. The heightened awareness of the benefits of an integrated pain therapy has markedly increased the number of patients referred to the pain clinics for coordinated treatment by a multidisciplinary team of specialists. However, while patients suffering from the various severe chronic pains of urogenital (UG) origin are especially suited to benefit from the interdisciplinary approach, the trend continues for separate treatment by a variety of specialists: urologists, gynecologists, neurologists, psychologists, anesthesiologist, or rehabilitation health professionals. This approach lacks the essential input of diagnostic assessment by a pain specialist and the advantage of a comprehensive multidisciplinary pain treatment strategy (1,2). There is a need for specially trained health providers who have completed a professional education training program in the specific dilemmas of UG pain management so that understanding of its nociceptive mechanisms can be further refined to provide rational new therapies based on the model of interdisciplinary team approach. The purpose of this chapter is to emphasize basic requirements for candidates interested in studying and perfecting their techniques in UG pain management. The International Association for the Study of Pain (IASP) has a chronic UG pain curriculum, which outlines the clinical training requirements and presents a list of relevant references for each topic, supplied valuable material for the guidelines presented here (3). CHRONIC UG PAIN—DIDACTIC PROGRAM UG Neuroanatomy A neurocomplex consisting of somatic, sympathetic, and parasympathetic nerves and plexuses innervates the structures of the UG systems and coordinates their many functions related to micturition, defecation, copulation, and reproduction (4). Chronic UG pain syndromes may be induced by obstruction of the lower urinary tract, and/or focal infections in the region, distant pathology of genital organs, or even overlap with pain from a nonpelvic structure, e.g., the lumbosacral spine. For these reasons it is evident that the training in UG pain must be based on a perfect knowledge of the neuroanatomy of the urological and gynecological systems. Neurophysiology of UG Pain Syndromes The etiology is not known of many chronic, complex UG pelvic, and perineal pain syndromes, related to the vulva, prostate, testis scrotum, pelvic floor, and urethra. The studies and research of Mc Mahon (5) and Giamberardino et al. (6) fully described the neuropathic background for many of these localized visceral pains, occasionally accompanied by a distant, somatic, referred hyperalgesic type of pain, which is maintained by the sensitization of peripheral nociceptors, as well as by a central sensitization mechanism. These disorders were included in a group designated as “complex visceral pain syndromes” with characteristics similar to the complex

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regional pain syndromes. The application of an appropriate, efficient multimodal treatment regimen is fully dependent on correct identification and diagnosis of the pathophysiology of the presenting symptoms. This implies that the learning of anatomy must be complemented with the learning of the neurophysiology of the complex visceral pain characteristics, its causes, and its treatment. Case History and Examination of UG Pain Even with accurate theoretic knowledge of the neuroanatomy and neurophysiology of the UG systems, it would be impossible to arrive at the correct diagnosis without conducting a thorough history-investigation of the symptoms, their resulting psychological impact on patient mood and functioning, and evaluations of previous therapies. With the exclusion of patients suffering from inflammatory or obstructive etiologies treated competently by urologists, gynecologists, internists, or gastroenterologists, for many patients the cause of the persistent pain that accompanies these conditions cannot be explained by physical lesions or physiological dysfunction. In addition, the situation is rendered more complicated when the results of all the standard laboratory imaging examinations and workups are normal. Patients afflicted by any of these syndromes may pass from one physician to another without obtaining sufficient help. The history may reveal important information for future therapy, such as detection of an initiating event in connection with the present symptomatology, previous pelvic infection, surgery, sexual abuse, and/or detection of aggravating or facilitating factors (7). The physical examination uncovers findings about the site of physical pain and exposes hyperalgesic zones, signs of nerve entrapment, or the presence of trigger points. In order to arrive at this precise assessment, it is necessary to acquire good consultation skills so as to obtain a thorough history and a “hands-on” competent clinical examination. A review of the literature on UG pain by Verhaak et al. in 1998, produced the conclusion, based on the 15 articles published at that time, that there was a reported overall prevalence of 15% (2–40%) of chronic benign pain among the adult general population (8). Another review, summarizing the Medline database on the prevalence of chronic pelvic pain in women, estimated from a U.S. national survey, that 15% of the 5263 women investigated suffered from chronic pelvic pain. In a single study of women in the United Kingdom, a rate of 39% for chronic pelvic pain unrelated to menstruation was reported (9). Chronic pain prevalence, from a survey of a large group of patients (17,543) in Australia published in 2001, established a rate of 17.1% chronic pain reported by men and 15% by women. The authors concluded that “chronic pain impacts upon a large proportion of the adult population and should be a priority area for future research” (10). Although there are not many conclusive reports on the prevalence of chronic pain of UG origin, it is accepted that this debilitating condition is frequent and may affect millions of patients worldwide. In the last 10 years, there has been a surge of interest in UG pain. In order to draw attention to this aim and provide responsible guidance in the field of chronic pain syndromes of UG origin, some significant moves were made, for instance, the foundation of the IASP Special Interest Group in UG pain (11), the publication of the core curriculum in UG pain (3), and the London Urology Associates requirements. Learning Objectives of Training in UG Pain Management The goals of UG pain management training include: 1. To stimulate awareness in all trainees in the various specialties, particularly urology, gynecology, pain medicine, internal medicine, neurology, psychology, psychiatry, and physical medicine, and rehabilitation regarding the importance of learning about the specific diagnostic aspects and modes of therapy related to the common UG pain syndromes 2. To supply opportunities to postgraduate candidates for exposure to learning activities related to UG syndromes pain management and to encourage their participation in fellowships of various duration in accredited institutions, symposiums, and meetings on related subject matter

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3. To train specialists in the knowledge and experience required for identifying and applying the multidisciplinary pain treatment appropriate for each of the UG pain syndromes, which have been so clearly described but so poorly understood. Patients with chronic UG pelvic and perineal pain are sometimes too embarrassed by their personal condition to seek medical assistance. In other cases, even when aid is sought, they are treated mistakenly by their practicing physicians who, when no specific lesion can be identified, consider their symptoms to be of a psychological and not of a physical origin. Therefore, the mandatory topics of the full theoretical and practical training in the field of complex visceral pain syndromes of UG origin are in men: identification of symptoms, investigation and treatment options of—focal chronic pain syndromes, relating to the prostate, testicule/scrotum pain, penis, perineum, epididymitis, and the urethra as well as entrapment nerve pain and cancer. In women, the same requirements are to be taught with regard to the pain syndromes related to the vulva, vestibule to endometriosis, dysmenorrhea, bladder as well as ovarian cycle-dependent pain, musculoskeletal pain, postsurgical pain, and differential diagnosis from pain caused by malignancy. Management of Chronic UG Pain The treatment of the chronic UG pain syndromes can be frustrating both for the physician and for the patient. Despite the best efforts of physicians, patients often sense that their complaints are not fully understood or believed. The role of adequate therapy is not only to alleviate the pain but also to prevent the changes from progressing toward a chronic state and a superimposed psychological depression. The successful management of pain of UG origin starts by establishing a warm relationship between the treating physician, the members of the pain team, and the patient, at the same time adapting the treatment to the individual needs of each patient. The section on therapy in the UG curriculum requires knowledge of the appropriate pharmacology and the use of drugs, as well as the application of local infiltration with local anesthetics and nerve blocks, electrical stimulation techniques, physical therapy, and rarely surgical interventions. The symptoms associated with chronic neuropathic pain do not respond favorably to surgery. In fact the opposite is mostly true and prevention of unnecessary surgical procedures depends on the correct selection of therapy. Psychological behavioral approaches and biofeedback management are other significant, specific areas of therapy. Simple over-the-counter analgesics may be given a trial, in addition to the prescription of more powerful groups of non-steroidal anti-inflammatory (NSAID) or mild opioid drugs. When the low potency drugs have failed, stronger narcotics may be indicated in selected patients if the risk of their use is carefully calculated (12). However, the best results have been obtained by neuropathic analgesics consisting of moderate dosages of tricyclic antidepressants drugs (1,13) and sometimes by muscle relaxant drugs (1) or IV lignocaine for its role as a sodium channel blocker (14). Nerve blocks for diagnostic or therapeutic purposes with local anesthetic agents, or with neurolytic substances or radio frequency neuroablation, as well as local infiltration of trigger points may have a long-lasting effect and are part of the therapeutic methodology, especially when a nerve entrapment syndrome, or a segmental type of hyperalgesic pain has been diagnosed. The physical therapies include stretching exercises, traction, and manipulation for alleviating excess muscle contraction and pain, transcutaneous electrical nerve stimulator (TENS) stimulation, ultrasound, hot or cold applications, and massages. A prolonged biofeedback program has been developed and offers good results for relaxation of contracted pelvic floor muscles, or for the opposite effect of strengthening their power, if their performance has become weak. Surgical interventions are indicated only when pelvic abnormalities or nerve entrapment causes have been clearly identified. Other important additions to therapy are instruction in a self-management mode of therapy and learning to recognize positive practices and to avoid negative ones in daily life activities.

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The essential messages in conveyed in this chapter are these: 1. Because of the neuropathic character of the pain in the chronic UG syndromes, it is of utmost importance to avoid the development of chronicity, which results from neuroplastic changes due to the excessively prolonged pain stimulation. Knowing the underlying pathophysiological mechanism and the natural course of the condition under treatment are the pathways to defeating its ill consequences. 2. Early aggressive, correct multimodal treatment strategies, currently available, will provide pain relief in almost all patients even if a complete cure is not achievable (9). The referral of the patient, as soon as possible, to a colleague, or a service with special training and interest in these syndromes is the key to conquering the pain. TRAINEES IN UG PAIN MANAGEMENT The instructions from subsections 1–3 of the Chronic UG Didactic Program need to be made available to all physician residents in subspecialty-related fields, or to any other health provider intending to become an active member of the team of therapists responsible for the treatment of chronic UG pain. It is strongly recommended that a complete training in the subspecialty of UG pain be integrated in the postgraduate curriculum of students in pain medicine, or other interested physicians after they have graduated from one of the recognized residency specialties in medicine, particularly pain medicine, urology, gynecology, anesthesiology, neurology, psychiatry, and physical rehabilitation. Paramedical professionals, psychologists, nurses, physical therapists, technicians, etc., prepared to pursue such a training, should also be admitted to attend the whole course or a shortened program. Fellowships of varied duration and specialization in a particular field, e.g., biofeedback for pelvic floor disturbances, invasive electrical stimulation methods, research projects, etc., can supplement education in the field of UG pain. Full- or part-time exposure to research activities is an important aspect of training in UG pain. Clinical and experimental research in UG pain offers a wide and exciting field of exploration. Significant epidemiological studies in chronic UG pain syndromes are lacking. The mechanism of most persistent UG pain is poorly understood, and for this reason the treatment is mostly empirical and aimed to ease the symptomatology. Investigations into the effect of new drugs and new modes of treatment await clarification. The bladder is an internal organ that offers an accessible route for pathological and endocrinological studies, and it has been selected for study in several animal models. Many research programs, focused on UG pain, have been published, while others are currently works-in-progress. The same holds true for the opportunity to participate in staff meetings where difficult cases are critically discussed, also seminars and scientific congresses where up-to-date presentation of related topics are addressed. It is predictable that in the foreseeable future a formal training program in UG pain will be also accessible on the Web, similar to the postgraduate education course in pain management, initiated by the Pain Management Research Institute of the University of Sydney (15). This course offers online teaching material put together by an international faculty of experienced specialists in the field of pain. The affiliates may receive a certificate of specialist in pain management if they so choose, and if they have succeeded in passing the E-examinations that form a separate section of this course. If an online training program is realized based on the curriculum already endorsed by the IASP and the Special Interest IASP Group in UG pain, pain of UG origin (PUGO), it may serve as a prospective, valuable, additional source of selfinstruction for interested persons who lack the opportunity of a more direct teaching program. REFERENCES 1. Wesselman U. Guest Editorial: Pain—the neglected aspect of visceral pain. Eur J Pain 1999; 3:189–91. 2. Wesselmann U, Magora F, Ratner V. Pain of urogenital origin—to often neglected. Pain Clin Updates 2000; 8(5):1–4.

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3. Charlton JE, ed. Core Curriculum for Professional Education in Pain. 3rd ed. Seattle, WA: IASP Press 2005; 179–81. 4. Burnett AL, Wesselmann U. Neurobiology of the pelvis and perineum: principles for a practical approach. J Pelvic Surg 1999; 5:224–32. 5. Mc Mahon SB. Are there fundamental differences in the peripheral mechanism of visceral and somatic pain? Behav Brain Sci 1997; 20:381–91. 6. Giamberardino MA, Vecchiet L. Visceral pain, referred hyperalgesia and outcome: new concepts. Eur J Anesth 1995; 12(Suppl. 10):61–6. 7. Collet BJ, Cordle CJ, Stewart CR, Jagger C. A comparative study of women with chronic pelvic pain, chronic nonpelvic pain and those with no history of pain attending general practitioners. Br J Obstet Gynaecol 1998; 105:87–92. 8. Verhaak PF, Kerssens JJ, Dekker J, Sorbi MJ, Bensing JM. Prevalence chronic benign pain disorder among adults: a review of the literature. Pain 1998; 77:231–9. 9. Zondervan KT, Yudkin PL, Vessey MP, Dawes MG, Barlow DH, Kennedy SH. The prevalence of chronic pelvic pain in women in the United Kingdom: a systematic review. J Obstet Gynecol 1998; 105:93–9. 10. Blyth FM, March LM, Brnabic AJ, Jorm LR, Wiliamson M, Cousins MJ. Chronic pain in Australia: a prevalence study. Pain 2001; 89:1127–34. 11. Schmidt R. Pain of Urogenital Origin. Chairman’s Message. Newsletter IASP SIG, April 1999. 12. Baranowski AP. Practical applications and procedures. In: Rice ASD, Warfield CA, Justins D, Eccleston C, eds. Pharmacologic Diagnostic Tests in Clinical Pain Management. London: Arnold, 2003:39–47. 13. Pranikoff K, Constantino G. The use of amitriptyline in patients with urinary frequency and pain. Urology 1998; 51:179–81. 14. Ferrante FM, Paggioli J, Cheerukuri S, Arthur GR. The analgesic response to intravenous lidocaine in the treatment of neuropathic pain. Anesth Anal 1996; 82:91–7. 15. Loftus S, Taylor I, Harris R, Cousins M. A Web-based Multidisciplinary Course in Pain Management: Proceedings of the 9th Congress on Pain Vol. 16, eds. Devor M, Rowbotham MC, Wisenfield-Hallin Z. Seattle, WA, ISAP Press 2000; 41–6

The Pain Syndromes

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n many ways the next section of this book was one of the most difficult to edit. It attempts to summarize what is known about the various pain syndromes. It does not aim to cover well-defined pathologies, but a range of clinical conditions, some of which are difficult to describe. A number of interesting issues require ongoing debate, backed up by high-quality research TERMINOLOGY PROBLEMS In this section of the book a wide range of terminology has been used. The reason for this is historical and probably relates to an end-organ approach, where inflammation/infection has been viewed as a potentially reversible cause of pain, for example, “chronic prostatitis.” However, it is becoming widely believed that these conditions should be considered chronic/persistent pain problems. We have tried to rationalize the terminology where possible. However, when referring to past literature with poor inclusion criteria, this has not always been possible. Also, as a greater understanding occurs, the terminology is constantly developing. For example, vulvar pain syndrome, could (should) be subdivided according to the following criteria: & & & &

Site(s), localized or generalized Cause(s), known or unknown Precipitating or relieving factors Continuous or intermittent

At present, a variety of terms are used such as “vulvodynia” and “vulvo vestibulitis” without reference to the criteria above. It is also likely that the diagnosis of patients currently labeled “prostatitis” will be redefined. A minority of patients have either symptoms or signs of infection or a prostate painful to palpation. Such patients might be better viewed as suffering from chronic pelvic pain or chronic perineal pain, depending on where they feel the pain. “NEW” CONDITIONS A second challenge relates to the fact that, as a better understanding occurs, some conditions will become recognized as having distinct pathologies while others will move into the pain syndrome category. For example, pudendal neuralgia is becoming recognized as a pathological entity, whereas it was rarely diagnosed a few years ago. This is an example of how a collection of symptoms and signs may evolve into a better understood condition: There are several chapters on this subject. However, such prominence should not suggest that it is of any greater importance than any of the other conditions. “OLD” CONDITIONS REDEFINED An example of how a condition may change from being well defined to being considered a pain syndrome would be bladder pain syndrome. There has been a move toward accepting that many patients with bladder pain do not have the cystoscopy or biopsy changes considered pathognomonic of interstitial cystitis and that they should form a part of a bladder pain syndrome group as opposed to being considered a single group under the diagnosis of intestitial cystitis, implying a single well-defined disease.

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MULTISYSTEM ETIOLOGY Further confusion stems from the fact that many conditions are probably multifactorial, involving the end organ, musculoskeletal, and nervous systems. It is the experience of most pain medicine specialists that chronic pain will involve multiple systems, even when the precipitating injury and pathology is well defined and may even have been resolved. A patient with a brachial plexus injury will develop peripheral and central neuropathic pains but will also develop muscular pain along with the symptoms and signs associated with denervation and dysfunction of the nervous system (including vascular, pseudomotor, and motor changes), and, occasionally, a dystrophic limb. Similar changes can be seen with urogenital pain. This is something that must be born in mind when managing this group of patients.

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Renal Disease and Pain Maria Adele Giamberardino and Giannapia Affaitati

Pathophysiology of Pain Laboratory, Ce.S.I., G. D’Annunzio Foundation and Department of Medicine and Science of Aging, University of Chieti, Chieti, Italy

Raffaele Costantini

Department of Experimental and Clinical Surgical Science, G. D’Annunzio University of Chieti, Chieti, Italy

INTRODUCTION Pain of renal origin is very frequent in medical practice. Its most typical expression, the renal colic, represents one of the most prominent and paradigmatic forms of visceral pain (1). This type of pain has been the subject of extensive investigation not only in clinical studies but also in basic research studies on animal models, to assess the profile of the sensory and trophic changes that appear in the referred area and investigate their pathophysiological bases (2,3). This chapter is intended to provide an overview of the current knowledge on pain phenomena of renal origin, in terms of clinical characterization, mechanisms of generation, diagnostic tools, and therapeutic approach. URINARY COLICS FROM CALCULOSIS Clinical Profile The overall probability of forming urinary stones differs in various parts of the world (4), however in industrialized nations kidney stones are very common (5) and their prevalence continuously increased during the 20th century (6). It is also estimated that up to 80% of patients with calculi who are untreated will experience one or more recurrences within five years (7). Risk factors for formation of stones include urinary promoters (calcium, urate, cystine, and sodium) and urinary inhibitors (magnesium, citrate, and nephrocalcin) (5). Most kidney stones are symptomatic and up to 10% of the population is estimated to suffer from ureteric colic at least once in their lifetime (8). The pain from urinary stones can be excruciating; together with that of childbirth it is among the most intense pains that a human being can experience to the point that even strong doses of major analgesics may not produce sufficient relief (9,10). Its location depends on the position of the stone within the urinary collecting system (1). Calculosis of the upper urinary tract typically produces pain in the ipsilateral lumbar region (L1) which radiates downward on the anterior, from the flank toward the groin, often accompanied by frequent urination, dysuria, oliguria, hematuria, acute nausea, and hypotension. Spontaneous symptoms are associated with sensory/trophic changes of the somatic tissues in the painful area. In symptomatic upper tract calculi, hypersensitivity appears at lumbar level, as revealed by a painful reaction of the patient to the clinical maneuver of compression of the lumbar area (a clean blow dealt with the ulnar edge of the hand at L1 level), testifying hyperalgesia of the deep layers of the body wall (11). This hyperalgesia has been quantified instrumentally through evaluation of pain thresholds to pressure and electrical stimulation in several studies. In patients who had suffered from a few (one or two) colic episodes from a calculus of one upper urinary tract, hyperalgesia was detectable in the ipsilateral lumbar region (L1) in the pain-free interval in the three tissues of the body wall, i.e., skin, subcutis, and muscle, but particularly in the muscle (oblique musculature). Muscle pain thresholds were, in fact, significantly lower on the side of the affected kidney/ureter than contralaterally or in normal subjects. In patients experiencing a

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larger number of colic episodes four to six the extent of the muscle hyperalgesia was much greater than in those with a limited number (11,12). Muscle hyperalgesia also persisted in most patients (90%) who had previously suffered from renal colic, but had spontaneously eliminated the stone a long time prior to examination (3–10 years), and had no current instrumental evidence of a new calculus or other pathology of the urinary tract. A few of these patients also reported episodic spontaneous colic-type pain with a pattern similar to that experienced at the time of the calculus; electrical stimulation of the hyperalgesic muscle for pain threshold measurement in these cases was able to trigger pain with exactly the same characteristics (quality and spatial distribution) as that perceived spontaneously during the original colic (13). Similar findings were obtained in patients in whom elimination of the stone was promoted through extracorporeal shock wave lithotripsy (ESWL). Muscle thresholds on the affected side were considerably lower than normal before lithotripsy. They tended to increase progressively with the elimination of the stone fragments but remained still significantly lower than normal after complete elimination (14). Thus, in symptomatic urinary calculus, hyperalgesia (mostly muscular) appears at an early stage, is accentuated by the repetition of the painful episodes and is long lasting, sometimes remaining even after the primary visceral focus has been removed. However, hyperalgesia never appears in a urinary calculus which is not symptomatic (2). Detection and, possibly, quantification of the muscle hyperalgesia in the referred pain area should always be part of the examination of the patient. If hyperalgesia is present, muscle infiltration of the painful area with a local anesthetic may produce significant pain relief while no effect is obtained by this procedure in the case of a “referred pain without hyperalgesia” (which is sometimes perceived in the very early stages of the process of pain referral) (15). Together with hyperalgesia, trophic changes are also often present in the referred area, i.e., an increased thickness of subcutis and a decreased thickness of muscle (tendency to muscle atrophy), detected by clinical means (pinch palpation) but also measured instrumentally. Ultrasound evaluation in symptomatic calculi documented a significantly greater subcutis thickness and significantly lower muscle thickness on the affected side than contralaterally. No changes were observed, in contrast, in patients with asymptomatic urinary stones (12). Thus, trophic changes accompanying referred hyperalgesia from viscera, are set off only by nociceptive impulses (“painful” messages) from the internal organ (16). Pathophysiological Mechanisms Acute renal colic from a calculus can be precipitated by dehydration and reduced urine output, increased protein intake, heavy physical exercise, and various medicines (5). Algogenic conditions of other internal organs with partially overlapping innervation, e.g., the female reproductive organs, can also represent a triggering factor for the colic (see next section). Renal pain derives mainly from acute pelvis dilatation due to wedging of the stone in the ureteral lumen (9). When a urinary stone moves into the urinary collecting system the resulting increase in intraluminal pressure stretches nerve endings in the mucosa. Ureteric obstruction also causes increased synthesis and release of prostaglandins, which in turn both increase glomerular filtration and renal pelvic pressure and sensitize nociceptors locally (5). Hypermotility of the ureteral wall above the obstacle also significantly contributes to the symptomatology (17–19). The ureteral nociceptors stimulated in the course of a colic are presumably U-2 type units. These are a large population of high threshold units originally identified in the guinea-pig’s ureter; unlike the U-1 type units, they respond to intense distension but not to peristalsis (20,21). Investigation of mechanisms underlying referred phenomena from symptomatic urinary calculi has been greatly helped by the setting up of an experimental model of the condition. The clinical characteristics of urinary colic have been reproduced in rats with an artificial stone formed in the upper third of one ureter by injection of dental cement (22,23). At long-term nonstop videotape recordings, stone-implanted animals manifest complex behavioral episodes, similar to the writhing behavior characteristic of noxious visceral stimulation in animals (24). These are never manifested in sham-operated rats or rats subjected to non-algogenic ureteric interventions. The episodes vary in frequency and duration. Their number and duration decrease significantly and linearly with time after insertion of the “stone,” and are mostly

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visible during the first three to four days. Number, duration, and complexity of the episodes are significantly reduced in a dose-dependent fashion by chronic treatment with morphine. All these observations together support the notion that this behavior is an index of perceived visceral pain and thus the equivalent of urinary colic in humans. The animals also develop hypersensitivity of the ipsilateral obliquus externus (the same muscle as in humans), as shown by a decrease in the vocalization threshold to electrical muscle stimulation. This hypersensitivity appears on the first day after stone implantation and, although particularly pronounced during the first three to four days, usually lasts for more than a week. A significant direct linear correlation exists between the number of episodes of abnormal behavior and the extent of the ipsilateral muscle threshold decrease, so that hyperalgesia is more accentuated in rats with a higher number of episodes than in those with a smaller number. Furthermore, the hyperalgesia is still detectable one week after stone implantation, even in rats which, at autopsy, prove to have expelled the stone spontaneously. Its extent is dose-dependently reduced by treatment with morphine, tramadol, metamizol, nonsteroidal anti-inflammatory drugs (NSAIDs), or spasmolytics (22,25,26). This animal model of artificial calculi closely resembles the clinical condition of ureteric colic. With respect to the referred hyperalgesia, as in patients, the phenomenon: (i) is mainly localized in muscles of the lumbar region ipsilateral to the affected urinary tract; (ii) appears at an early stage with respect to the start of the activity of the visceral focus; (iii) is accentuated by repetition of painful visceral episodes; and (iv) tends to persist for a long time. This animal model has therefore been used to test pathophysiological hypotheses on referred muscle hyperalgesia. The first theory, which claims a process of central sensitization, triggered by a massive afferent visceral barrage upon convergent viscero-somatic neurons in the central nervous system (CNS) (27,28), has been verified in electrophysiological experiments at spinal cord level. In fact, changes in the excitability and response properties of dorsal horn neurons receiving input from the hyperalgesic muscle in rats with artificial calculi were found compared to control animals. A significantly increased percentage of dorsal horn neurons displayed a receptive field in the hyperalgesic muscle, a significantly higher percentage of which also showed ongoing activity. Neurons with muscle input also presented a decreased threshold of activation via mechanical stimuli. These changes were more marked in animals that had more visceral episodes and muscle hyperalgesia (29). Similar results were obtained by Roza et al. (30), employing this same model, in electrophysiological experiments in which they examined the characteristics of neurons processing information from the ureter (in rats with a calculus vs. rats with an intact ureter). These authors concluded that the presence of a ureteric stone evokes excitability changes in spinal neurons (enhanced background activity, greater number of ureterdriven cells, and decreased threshold of convergent somatic receptive fields) which likely account for the referred muscle hyperalgesia seen in rats with calculi. Based on the results of several experimental studies, N-methyl-D-aspartate receptors would seem to play an important role in the generation of these central hyperexcitability changes (27). The fact that hyperalgesia often outlasts the presence of the “macroscopic” peripheral visceral focus in the clinical setting, has led to the hypothesis that the central plastic changes, once established may persist, becoming relatively independent of the primary triggering event (31). However, the results of studies on ureteric motility in rats with artificial ureteral calculi (abnormal hypermotility persisting long after stone elimination) (17), suggest that a number of “clinically inapparent” peripheral visceral changes are likely to outlive the presence of the primary focus, and thus maintain the state of central hyperexcitability due to persistence of the peripheral drive. Central changes, however, are probably not the sole mechanism involved in referred muscle phenomena, as suggested by the presence of objective (trophic) changes in deep somatic tissues. The afferent barrage from the internal organ is likely to activate a number of viscero-somatic reflexes toward the periphery responsible for both the increased sensitivity and the changes in thickness and consistency of subcutis and muscle (16,28). Regarding the muscle, in particular, the “reflex arc activation” would promote reflex muscle contraction, in turn possibly responsible for sensitization of nociceptors locally, which would account for the hyperalgesia (32). This theory had originally been put forward on the basis of the clinical observation of the sustained muscle contraction that so often accompanies the states of prolonged visceral pain in the area of referral (11,28). Recent studies by this group have provided some experimental evidence for this so far

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theoretical mechanism, by employing the previously described animal model of artificial ureteric calculi. In stone rats, the possible correlations were investigated between the condition of hyperalgesia of the ipsilateral oblique musculature and some morpho-functional indices of skeletal muscle contraction (33). In specimens from the hyperalgesic obliquus externus compared to the contralateral muscle, the following significant changes were found: (i) decreased I band length/sarcomere length ratio (ultrastructural contraction index); (ii) increased muscle cell membrane fluidity; (iii) increased sarcoplasmic reticulum (SR) Ca2Cuptake capacity (measured as Ca2C-ATPase activity), which correlated linearly to the number of ureteral “crises,” and (iv) decreased SR-Ca2C release capacity (measured as ryanodine binding). These results suggest the presence, proportional in degree to the activity of the ureteral pain focus, of a state of skeletal muscle contraction in the oblique musculature ipsilateral to the stone, which could contribute to the generation of the local hyperalgesia via sensitization of muscle nociceptors. In a parallel study, c-Fos expression was explored in the spinal cord (T9–L3) of stone rats versus sham controls (34). Fos-labeled cells were never observed in sham controls. In stone rats, they were found throughout the dorsal horn (laminae I–VI) bilaterally, but significantly more on the side ipsilateral to the implanted ureter. As expected, most of the Fos expression was in the superficial dorsal horn but Fos-labeled cells were also found in the ventral gray (laminae VII–X), mostly in lamina VII (containing preganglionic sympathetic neurons of the intermediolateral nucleus in segments T1–L3) and in lamina IX (motoneurons). These results thus suggest that nociceptive input from the ureter in this model activates not only sensory neurons but also efferent neurons in the spinal cord, supporting the notion that reflex arcs are triggered by the visceral focus and that the muscle contraction in the referred site may result from a reflex mechanism. Diagnosis In the acute setting (i.e., renal colic), documentation of stone characteristics (type, size, and location) is extremely important. Intravenous pyelography remains the gold standard for such identification, although there is a risk of allergy and contrast nephropathy. Ultrasonography can indicate whether a stone is in the kidney or ureter, the degree of any obstruction, and quality of renal parenchyma. Plain abdominal radiography is useful for stones above the pelvic brim, and, with ultrasonography, is the investigation of choice in patients unable to tolerate an intravenous pyelogram (5,9). Therapy Renal colics require prompt symptomatic treatment. The NSAIDs are considered a first-line treatment (35–37). They inhibit renal prostaglandin synthesis, with consequent decrease in renal blood flow and diuresis, and pressure lowering in the renal pelvis and ureter. Experimental studies have also shown a positive effect of NSAIDs on ureteral contractility, though the clinical impact of this spasmolytic action remains to be demonstrated (36,38). Apart from the possible spasmolytic effect of NSAIDs, both clinical observations and experimental studies suggest that the association of a NSAID with a specific spasmolytic compound is more effective in relieving the pain of a urinary colic than NSAIDs alone (25). Though NSAIDs given orally or intravenously have good analgesic properties in patients, they also have serious gastrointestinal and renal side effects. Renal side effects are especially important in dehydrated patients and those at risk of allergy to these drugs. Cyclooxygenase-II inhibitors have been developed to reduce gastrointestinal effects, but they also inhibit renal vasoactive substances and are contraindicated in patients with renal insufficiency. Paracetamol given every four hours is well tolerated, but pain relief is often inadequate with this agent alone. Dipyrone is a non-opioid analgesic which has also been shown to be effective in relieving the pain of renal/ureteric colics in controlled clinical trials (39). Its action has also been tested experimentally in calculosis rats, where it inhibited the pain behavior of the animals, the ureteric peristalsis, and the activity of nociceptive dorsal horn neurons with ureteric input (26,40). Narcotic analgesics including morphine (given intramuscularly or intravenously in patients) and pethidine offer good pain relief and have so far been drugs of choice in many

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countries for the treatment of renal colics (35). However, they are sedative and have the risk of dependence if used for a long time. More recently, tramadol (another centrally active drug with lesser side effects, lower respiratory depression, tolerance, and dependence than morphine) has also proven effective (41,42). Medical management of a stone depends on the type of stone, and includes correction of dietary aberrations, metabolic defects, or both (5). ESWL is another important therapeutic approach for stones larger than 5 mm (smaller stones normally pass spontaneously) (5,43,44). As already reported above, ESWL induces fragmentation of the stone and thus promotes spontaneous elimination of the fragments afterwards. The procedure is normally well tolerated by the patients and requires only minimal sedation/analgesia, though women seem to report more discomfort than men during treatment (45).

URINARY COLICS AND VISCERO-VISCERAL HYPERALGESIA Viscero-visceral hyperalgesia is a phenomenon of enhancement of visceral pain symptoms because of the concurrence, in the same patient, of algogenic conditions in two internal organs which share at least part of their central sensory projection (2). In the case of painful diseases from the urinary tract, viscero-visceral hyperalgesia may occur when algogenic conditions are simultaneously present in the female reproductive organs. An example is provided by patients affected with urinary calculi and dysmenorrhea (common projection between uterus and upper urinary tract: T10–L1) (46,47). In both a retrospective study over a three-year period, and a prospective study over two years, patients affected with the two conditions have been shown to present a significantly higher number of colic episodes, than patients with renal calculi only, and a significantly higher degree of referred muscle hyperalgesia at lumbar level, in the typical area of pain referral from the upper urinary tract (47). These patients also have more painful menstrual cycles and referred muscle hyperalgesia in the lower abdominal quadrants (area of pain referral from the uterus) than patients with dysmenorrhea only. The interesting observation is that the enhancement of symptoms between the urinary area and the female reproductive area occurs also when one algogenic visceral condition is latent. In fact, women with silent endometriosis (documented at laparoscopy performed for infertility reasons but with no spontaneous pelvic pain) have an increased number of colic episodes, and a greater degree of referred lumbar muscle hyperalgesia than women with urinary calculi only, over a comparable period of time (47,48). Though no systematic studies have so far been conducted to document the trophic changes in the referred areas of patients with viscero-visceral hyperalgesia as compared to patients with one condition only, the clinical observation suggests that these changes, too, are enhanced, similarly to what has been documented for referred hyperalgesia (15,16). A plausible hypothesis to account for viscero-visceral hyperalgesia is that of sensitization of viscero-visceral convergent neurons in the CNS. Viscero-visceral convergences have been documented in the CNS between different internal organs, in particular, between the female reproductive organs and the urinary tract [see Refs. 16,49]. Thus an increased afferent input from one visceral domain would enhance the central effect of the sensory input from the second internal organ, producing the enhancement of symptoms. Since neurons receiving visceral inputs systematically receive convergent input from somatic structures, sensitization of viscero-visceral convergent neurons would also result in an enhancement of the referred somatic hyperalgesia from the visceral areas involved. This hypothesis needs of course to be verified in experimentally controlled studies. One promising animal model of viscero-visceral hyperalgesia is that of ureteric calculi combined with experimental endometriosis in female rats (49). In this model, mimicking the human condition of viscero-visceral hyperalgesia between the urinary tract and the female reproductive organs, an enhancement is observed not only of the spontaneous pain behavior of the animal (both “ureteral” and “uterine”) but also of the referred lumbar muscle hyperalgesia, with a post-stone decrease in vocalization thresholds to electrical muscle stimulation significantly more pronounced than in rats with a stone only, or rats with sham endometriosis plus stone. Similarly to what is observed in humans, treatment of only one condition in this model relieves symptoms from the other, i.e., treatment of

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endometriosis before stone formation (with NSAIDs or tramadol) prevents the enhancement of pain symptoms from the ureter (ureteral colic and referred lumbar muscle hyperalgesia) (49). Preliminary electrophysiological studies in rats with endometriosis plus ureteral calculosis, versus rats with sham endometriosis plus ureteral calculosis, have shown that neurons with an input from the hyperalgesic muscle (located in the deep portion of the dorsal horn, where projections of the involved viscera are also found) present significant increase in excitability and expansion of their receptive fields. These findings, indicative of sensitization, would support the notion that central mechanisms contribute to the phenomenon of pain enhancement between two viscera. The diagnosis of viscero-visceral hyperalgesia from the urinary tract in the clinical setting is often not easy, but the phenomenon should always be suspected when colic is particularly frequent and the referred lumbar hyperalgesia abnormally intense in relation to the position of the stone in the urinary collecting system. In these cases, exploration of other possible sources of algogenic impulses in neuromerically connected visceral organs, especially those of the female reproductive area, is always advisable (15). “Viscero-visceral hyperalgesia” is receiving increasing attention in medical practice as evidence is growing not only about the high frequency of the co-occurrence, in the same patients, of algogenic conditions in visceral organs with partially overlapping innervation but also about the therapeutic implications of the phenomenon. It has been shown, in fact, that effective treatment of one condition may significantly improve typical symptoms from the other, e.g., decrease in urin pain and referred hyperalgesia at lumbar level, after hormonal treatment of dysmenorrhea, or decrease in menstrual pain and referred abdominopelvic hyperalgesia after urinary stone elimination following lithotripsy (2,16,47). CONCLUSION Renal pain is a major clinical entity not only in its direct expression but also because of its indirect consequences, in terms of long-term sensory and trophic changes produced in the area of referral (16). Its prompt recognition and treatment are therefore mandatory not only for the patient’s relief, considering its often extreme intensity, but also for the prevention/limitation of these changes. Renal pain can furthermore also trigger and be triggered by algogenic conditions of other visceral structures with sensory projections partially overlapping with the urinary collecting system. This relatively recent notion is of the utmost importance in clinical practice and stresses the necessity for a comprehensive evaluation of the pain patient, i.e., including several areas, even when pain seems absolutely typical of that from the urinary tract (15). The lesson that clinicians should therefore learn is that optimal management of urinary pain may also involve the effective management of other visceral conditions even though these are at a latent algogenic stage. REFERENCES 1. Vasavada PV, Comiter CV, Raz S. Painful diseases of the kidney and ureter. In: Loeser JD, ed. Bonica’s Management of Pain. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2001:1309–25. 2. Giamberardino MA. Visceral hyperalgesia. In: Devor M, Rowbotham MC, Wiesenfeld-Hallin Z, eds. Proceedings of the 9th World Congress on Pain. Progress in Pain Research and Management. Vol. 16. Seattle, WA: IASP Press, 2000:523–50. 3. Giamberardino MA. Urogenital pain and phenomena of viscero-visceral hyperalgesia. In: Giamberardino MA, ed. Pain 2002—An Updated Review, Refresher Course Syllabus. Seattle, WA: IASP Press, 2002:413–22. 4. Ramello A, Vitale C, Marangella M. Epidemiology of nephrolithiasis. J Nephrol 2000; 13(3):45–50. 5. Bihl G, Meyers A. Recurrent renal stone disease—advances in pathogenesis and clinical management. Lancet 2001; 358:651–6. 6. Trinchieri A, Coppi F, Montanari E, et al. Increase in the prevalence of symptomatic upper urinary tract stones during the last ten years. Eur Urol 2000; 37:23–5. 7. Laerum E, Murtagh J. Renal colic and recurrent urinary calculi. Management and prevention. Aust Fam Physician 2001; 30:36–41. 8. Rinnab L, Gottfried HW, Hautmann RE, et al. Rational diagnostic and therapy of renal colic in the year—what’s new? Zentralbl Chir 2005; 130(6):505–13.

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9. Ansell JS, Gee WF. Diseases of the kidney and ureter. In: Bonica JJ, ed. The Management of Pain. 2nd ed., Vol. 2. Philadelphia, PA: Lea & Febiger, 1990:1232–49. 10. Loeser JD, ed. Bonica’s Management of Pain. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2001, 2178. 11. Vecchiet L, Giamberardino MA, Dragani L, et al. Pain from renal/ureteral calculosis: evaluation of sensory thresholds in the lumbar area. Pain 1989; 36:289–95. 12. Vecchiet L, Giamberardino MA, Dragani L. Referred muscular hyperalgesia from viscera: clinical approach. Adv Pain Res Ther 1990; 13:175–82. 13. Vecchiet L, Giamberardino MA, de Bigontina P. Referred pain from viscera: when the symptom persists despite the extinction of the visceral focus. Adv Pain Res Ther 1992; 20:101–10. 14. Giamberardino MA, de Bigontina P, Martegiani C, et al. Effects of extracorporeal shock-wave lithotripsy on referred hyperalgesia from renal/ureteral calculosis. Pain 1994; 56:77–83. 15. Giamberardino MA. Visceral pain. Pain Clin Updates 2005; XIII(6):1–6. 16. Giamberardino MA, Affaitati G, Costantini R. Referred pain from internal organs. In: Cervero F, Jensen T, eds. Handbook of Clinical Neurology. Vol. 81. Amsterdam: Elsevier, 2007:343–61 . 17. Laird JMA, Roza C, Cervero F. Effects of artificial calculosis on rat ureter motiliy: peripheral contribution to the pain of ureteric colic. Am J Physiol 1997; 272:1409–16. 18. Rose GJ, Gillenwater JY. Effects of obstruction on ureteral function. Urology 1978; 12:139–45. 19. Thulesius O, Angelo-Khattar M, Sabha M. The effect of ureteral distension on peristalsis. Studies on human and sheep ureters. Urol Res 1989; 17:385–8. 20. Cervero F. Visceral nociceptors. In: Belmonte C, Cervero F, eds. Neurobiology of Nociceptors. Oxford, NY: Oxford University Press, 1996:220–40. 21. Cervero F, Sann H. Mechanically evoked responses of afferent fibres innervating the guinea-pig’s ureter: an in vitro study. J Physiol 1989; 412:245–66. 22. Giamberardino MA, Valente R, de Bigontina P, et al. Artificial ureteral calculosis in rats: behavioural characterization of visceral pain episodes and their relationship with referred lumbar muscle hyperalgesia. Pain 1995; 61:459–69. 23. Giamberardino MA, Vecchiet L, Albe-Fessard D. Comparison of the effects of ureteral calculosis and occlusion on muscular sensitivity in rats. Pain 1990; 43:227–34. 24. Le Bars D, Gozariu M, Cadden SW. Animal models of nociception. Pharmacol Rev 2001; 53:597–652. 25. Giamberardino MA, Valente R, de Bigontina P, et al. Effects of spasmolytics and/or non-steroidal antiinflammatories on muscle hyperalgesia of ureteral origin in rats. Eur J Pharmacol 1995; 278:97–101. 26. Laird JMA, Roza C, Olivar T. Antinociceptive activity of metamizol in rats with experimental ureteric calculosis: central and peripheral components. Inflamm Res 1998; 47:389–95. 27. Cervero F, Laird JM. Understanding the signaling and transmission of visceral nociceptive events. J Neurobiol 2004; 61(1):45–54. 28. Procacci P, Maresca M. Clinical approach to visceral sensation. In: Cervero F, Morrison JFB, eds. Visceral Sensation. Progress in Brain Research. Vol. 67. Amsterdam: Elsevier, 1986:21–8. 29. Giamberardino MA, Dalal A, Valente R, et al. Changes in activity of spinal cells with muscular input in rats with referred muscular hyperalgesia from ureteral calculosis. Neurosci Lett 1996; 203:89–92. 30. Roza C, Laird JM, Cervero F. Spinal mechanisms underlying persistent pain and referred hyperalgesia in rats with an experimental ureteric stone. J Neurophysiol 1998; 79(4):1603–12. 31. Melzack R, Coderre TJ, Katz J, et al. Central neuroplasticity and pathological pain. Ann NY Acad Sci 2001; 933:157–74. 32. Giamberardino MA, Affaitati G, Lerza R, et al. Relationship between pain symptoms and referred sensory and trophic changes in patients with gallbladder pathology. Pain 2005; 114:239–49. 33. Giamberardino MA, Affaitati G, Lerza R, et al. Evaluation of indices of skeletal muscle contraction in areas of referred hyperalgesia from an artificial ureteric stone in rats. Neurosci Lett 2003; 338:213–6. 34. Aloisi AM, Ceccarelli I, Affaitati G, et al. c-Fos expression in the spinal cord of female rats with artificial ureteric calculosis. Neurosci Lett 2004; 361:212–5. 35. Holdgate A, Pollock T. Nonsteroidal anti-inflammatory drugs (NSAIDs) versus opioids for acute renal colic. Cochrane Database Syst Rev 2005; 18(2):CD004137. 36. Mastrangelo D, Wisard M, Rohner S, et al. Diclofenac and NS-398, a selective cyclooxygenase-2 inhibitor, decrease agonist-induced contractions of the pig isolated ureter. Urol Res 2000; 28:376–82. 37. Shokeir AA, Abdulmaabound M, Farage Y, et al. Resistive index in renal colic: the effect of nonsteroidal anti-inflammatory drugs. BJU Int 1999; 84:249–51. 38. Nakada SY, Jerde TJ, Bjorling DE, et al. Selective cyclooxygenase-2 inhibitors reduce ureteral contraction in vitro: a better alternative for renal colic? J Urol 2000; 163:607–12. 39. Muriel-Villoria C, Zungri-Telo E, Diaz-Criel M, et al. Comparison of the onset and duration of the analgesic effect of metamizol, 1 or 2 g, by the intramuscular or intravenous route, in acute renal colic. Eur J Clin Pharmacol 1995; 48:103–7. 40. Neugebauer V, Schaible H-G, He X, et al. Electrophysiological evidence for a spinal antinociceptive action of metamizol. Agents Actions 1994; 41:62–70.

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41. Affaitati G, Giamberardino MA, Lerza R, et al. Effects of tramadol on behavioral indicators of colic pain in a rat model of ureteral calculosis. Clin Fundam Pharmacol 2002; 16:23–30. 42. Dayer P, Desmeules J, Collart L. Pharmacology of tramadol. Drugs 1997; 53(2):18–24. 43. Kravchick S, Bunkin I, Stepnov E, et al. Emergency extracorporeal shockwave lithotripsy for acute renal colic caused by upper urinary-tract stones. J Endourol 2005; 19(1):1–4. 44. Tombal B, Mawlawi H, Feyaerts A, et al. Prospective randomized evaluation of emergency extracorporeal shock wave lithotripsy (ESWL) on the short-time outcome of symptomatic ureteral stones. Eur Urol 2005; 47(6):855–9. 45. Robert M, Lanfrey P, Rey G, et al. Analgesia in piezoelectric SWL: comparative study of kidney and upper ureter treatments. J Endourol 1999; 13:391–5. 46. Giamberardino MA, Berkley KJ, Iezzi S, et al. Pain threshold variations in somatic wall tissues as a function of menstrual cycle, segmental site and tissue depth in non-dysmenorrheic women, dysmenorrheic women and men. Pain 1997; 71:187–97. 47. Giamberardino MA, De Laurentis S, Affaitati G, et al. Modulation of pain and hyperalgesia from the urinary tract by algogenic conditions of the reproductive organs in women. Neurosci Lett 2001; 304:61–4. 48. Farquhar CM. Extracts from the “clinical evidence”. Endometriosis. Br Med J 2000; 320:1449–52. 49. Giamberardino MA, Berkley KJ, Affaitati G, et al. Influence of endometriosis on pain behaviors and muscle hyperalgesia induced by a ureteral calculosis in female rats. Pain 2002; 95:247–57.

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Loin Pain in Hematuria Syndrome Guy H. Neild

Institute of Urology and Nephrology, University College London, London, U.K.

Christopher M. Bass

Department of Psychological Medicine, John Radcliffe Hospital, Oxford, U.K.

SUMMARY Loin pain hematuria syndrome (LPHS) is a descriptive account of recurrent episodes of severe loin pain, often accompanied by hematuria, in which investigations do not reveal adequate pathology to account for the symptoms. The majority of patients present between 20 and 40 years of age. Women are more commonly affected. The patients are a relatively homogeneous group and should be reassured, along with their doctors, that they will maintain normal renal function and need no further investigation. The pain is characteristically unilateral and can be typical of renal colic. Pain may occur on both sides, but rarely at the same time. When present hematuria may be either microscopic or macroscopic, the latter can occur with clots. Pain and hematuria can occur together or independently of each other. Nothing relieves the pain except nonspecific analgesia. Some episodes of pain are very severe that they result in hospital admission and require opiate analgesia. The pain may be continuous and intense leading to the requirement for addictive analgesics: management often becomes very difficult and frustrating for medical practitioners. A significant number of patients report psychological and social problems. It is important that their assessment includes a detailed developmental and psychiatric history, and obtaining previous medical and primary care notes is invaluable. This may reveal a previous history of medically unexplained or functional syndromes. Although most patients do not have conspicuous mental illness, exploration of life events, illness beliefs, and pain coping strategies often yield useful information. Renal function, blood pressure, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are normal. Intravenous pyelograms (IVPs), retrograde pyelograms, cystoscopy reveal no abnormalities that account for the symptoms. The urine is sterile. Ureteric catheterization at the time of bleeding may demonstrate unilateral hematuria. The renal arteriogram is usually normal, but focal disorganization of peripheral arteries has been reported. The renal biopsy is normal, except that red cells are seen in tubules and often arteriolar and arterial hyalinosis are seen, which is out of proportion to the patient’s age and blood pressure. The etiology and pathogenesis are unknown. There are several reported cases in which the condition was precipitated by starting oral contraceptives and resolved after the pill was stopped. Evidence of platelet activation in the circulation has been described, but antiplatelet therapy has been unsuccessful. Some patients have a previous history of passing stones, although nephrolithiasis is not seen radiologically; others have had documented episodes of pyelonephritis. Surgical intervention with capsulotomy, denervation, and auto-transplantation has sometimes been undertaken as a last resort. Renal denervation can relieve the pain for one or more years, but it almost invariably recurs. In the meantime the pain transfers to the other side, gradually becoming as severe.

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We believe that this difficult group of patients should be seen in those regional specialist centers which also have suitable facilities for the management of chronic pain, which includes the provision of psychological assessment and support. INTRODUCTION In 1967, Little and his colleagues described a syndrome consisting of unexplained symptoms of severe loin pain and intermittent hematuria in three women (1). They observed that during episodes of pain fever might occur, that the patients did not appear ill, but all had marked unilateral or bilateral loin tenderness. They described the typical patient as: “On admission they were anxious, introspective and demanding of medical attention and occasionally fabricated evidence, presumably in an attempt to demonstrate that their pain was genuine. All had been seen by a variety of specialists, including psychiatrists, neurologists, orthopedic surgeons, gynecologists, and physicians in physical medicine.” Ten years later, Aber and his colleagues (1975) reported a larger group of 12 similar patients, although hematuria was not an invariable feature (2). They noted that all were women and five were nurses. A third center soon reported (1979) another nine cases, again all women (3). They did not comment on occupation but noted that two showed “frank neurotic features.” The original reports (1,2) also emphasized that all cases had evidence of disease of the peripheral renal arteries demonstrated by renal angiogram. Other centers, however, were not able to confirm the regular presence of the angiographic changes (4), and these are now ascribed to injection artifacts (5). Since the 1970s, there have been sporadic reports of LPHS in which pathogenesis and treatment have been investigated, but there has been no further large contribution to the demography of the syndrome. In this review, we report our own experience which includes over 100 patients referred with a diagnosis of LPHS. CASE DEFINITION It has proved impossible to achieve a satisfactory case definition for LPHS (6,7). At best, LPHS is a descriptive account of patients with recurrent episodes of severe loin pain, which may be accompanied by hematuria, in which investigations do not reveal relevant organic pathology to account for the symptoms. Among the problems of describing this heterogeneous group is that some patients do not have documented hematuria; some patients have certainly passed stones in the past; others have certainly had previous episodes of pyelonephritis and may even have renal scars documented by static isotope scanning using 99Tc-DMSA. But in all these examples, the pain currently experienced cannot be attributed to these past problems—unless one postulates some form of “renal neuralgia” resulting from previous injury.a What describes all our patients with LPHS is that they attend a renal clinic having been convinced that their pain is of renal origin. PATIENT CONSULTATION WITH NEPHROLOGIST For the patient this is a most important day and they have a lot to tell you. They have seen any number of specialists and you are their last hope. We always see them at the end of a clinic, and set aside at least one hour for the consultation. We listen to the whole story from the patient and later only compare it with events in the accumulated correspondence. The normal structure of a medical consultation is followed but with more detail and emphasis on certain aspects. a

Of the three original patients described by Little (1), case 1 would now be considered to have secondary FSGS as a consequence of reflux nephropathy; case 2 was documented as having passed a stone; and case 3 would probably now be found to have IgA nephropathy.

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History of the Pain Establish the exact time and date of onset of the pain and all the details of the initial episode. Ask for details of the second episode and then discuss the current situation. Establish the current level of medication and in particular the extent to which analgesia helps the pain. Ask for factors that may initiate or exacerbate the pain, and factors that alleviate the pain. Establish if and when opiates were first used. In any given year how often has the patient had to go to A&E for pain treatment or admission, or call out the general practice (GP) for similar reasons? Hematuria Some of the patients will report hematuria. It is important to elicit precise details of the evidence for blood in the urine; particularly whether microscopic hematuria is intermittent, and the relationship if any with the pain. If hematuria is present, then did the patient ever have a previous urine test that might be documented in GP files or hospital records before the current illness? Can one establish that the patient with hematuria was definitely known not to have hematuria at an earlier date? If there is persistent microscopic hematuria ask for other family members to be tested, i.e., parents, siblings, and children, to see if there is any familial association.b Past History A conventional history is taken, but direct questions asked about other specialists seen for other symptoms, and other procedures related to these consultations. Ask about the amount of contact with GP so that one would have an opinion about the volume of GP records. Further questions are asked that relate to stress in the past, or specific treatment for “nerve” problems. It is important to determine whether the patient has previously experienced symptoms that, despite investigation, have not been explained. Family and Social History It is important to determine whether other members of the family have had kidney problems— particularly kidney stones or kidney cancer. Whether there is a family history of premature cancer, and if any member of the family was remarkably ill, or died, at the time of onset of the patient’s symptoms. It is important to know whether either parent was unusually or persistently unwell during the patient’s childhood (see Section entitled “Psychological Characteristics”). Many patients will be out of work because of the pain, but one needs to establish the kind, and pattern, of work at the time of onset of the pain and the subsequent episodes of time off work. If patients are still at work, establish the number of hours or days lost per week. To what extent does the pain interfere with social life, and prevent the patient from carrying out routine tasks such as shopping and taking children to school. Current Health The age group generally affected should be fit and well—so it is important to establish whether there are other symptoms that interfere with life or have required consultation with the GP. In particular, symptoms that have been investigated without any abnormality being found (such as fatigue, abdominal pain, frequency, and urgency). b

It is sometimes clear that the patient has had asymptomatic microscopic hematuria for years, but when an abdominal, back, or loin pain occurs, the hematuria is “discovered,” and the kidneys are blamed for the pain—even though there is nothing about the pain that would ever make one consider a renal origin.

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Examination In particular one should try to establish whether there is a full range of painless, thoracic and lumber spine movement. When pain is present it is often clear that spinal movement is severely limited by paraspinal muscle spasm. Also determine whether in the area of pain there is local tenderness of the skin or deeper structures, and any evidence of hyperalgesia.

INVESTIGATING THE PATIENT Loin pain hematuria (LPH) patients are usually referred after they have already been extensively over-investigated. Renal function, blood pressure, and CRP and ESR are normal. The urine is sterile and urine cytology unremarkable. Plain abdominal X rays, renal ultrasound, IVPs, retrograde pyelograms, cystoscopy, all reveal no abnormalities that accounts for the pain. Today magnetic resonance imaging and computerized tomography (CT) scans are added to the lists. Urological It is vital not to repeat tests that were previously normal—unless there is an appropriate new reason. Patients may consume vast quantities of analgesics and over the counter remedies, and so a change in the pattern of hematuria, or new onset hematuria, will warrant repeat cytology and when appropriate repeat cystoscopy. Some patients will have passed stones in the past and so a plain film of the abdomen, sometimes with a renal ultrasound, will be necessary from time to time. The passage of either gravel or stones is reported by some patients without supporting documentation. Some patients with LPHS present with severe renal colic and macroscopic hematuria. The signs and symptoms are typical of renal stones but the passage of a stone is never documented, nor stones confirmed radiologically. This is very frustrating for patient and doctor alike. For patients with recurrent macroscopic hematuria we would always attempt to cystoscope the patient during an episode. It is vital to confirm that the patient does have hematuria before cystoscopy is performed. Ureteric catheterization at the time of bleeding may demonstrate unilateral hematuria, and sometimes retrograde ureteroscopy is indicated. There are also anecdotes of patients whose pain and symptoms have vanished after ureteric reimplantation for “vesico-ureteric reflux” or after nephropexy for nephroptosis (see below). Nephrological Loin pain can be a feature of acute glomerulonephritis, particularly IgA nephropathy in which it is associated with hematuria (8); the etiology of the pain in these cases remains unknown. For some patients with recurrent macroscopic hematuria and bilateral symptoms, and for all patients with hematuria and significant proteinuria, a renal biopsy is indicated. We have found renal biopsy unrewarding as an investigation for unexplained hematuria—without proteinuria (see the following section entitled “Histopathology”). Even if the biopsy does show thin glomerular basement membrane disease or IgA disease, both of which will explain the hematuria, it will not alter the management when the issue is severe loin pain. On the other hand, renal biopsy may reassure patients that, despite their intractable symptoms, a good prognosis without renal failure can be assured.

DIFFERENTIAL DIAGNOSIS There are many causes of loin pain that may be associated with hematuria and vice versa. The important differential diagnoses are shown in Table 1.

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TABLE 1 Causes of Hematuria with Loin Pain

Surgical causes Transitional cell carcinoma bladder, ureter, renal pelvis Renal cell carcinoma Stone disease Uroepithelial arteriovenous malformation Trauma Vesicoureteric reflux Nephroptosis Papillary necrosis Analgesic abuse Sickle cell disease HbS (trait), HbSC Glomerular disease IgA nephropathy Thin GBM disease Membrano-proliferative gn Vasculitis Nonglomerular medical causes Tuberculosis bladder, ureter, renal pelvis Other renal infection malakoplakia, xanthogranulomatous Schistosomiasis Drug-induced interstitial nephritis Blood dyscrasias anticoagulation Exercise-induced hematuria Hereditary telangiectasia

Intermittent macroscopic

Loin or ureteric pain

C C C C C C ?C

C C C 0a C C ?C

C C C C C C C C C C C C C C C

C C C C C C C C C C C C 0 0 0

a

Any cause of gross macroscopic hematuria may be associated with concomitant clot-colic. Abbreviations: GBM, glomerular basement membrane; HbS, Hemoglobin S; HbSC, Hemoglobin SC.

HISTOPATHOLOGY Given that many of the patients have had previous demonstrable renal symptoms (such as stones, or pyelonephritis), it is not surprising that a variety of other nonspecific changes such as minor, focal ischemia are often mentioned. The only renal histopathology that has been reported with any degree of consistency is a range of abnormalities of renal vasculature, from focal disorganization of peripheral arterioles to severe atherosclerotic and occlusive lesions with areas of cortical infarction. Focal C3 deposition in renal arterioles has also been commonly described (3,9,10). The published literature is reviewed in more detail by Weisberg and his colleagues (6). The first report of LPHS gave a detailed account of histological changes in the three cases (1). In case 1, a wedge biopsy revealed “scattered foci of interstitial fibrosis and scattered, sometimes grouped, fibrous glomerular tufts. There were a few foci of interstitial lymphocytic infiltration. Occasional tubules were atrophic. Occasional scattered arterioles showed “fibrous” intimal thickening, but no elastic hyperplasia. This intimal change was conspicuous and appeared to narrow the lumen (illustrated in paper). In the hila of three contiguous glomeruli, there were small deposits of fibrinoid material.”c A second needle biopsy performed a year later showed “less-marked changes” but also showed one tubule distended by colloid with atrophic epithelium. In retrospect, one can say that these changes are all typical of mild reflux nephropathy. In case 2, a 25-year-old woman who had passed a small stone containing calcium, oxalate, and phosphate, an open renal biopsy showed “areas of interstitial fibrosis especially beneath the capsule. Some large arterioles showed slight fibroelastic intimal hyperplasia; some glomeruli were replaced by collagen. Apart from one focus of 30 lymphocytes and histiocytes, there were very few such cells.” Case 3, who c

The glomerular changes are entirely in keeping with those now described as “secondary focal and segmental glomerulosclerosis with hyalinosis” and associated with reflux nephropathy.

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had a history that we would now consider typical of IgA nephropathy (with hematuria following a sore throat), a needle biopsy in 1963 showed “slight glomerular capsular fibrosis, excessive for her age.” There was also marked narrowing of the lumina of some glomerular arterioles; these showed a curious concentric increase in the number of cells in the arteriolar wall (illustrated). A second biopsy showed only “a slight fibroelastic intimal hyperplasia in an arteriole.” This was before immunostaining was introduced and before the description of IgA nephropathy. The second significant report of LPHS described eight patients investigated with renal biopsy and arteriogram and emphasized how normal the biopsies appeared (3). There was “an increase in glomerular matrix and sometimes in the number of mesangial cells. Otherwise the glomeruli were normal in every aspect and no blood vessel changes were seen. Four out of eight showed deposits of immune reactive protein in arteriolar walls: IgM in one case, C3 and C4 in two cases, and C4 and C1q in one case.” A similar systematic investigation of four patients in Finland showed “only slight arteriolar hyalinosis or mild mesangial proliferation,. and minor deposits of C3 in mesangium and arterioles (9).” Our Experience We have been able to review biopsies from 27 patients, the great majority performed before 1990. Eighteen (67%) specimens were from women. Red cell in tubules, as evidence of hematuria, was seen in 20 (74%). In 11 cases (41%), there were either rare sclerosed glomeruli or small foci of scarring seen. We looked carefully for arteriolar hyalinosis. When seen it was often conspicuous but very focal (generally best seen on PAS-stained section). Hyalinosis or an inappropriate degree of intimal fibrosis of arteries was seen in 10 biopsies (37%). In three cases, the juxta-glomerular apparatus was conspicuously enlarged (a feature normally only seen in renal artery stenosis, nephrotic syndrome, or cyclosporine toxicity). In four cases there was borderline glomerular mesangial cell proliferation and in two of these IgM was seen in the mesangium. Electron microscopy was available in 20 cases and 25% showed focal areas of abnormal thinning of the glomerular basement membrane. These changes would now be considered consistent with “thin glomerular basement membrane disease.” Immunoperoxidase was available in 78% of cases; C3 deposition in arterioles was not commented on in any of our biopsy reports. PATHOGENESIS There are a number of features of LPHS that suggest possible pathogenetic mechanisms: 1. Loin pain can (rarely) be a feature of acute glomerulonephritis, particularly IgA nephropathy in which it is associated with hematuria (8); the etiology of the pain in these cases remains unknown. 2. Some patients report the passage of either gravel or stones, but the lack of confirmatory metabolic and radiological evidence raises doubts over the cause of these symptoms. Other patients have symptoms that are entirely typical of ureteric colic suggesting that there may be pathology or functional disturbance of the ureter. 3. Both hematological and histopathological reports had documented abnormalities which might reflect vascular injury in the kidney. Renal Pain There are approximately 15 small nerves that supply the kidney (11). They accompany the renal artery and its branches, and are distributed to the blood vessels and to the cells of the renal tubules. The sympathetic nerves are derived from the renal plexus, which is formed by branches from the coeliac plexus, the lower and outer part of the coeliac ganglion and aortic plexus, and from the lesser and lowest splanchnic nerves (T11–L2).

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Renal afferent pain fibers travel along sympathetic pathways through the sympathetic ganglia (coeliac and aortico-renal) and lumbar splanchnic nerves to reach the spinal cord over T11–L2 dorsal nerve roots. Some kidneys have a crossed sensory innervation. The upper abdominal ureter (upper third) receives innervation from renal plexus, via least splanchnic and pain is referred in a T12 distribution to inguinal region anteriorly, superior thigh, and lower back. The lower abdominal ureter (mid-third) from superior hypogastric plexus, via lumbar splanchnic, referred inguinal, pubic region, and superior, anterior thigh (L1–L2); Pelvic ureter from hypogastric plexus, via pelvic splanchnic, to posterior thigh, leg, and perineum (S2–S4). There are three types of renal pain: visceral, colic, and referred. Visceral pain is felt over the costovertebral angle and occasionally in the subcostal area. Stimulation (electrical, stretch, and pressure) of the peri-pelvic renal capsule, pelvis, renal artery or vein produces visceral pain. Renal colic does not result from hyperperistalsis, but is due to acute distension of the renal pelvis and upper ureter. Moreover, the pain of “ureteric colic” associated with the passage of a stone, is constant and not paroxysmal as occurs typically with intestinal obstruction. Referred renal pain may be felt in the dermatomes shared by the common afferent input to T11–L2 and simulate the pain from appendix, gallbladder, and epididymis. Most forms of visceral pain produce two additional sensory alterations: increased tenderness in remote and superficial areas of the body (“hyperalgaesia”) and enhanced pain sensitivity of the same or adjacent viscera (“visceral hyperalgaesia”) (12). Clinical and experimental observations indicate that these phenomena originate in the central nervous system (“central sensitization”). A contribution of central sensitization to the development of noncardiac chest pain has been demonstrated (13). Visceral hypersensitivity is frequently found in patients diagnosed with “irritable bowel syndrome,” although hyperalgaesia does not seem to be a constant reproducible feature (14). Hematological Abnormalities We have previously reported the clinical, hematological, and pathological details of 25 patients who had chronic symptoms of inexplicable loin pain with or without hematuria (15). We investigated the hematological and rheological profile of these patients and compared them with the same number of healthy age and sex-matched controls (15). In particular we found evidence of mild platelet activation in the LPH group with an increase in circulating platelet aggregates, elevation of plasma b-thromboglobulin (p!0.001); increased platelet aggregation in response to 5-hydroxytryptamine (serotonin) and adenosine diphosphate (ADP) (p!0.05 and p!0.03). We found normal intra-platelet ATP:ADP ratios, although elevated ratios have been reported in pathological conditions in association with intravascular platelet activation (3,16). Our results were similar, however, to those of Parbtani and Cameron (17), who found elevation of plasma serotonin and suggested that local platelet consumption occurs within the kidney, so that degranulated platelets are undetected in the peripheral blood. We found a slight elevation of D-dimer, a breakdown product of cross-linked fibrin, that might reflect a mild thrombotic process in these patients, but we found no abnormalities in concentrations of the coagulation inhibitors protein C and antithrombin III, blood rheology, or fibrinolysis suggestive of a prothrombotic state. Nor was there evidence of severe or extensive vascular injury: markers of endothelial injury such as von Willebrand factor and its antigen were not significantly elevated. Other reported abnormalities have included a shortening of the heparin/thrombin clotting time (indirect evidence for release of platelet factor 4 into the circulation) (3), case reports of factor XII deficiency (18) and prostacyclin-stimulating factor deficiency (16). Migraine-Like? Several features of LPHS are consistent with the hypothesis that regional renal vasospasm may occur, analogous to that of migraine. The renal vascular lesions (Fig. 1) are similar to those seen in cyclosporine nephrotoxicity (Fig. 2), which are also considered to be the consequence of vasospasm. Furthermore, the pattern of increased platelet responsiveness to

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FIGURE 1 (See color insert. ) Renal biopsy showing vascular hyalinosis, from patient with loin pain hematuria syndrome.

FIGURE 2 (See color insert. ) Renal biopsy showing vascular hyalinosis, from a transplant patient with cyclosporine nephrotoxicity.

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5-hydroxytryptamine, together with evidence of circulating platelet aggregates, has been reported in patients with migraine (19,20), suggesting that the two conditions may share common pathophysiological features. Like migraine, loin pain and hematuria syndrome can be associated with the use of the contraceptive pill (2,3,21), food allergies, and hypersensitivity to common allergens (22). No migraine remedies, however, have been found to be of clear benefit. We have looked for regional differences in renal blood using fast spiral CT without consistent abnormality found. Vascular Pathology Several authors initially described pathological abnormalities of peripheral renal vessels on arteriography (1,2), but it is likely that such lesions are artifactual, or owing to transient spasm, and related to angiographic technique (4,5,9). The published literature is reviewed in detail by Weisberg and his colleagues (6). Nevertheless, it is incontrovertible that in some cases there is a vasculopathy present, which cannot be attributed to age or blood pressure, and for which there is no obvious cause except related to LPHS (Fig. 1). Disorder of Ureteric Peristalsis? At the Institute of Urology and Nephrology in the 1980s, Hilson and his colleagues developed an extension to basic dynamic renal scintigraphy (99Tc-DTPA), which involved fast-frame acquisition and a modified analysis, and allowed ureteric function to be examined. Normally functioning ureters exhibit peristaltic contractions at a frequency of up to 3 per minute (23). In obstruction (24), and other abnormal urological states abnormal peristalsis was documented (25). In a study of our LPHS patients, we examined ureteric peristalsis using dynamic isotope scanning to investigate the hypothesis that LPH patients had abnormal peristalsis. We had noticed that a number of patients appeared to have marked abnormalities, but when studies were compared with normal controls in a blinded manner no significant differences were observed (26). Nephroptosis? Dietl’s crisis was a term indicating episodic severe abdominal pain of renal origin, blamed on a mobile kidney that resulted in kinking or obstruction of the ureters on standing erect (“nephroptosis”) (27). A century ago this diagnosis led to a huge industry of surgical fixation of the kidney (“nephropexy”). In 1984 nephropexy for nephroptosis was included amongst “other ineffective treatments for imaginary diseases” (28). Nevertheless, more recent publications have periodically emphasized the importance of upright imaging to exclude nephroptosis (11,29,30). With laparoscopic surgery has come a spate of publications on laparoscopic nephropexy and its potential benefits (31). THE CLINICAL SYNDROME Our Experience Since 1980 over 145 patients considered to have LPHS have been referred to us. We have reviewed the case records of as many as these as possible and present demographic data on 95 cases (Table 2). From the 145 names, old records could not be retrieved in 27 cases, and 24 had a diagnosis other than LPHS. Of the 95 patients attending with “pain considered to be of renal origin,” 72 had loin pain of which the character and localization was consistent with a renal origin. Of the other 23 patients, four had abdominal pain and hematuria, two had backache and hematuria, three had predominantly recurrent hematuria with minimal pain, five had multiple somatoform disorders, eight had renal stones (although these were not of size or location to be make the pain likely to be active renal colic), and one had muscle spasm (Fig. 3).

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TABLE 2 Demographic Details of Our Patients With Loin Pain (nZ95)

Nos. All pain

95

All loin pain

72

Other pains

23

Mean Median

Duration of pain at referral (years)

Age at referral (years)

Age at pain onset (years)

7.2 4.0 6.3 4.0 10.1 6.0

38 39 37 38 42 42

31 30 31 30 32 32

Male (%)

Paramedic (%)

Other organs

Procedures

27

22

19

29

52

4

2.5 2.0 2.4 2.0 2.9 3.0

1.3 1.0 1.3 1.0 1.4 1.0

Note: Paramedic: had worked in a paramedical profession; other organs: number of episodes of medical consultations for other symptoms for which no clear explanation could be found; procedures: number of operative (invasive) procedures that resulted from these consultations.

The separation of these 23 cases from the other 72 was rather arbitrary but we were interested to see whether we could define a definite syndrome. Patient Demographics Ninety-five patients have been reviewed in detail. Their mean (median) age at onset was 31 (30) years, with a range of 9 to 63 years. Seventy-two percent presented between 20 and 40 years of age. When first seen by us, duration of symptoms was 7.2 (4.0) years, 27% were male; 22% had worked in a paramedical profession. Macroscopic hematuria had been seen in 57%, microscopic hematuria documented in 32%, and 11% had no hematuria. The loin pain first occurred on the right-hand side in 53%, on the left in 30% and was bilateral in the remaining 17%. Opiates were used in pain management in 60% of all patients. We then compared different subgroups. First, we examined the 72 patients who had loin pain that was consistent with a renal origin. We divided the 72 patients with loin pain into three groups:

All

Other diagnoses

146

24 All pain patients

Insufficient information

27

Other pains

23

95

Loin pain LPHS

72 44

Renal stones Multiple somatoform disorders

8 5

LPH LP

19 9

Abdominal pain + hematuria Predominantly hematuria

4 3

Backache + hematuria Muscle spasm

2 1

FIGURE 3 Key to patients who were investigated for loin pain: LPHS, the syndrome (including blood) without any other reasonable explanation; LPH, the syndrome (with blood) but some other contributing factor (e.g., renal stones, but no current evidence); LP, loin pain, possible renal origin, but no blood.

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1. LPHS: the syndrome (including blood) without any other reasonable explanation (nZ44). 2. LPH: the syndrome (with blood) but some other confounding factor (e.g., past history of renal stones—but no current evidence) (nZ20). 3. Loin pain: possible renal origin, but no blood (nZ8). There were no differences in the demographic details of these three groups. Macroscopic hematuria was reported in 61% of the LPHS group and 70% of the LPH group. Opiates were used in 57% of all 72 patients, and in 63% of those designated LPHS. Pain started on the right in 56% of all, and in 61% of LPHS. Only 7% of LPHS had bilateral pain initially. We also divided these 72 patients into three groups based on the presence and degree of hematuria: (i) macroscopic hematuria (nZ41), (ii) microscopic hematuria (nZ23), or (iii) no documented hematuria (nZ8). Again, no differences were seen. There was, however, one significantly different subgroup in 23 patients with other forms of pain and hematuria, which was a group of eight patients with known kidney stones. They presented at a younger age of 28 (27) years, 52% were male, none had a paramedical occupation and their symptoms had been present for 21.5 (22) years. Patient Symptoms When summarizing and tabulating data from the medical records we wished to record in particular. 1. Evidence of medical consultations for other symptoms for which no clear explanation could be found (such as tiredness, malaise, depression, backache, breathlessness)—bearing in mind that these were all young otherwise healthy people. This was called “Other Organs” and patients scored 1 for each organ symptom, so that repeated consultations for (i) headache and (ii) fatigue would score 2. 2. Operative (invasive) “Procedures” that resulted from these consultations. These scored 1 each as well. So that a woman who had symptoms that resulted in a hysterectomy would score 1. The data we present are principally obtained from the primary consultation with us and is therefore a significant underestimate of what had probably occurred, and takes little account of subsequent events. Nevertheless, it gave us some insight into the likelihood of a significant somatoform disorder. The scores in the different subgroups are remarkably similar, again with the exception of the small group of eight patients with renal stones who had scores of 1.0. When this group of eight patients was removed from the other patients with “Other Pains,” the remaining 15 patients had very high scores for “Other Organs” of 3.6 (3.0). In the subanalysis of the three different loin pain groups, the scores for “Other Organs” were remarkably similar. Reported Experience of Others It is appropriate that these difficult and time-consuming patients should be seen in only a few centers. Two other groups in England have published data on large series. Aber and his colleagues in Stoke published reports on several aspects of LPHS (2,32,33) and in a final paper in 1982 commented on 51 patients (34). Twenty-five had pain and macroscopic hematuria, eight pain and microscopic hematuria, and 18 loin pain only. The onset was between ages of 16 and 50 years. They found that all had abnormalities of vessels seen on selective renal arteriography. At follow-up (2–17 years), available on 43 patients, pain had ceased immediately when the contraceptive pill was stopped in five patients and in two when they were pregnant. In 16 the pain settled spontaneously, but in 18 there was no relief. They concluded that “there seems no reason to doubt the basis of the loin pain/hematuria syndrome lies in abnormalities in the smaller renal arteries and arterioles” (34).

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Another large series was seen by Dr Norman Jonesd at St Thomas’ Hospital between 1972 and 1985. Of 100 referrals with this possible diagnosis, 44 were found to have other diagnoses to account for their pain and hematuria (such as IgA nephropathy and thin glomerular basement membrane (GBM) disease). Of the remaining 56 patients, 41% were male. Fifty-two had renal biopsies of which 24 were considered entirely normal, 14 possibly abnormal, and 18 showed some clear abnormality. Renal angiograms performed in 19 were all considered normal. Psychiatric review detected some abnormality in 10 out of 21 women and 2 out of 11 men. A pilot study that investigated the use of infusions of capsaicin into the ureter and renal pelvis described the demographic details of the 26 subjects. All were receiving opiate analgesia; the mean age was 39 years with pain duration of 7.1 years; 10 (38%) were male. Twelve had right-sided pain, 10 left-sided, and 4 bilateral pain (35). In Table 3, we have tabulated the available demographic data from the largest published series. PSYCHOLOGICAL CHARACTERISTICS In a study carried out in collaboration with the Institute of Psychiatry at the Maudsley Hospital, we investigated the psychological characteristics of 15 LPH patients and compared them with 10 contemporary patients receiving treatment for complicated and painful renal stone disease (36). The control was matched as closely as possible so that the mean age of the two groups was 46 years, the mean duration of symptoms was 14 years, and 80% to 90% were female. Subjects were interviewed, using a set of semi-structured interviews: (i) Childhood Illness Experience Interview (to recall experience of parental attitudes and behavior), (ii) Parental Bonding Instrument (to assess degree of parental affection), (iii) psychological stressors (acute adverse life events and enduring adverse circumstances) and past episodes of depression and anxiety were diagnosed according to third edition of Diagnostic and Statistical Manual of Mental Disorders, (iv) previous episodes of medically unexplained symptoms were assessed by diagnostic interview schedule (DIS), and (v) current levels of anxiety, depression, anger, and somatization were assessed by the Hospital Anxiety and Depression scale, the Symptom Check List-90 and the Illness Behaviour Questionnaire. LPH patients more frequently recalled serious parental illness and disability in childhood (p!0.001), and a higher proportion felt responsible for causing or alleviating parental illness or distress. Patients had three times more medically unexplained somatic symptoms than controls. The onset of pain was associated with an adverse psychologically important life-event in eight of the LPH patients but none of the controls. Current depression and anxiety were similar in the two groups, but both groups had high rates of lifetime depression. LPH patients expressed lower levels of anger and hostility than controls (p!0.002). A higher proportion of patients took analgesics regularly (87% vs. 30%) and no stone patients used opiates versus 27% of LPHS. Our data suggested that LPHS represented a hitherto unrecognized example of a persistent somatoform pain disorder (36). PSYCHOLOGICAL ASSESSMENT There are three reasons to request a psychiatric assessment. 1. There is an important association between chronic pain and psychiatric disorder (37). This association may arise as a consequence of the psychosocial impact of pain, yet it is well known that in many forms of psychiatric disorder (particularly depression) physical symptoms such as pain may be prominent. 2. As pain becomes chronic, psychosocial factors become more relevant. These are relevant to management and may contribute to disability.

d

Findings reported at a meeting of the London Medical Society 26 October 1992.

26

46

22

Bultitude et al. (35)

Sheil et al. (46)

Chin et al. (47)

32

20

38

6

41

27

20

X

X

50

X

57

36 (21 55)

33 (18 61)

39.5

16 50

X

38.0

Age M-hematuria at (%) presentation

X

X

7.1

X

X

7.2 (4.0)

Duration pain

X

32

X

100

93

37

Biopsy (%)

(100)

(100)

X

100

37

11

Arteriogram

Note: X, data not given in cited paper; psychiatric assessment, percentage of patients referred for formal psychiatric assessment. a Findings reported at a meeting of the London Medical Society, October 26, 1992.

51

56

Aber and Higgins (34)

Jones

95

a

Nos.

Neild and Bass

Male sex (%)

LPH: Clinical Summary from Published Series

Reference

TABLE 3

100

100

100

X

57

39

Psychiatric assessment (%)

X

100

92

X

X

60

Opiate use (%)

X

9

12

X

X

22

Paramedic (%)

77

X

46

X

X

53

Pain on right (%)

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159

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3. Iatrogenic reinforcement of the symptoms and the “expectation of cure” is common and contributes to the chronicity of the patient’s disability (38). Kelly has pointed out that in some patients with LPHS, psychosocial and psychopathological factors are paramount and perhaps explanatory (39). Medical staff may contribute directly to abnormal illness behavior. A doctor’s response to a patient’s symptoms may be either inappropriately illness-affirming or denying. Such “abnormal treatment behavior” may be characterized at times by the selective attention to physical complaints and diagnoses and surgical solutions that can be extremely harmful. Psychosocial Assessment By the time these patients arrive for psychiatric assessment they have usually accumulated a thick folder of notes and many have become demoralized. They may have been provided with different and inconsistent explanations for their pain by a number of different medical and surgical specialists. Surprisingly, most patients do not baulk at seeing a psychiatrist, usually perceiving the referral as another opportunity that may offer the hope of relief from pain. Our approach involves considerable preparation before the patient arrives for the interview. Ideally all the previous surgical and medical notes will have been scrutinized and summarized and, whenever possible, copies of the GP notes as well. Ideally, the latter is accompanied by a telephone conversation with the GP. We have found it helpful to summarize the past medical history on a specially prepared proforma (Fig. 4). This preparation is important and saves time in the long-term: a substantial number of patients (more than half in the series we have studied) have past histories of medically unexplained somatic symptoms, a finding that has been reported by others (36). We believe that the assessment is best carried out in a regional pain clinic, as this is more likely to promote patient compliance and attendance. The interview should begin with

Date (Age)

Symptoms (Life Events)

Referrals

Intervention

Diagnosis / Outcome

1984 (18)

Abdominal pain (left home)

GP → Surgical OPs

Appendicectomy

Diagnosis of IBS

1987 (21)

Acute left arm pain and hemiparesis (distressed by housing problems)

GP → Neurology OPs

Lumbar puncture & CT scan - NAD

?Functional weakness

1989 (23)

Bloating, abdominal pain, blackouts (stressful divorce)

GP → Gastroenterology and neurology OPs

Ba Meal and enema - NAD

?IBS

1990 (24)

Pelvic pain, Dysmenorrhoea, Deep dyspareunia

GP → O&G OPs

Exam Under GA Laparoscopy - NAD

Prescribed contraceptive pill and diazepam

1991 (25)

Fatigue (problems at work)

GP → Infectious disease clinic

NAD

Diagnosis of ME/CFS

1993 (27)

Severe abdominal pain, constipation, laxative abuse

GP → Psychiatrist

Home visit

“not convinced psychological factors are relevant”

1997 (31)

Chest pain, breathlessness, (son truanting from school)

A & E → Chest clinic

ECG, ECHO NAD

Probable hyperventilation

1999 (33)

Severe left loin pain and haematuria

GP → Nephrology OPs

IVP, ultrasound NAD

Referred to Pain clinic for pain management

FIGURE 4 Summary of a 15-year segment of illness history in a patient with multiple unexplained symptoms antedating onset of intractable loin pain and hematuria. Abbreviations: GP, general practice; IBS, irritable bowel syndrome; ME/CFS, myalgic encephalomyelitis/chronic fatigue syndrome; OPs, outpatient department.

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an explanation to the patient that psychosocial factors are important in the experience of pain, and it is hoped that management will be shaped by a psychosocial formulation. It is useful to explain that the interview will last one-and-a-half to two hours. The initial part of the interview, which deals with the illness history, explores the onset of the pain and the subsequent course and investigations that have been carried out, what the patient has been told and what

Clinical Vignette A 32-year-old, single woman reported an 18-year history of pain in the right loin that had begun suddenly at the age of 14 (in 1988) after a brief illness characterized by lethargy and headache. Pediatric investigations included a renal ultrasound scan that suggested minimal right hydronephrosis, but repeatedly sterile urine and a normal intravenous urogam (IVU). Microscopic haematuria was documented on two occasions. The pain persisted, and over the next 10 years, repeated tests included a normal static renogram (DMSA scan), a normal renal biopsy (in 1997), as well as innumerable ultrasound scans. Treatments included three local anesthetic lumbar sympathetic nerve blocks, none of which helped. She was given three intraureteric capsaicin installations as well as instillations of lignocaine into the renal pelvis in the early 1990s, but they provided only temporary relief. Oral pethidine was prescribed early on in the clinical history, but she become tolerant to it, and by 1998 was using up to 800 mg/day. A course of amitriptyline and the application of a Tens machine were not helpful, and insertion of a JJ stent gave no benefit. In 1998, she began intermittent alcohol abuse. Attempts to help her with counselling and psychological support failed initially, as she was unable to engage with treatment. Both she and her mother had trained in paramedical fields, although she was not able to take her final exams. The home atmosphere was affected by her long and continuing ill health, and family communications with health personnel resulted in frequent frustration and anger. From 1999 on, her management focused on helping her to identify her difficulties, while offering continued support. Addiction emerged as the main problem, with the loin pain being an integral part of drug-seeking behavior. She found it hard to relinquish the idea that surgery for her loin pain would help her to cope with her loneliness and the strains within her close family. Requests for surgery emerged at different times, and finding a physical soultion to life’s problems remained attractive to her. Careful management of her pethidine requirements involved outpatient management at a pain clinic, working closely with the psychiatrist and GP, as well as a brief admission to a pain clinic to attempt withdrawal of pethidine. This was very difficult for her emotionally, and there were at least two episodes of self-harm. Residential rehabilitation placements helped her address emotional problems and explore alternatives to pethidine and alcohol as coping strategies. She remains in pain (in 2006), but has been working full time for four years and recently acquired a degree. She remains off all opiates, and continues to be followed up in the pain clinic every three months by the pain specialist and psychiatrist. Her current medication is gabapentin 5.7 g/day. treatment given. Current occupational, social and physical disabilities should be established, with particular emphasis on behaviors avoided because of fear of harmful consequences or aggravation of the symptoms. After obtaining a history of the symptoms, the patient is asked what he believes to be the cause and likely consequences of his symptoms. For example, a simple question such as “what is your worst fear about your pain?” can be revealing. The Illness Perception Questionnaire is a

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useful adjunct to the interview, and the patient’s responses to individual questions may provide useful topics for discussion, for example: & & &

“My illness was caused by poor medical care in the past.” “What I do can determine whether my illness gets better or worse”? “My illness is likely to be permanent rather than temporary.”

The patients may believe, for example, that “doctors should be able to cure pain” which may lead in turn to the doctor introducing the idea that medicine “does not always have all the answers.” Exploring how the patient copes with symptoms can often be detected by asking about a “typical day,” which might reveal that they lie down for four hours each day in the afternoon, or that they keep seeking reassurance from repeated visits to the GP. At this stage it is useful to ask about analgesic use. Some patients may have used many different analgesics (including tricyclic antidepressants), and not infrequently have been prescribed opiate drugs such as morphine sulfate and oramorph. In some, this drug use may escalate in a chaotic fashion with adverse consequences. Because it is important for the analgesia to be carefully monitored we recommend that these patients are not only assessed, but then managed subsequently in a regional pain clinic (7). Asking about previous illness experience is crucial, and we use a biographical or developmental approach. Enquiry about childhood illnesses, experiences of physical and emotional symptoms at times of life transitions and stress, for example, menarche, examinations, marriage, childbirth, divorce. Experiences of exposure to illness in the family and the impact these had on the patient should be obtained. This may be particularly important if parental illness resulted in lack of care, and where physical symptoms may have become a means of communication within the family (40). Because these patients are often reluctant to discuss psychosocial issues we prefer to leave a detailed assessment of the previous psychiatric history and examination of mental state to the end of the interview. In our experience, however, there is seldom evidence of conspicuous current psychiatric illness, a finding that has been reported by others (36). Many patients have a past history of medically unexplained symptoms and a history of illness in the family. Previous episodes of deliberate self-harm and depression may be uncovered. There can also be advantages in conducting the interview with the patient in the presence of one or more family members. Evidence that a family member shares the patient’s beliefs about the complaint, e.g., “I’m sure the doctors have missed something” is likely to have an adverse influence on the prognosis. Finally, a period of self-monitoring may be helpful, especially if psychological treatment is going to be undertaken. Following the initial assessment interview, the patient is asked to keep a diary of symptoms and activities. This can provide an accurate account of frequency and pattern of symptoms, the patient’s activity level and its association with symptoms. It also introduces the patient to the active role they will be required to play in treatment. Medication used, especially analgesics and opiates, should be included in self-monitoring. These written diaries provide a record from which change can be planned and improvement assessed. They can begin as simple activity diaries, and later be expanded to include recording of thoughts and coping behaviors as necessary (41).

MANAGEMENT The treatment of loin pain and hematuria syndrome remains unsatisfactory. In our experience, pharmacological manipulation with a variety of agents including beta-blockers, antiplatelet, and antimigraine agents have been unsuccessful. It is always reassuring to both patient and medical staff to have some more radical therapy in reserve if all else fails. We have found, however, that offering surgical intervention is counterproductive.

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Reassurance In our opinion, reassurance and supportive care with avoidance of powerful analgesics remain the mainstays of therapy. The key word, currently, is “coping.” Patients are encouraged to continue as much as possible with their normal life style, not to anticipate a “cure,” but hope that symptoms will improve with time. To encourage the patient to persist, and not to seek additional medical opinions, we follow them at regular intervals. It is a great help if they can be seen by the same doctor, although these follow-up consultations tend to be lengthy. Analgesia To help the patient cope with the pain and continue a normal lifestyle analgesics are generally required. A suitable combination and regimen will be reached by trial and error. In severe cases, loin pain becomes intractable and disabling, and opiates are required. The risk of dependence on opiates is very low in patients with chronic pain syndromes (42) and following pain relief from denervation patients can usually stop their opiate analgesia immediately with no adverse effect. Opioid dependence is, however, a risk in patients’ with overt psychiatric problems (42,43). Psychological Management should, ideally, be coordinated from a joint clinic with a pain specialist and/or renal physician and psychiatrist. After the initial assessment, it is important to explain to the patient that the pain is real and distressing but not a sign of renal disease or damage. This may lead on to a discussion about how not all symptoms have an underlying detectable physical cause, e.g., analogy with irritable bowel syndrome or migraine is apposite. Patients are encouraged not to seek out surgical solutions to their pain. In particular, for those patients with intractable loin pain, which may be the latest symptom in a long history of persistent and recurrent unexplained somatic complaints, surgical treatment may not only be unnecessary but also potentially harmful, exposing individuals to excessive risk while neglecting the ongoing risks associated with untreated psychiatric disorder. One must aim to reduce the patient’s expectation of a surgical “cure.” This can initially create further problems when frustration and anger may lead to increased self-harm or escalating use of opiates. We suggest that the medical staff do not discuss surgery as a therapeutic option in these patients. Removal of the prospect of surgery as a potential “cure” forces the patient to cope using their own resources. This will lead to a discussion in which the patient is encouraged to manage their own pain with continuing support from the pain clinic. Treatment should be based on a specific management approach that includes a number of basic treatment recommendations which have been shown to improve physical functioning whilst reducing health care costs (44). In essence, the management plan involves the following elements: & & & & &

Avoiding surgery for the pain Reducing unnecessary medication if possible Reducing the number of doctors managing the patient Emphasizing continuity of care with the GP Avoiding referrals to other specialists whenever possible

Some patients will require written materials explaining that pain coping and not curing are the goal of treatment. Often patients have read about LPHS on the internet and when this is the case we supplement this information with our own information. Further management in the regional pain clinic depends on the psychiatric formulation and involves a number of different strategies. This includes promoting acceptance and conservative management of the pain; attempting to prevent the seeking of treatment elsewhere (which involves communicating the treatment plan to the GP—using both written and

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telephone contact): confronting dissimulation where this is apparent (in our experience this is rare); and attempting to prevent escalating opiate use and abuse (45). In some patients it may be necessary to consult with a member of the local psychiatric addiction services, and some of these patients do find their way into these services. We have found the regional pain clinic to be a useful resource for providing ongoing support for these patients (7). The patients usually require a longer appointment (up to one hour), during which the focus will be on promoting pain coping and problem solving, and reinforcing the message that surgery is contraindicated. The psychiatrist (or clinical psychologist) can help with pain coping strategies and the prescribing of psychotropic drugs and the pain specialist with the provision of analgesic medication, which may involve the use of opiates such as morphine sulfate. Follow-up in some patients is required every three or six months depending on the nature and severity of the pain and/or other psychological problems. It is not uncommon for some patients to require indefinite follow-up, and continuity of care is important. Clear communication with the patient’s GP is also essential, to prevent the possibility of inadvertent referral to another tertiary care center for further (unnecessary and costly) investigations. Long-term support is relatively inexpensive and can prevent further iatrogenic harm. Some patients may benefit from referral on to a clinical psychologist for further management of their pain and other psychosocial problems. Psychological treatment is more likely to be successful however if the patient accepts that psychosocial factors are contributing to the clinical problem and is able to negotiate mutually agreed treatment goals. Clearly if the patient does engage in this type of treatment then this is an encouraging sign. To date there are very few outcome studies of patients who have had conservative treatment for their chronic intractable loin pain. There have been many surgical studies (see below) and one follow-up study of patients carried out in a regional pain clinic. Surgery Our experience, and review of the literature, suggests that surgery has no role to play. Stents We made the serendipitous observation that inserting a double-J ureteric stent into the ipsilateral ureter often resulted in relief of pain. However, the stent had to be changed after six months or so and the longer one persisted with stents the more likely that complications would arise such as urinary tract infection. (On one occasion the loin pain was completely relieved but the patient required the same dosing of analgesia to cope with the new pain caused by the stent pressing on the bladder.) Since we achieved nothing in the long-term we have abandoned the procedure; we did not, however, formally evaluate whether this pain relief was in way prognostic or indicative of outcome. Infusions Intra-ureteric instillation of capsaicin has been reported to have a 60% short-term pain relief rate in a small uncontrolled series (35); no follow-up details were ever reported. Unfortunately, in another pilot study of 10 patients there were similar short-term benefits but there was gross deterioration in renal function in 20% of patients treated (48). Similar adverse experience was reported in a small study from Australia, which was quickly abandoned (49). Under no circumstances should this drug be used. Denervations Renal denervation may offer temporary relief of pain but in many patients the pain returns either in the previously denervated kidney or in the contralateral kidney. We have evaluated our experience of renal denervation (50). The case notes of 24 patients (having 33 renal denervations) were reviewed. The proportion of men (46%) was higher than

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generally reported (0–30%). Renal denervation resulted in relief of the pain in only 25% of patients, but reduced analgesic requirement in 33% of the remainder. Twenty-four of the renal denervations (73%) were followed by recurrent ipsilateral pain at a median of 11 months (range 0–120) after surgery. Men had more benefit from the treatment than women (55% relief vs. 15% in women). Thirty-eight percent of patients with recurrent pain went on to have a nephrectomy for pain control, which relieved the pain in 89%. The loin pain moved to the contralateral loin in 25% of patients following first renal denervation and in 33% of patients following nephrectomy (50). Outcome of renal denervation for LPHS had been previously reported in two large series (46,51). Andrews reported a pain relief rate of 25% in 27 renal denervations in 21 patients—with a median follow-up of 54 months. To achieve this, renal denervation was repeated once in three patients and twice in one patient. Pain relief after the other 23 operations in 18 patients lasted a median of six months. The median pain-free interval of the other seven reexplorations in six patients was 19 months (51). Sheil similarly reported a pain relief rate of only 33% in 18 patients treated with renal denervation who were available for follow-up examination, 12 (67%) developed recurrent renal pain, including four who had pain relief on the other side following previous renal auto-transplantation. The mean follow-up period for these patients was 8.0 years (6–9.9 years) (46). Both these findings are similar to ours. The long-term “cure” rate of a third is higher than would be expected from placebo effect alone (52). Patients with no recurrence of pain at 24 months are very unlikely to relapse and may to all intents be considered cured. In conclusion renal denervation fails to provide long-term pain control in 75% of patients with LPHS and should probably be limited to men, if done at all.

Autotransplantation Renal autotransplantation has been successful (53,54) but pain can also recur following this procedure (55). The literature is dominated by two large studies with very successful outcomes of 76% long-term pain relief from 30 auto-transplants (46) and 69% from 26 auto-transplants (47), respectively. In contrast, many other smaller series report a much more pessimistic view (55–59), with at best 25% pain relief (60). The surgical outcome of auto-transplant is prejudiced by prior denervation (50). Dense scarring following denervation makes the vascular anastomosis more difficult. If autotransplant is to be considered denervation should not be performed. Why does the pain recur following surgery? This question cannot be answered at present. For example, Blacklock and colleagues reported a 23-year-old man with LPHS who had recurrence of pain three months after auto-transplantation, despite deliberately interposing a polytetrafluoroethylene-prosthesis in the arterial anastomosis (59). This was done as the autonomic nerve supply to the kidney runs with the distribution of the renal artery and its branches but not the renal vein. It should be recalled that Mesmer had very good results by touching his patients on the head with an iron rod, results that others were not able to reproduce (with the same rod) (61).

Complications Surgical intervention is rarely successful in the long-term and may result in unnecessary nephrectomy.

REFERENCES 1. Little PJ, Sloper JS, de Wardener HE. A syndrome of loin pain and haematuria associated with disease of peripheral renal arteries. Q J Med 1967; 36:253–9.

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2. Burden RP, Booth LJ, Ockenden BG, Boyd WN, Higgins PM, Aber GM. Intrarenal vascular changes in adult patients with recurrent haematuria and loin pain—a clinical, histological and angiographic study. Q J Med 1975; 44:433–47. 3. Burden RP, Dathan JR, Etherington MD, Guyer PB, MacIver AG. The loin-pain/haematuria syndrome. Lancet 1979; 1:897–900. 4. Sherwood T. Loin pain/haematuria syndrome. Lancet 1979; 1:1033–4. 5. Tadavarthy SM, Castaneda W, Amplatz K. Redistribution of renal blood flow caused by contrast media. Radiology 1977; 122:343–8. 6. Weisberg LS, Bloom PB, Simmons RL, Viner ED. Loin pain hematuria syndrome. Am J Nephrol 1993; 13:229–37. 7. Winearls CG, Bass C. The loin pain haematuria syndrome. Nephrol Dial Transplant 1994; 9:1537–9. 8. Nicholls KM, Fairley KF, Dowling JP, Kincaid-Smith P. The clinical course of mesangial IgA associated nephropathy in adults. Q J Med 1984; 53:227–50. 9. Bergroth V, Konttinen YT, Nordstrom D, Laasonen L. Loin pain and haematuria syndrome: possible association with intrarenal arterial spasms. Br Med J (Clin Res Ed) 1987; 294:1657. 10. Pollock CA, Ibels LS, Eckstein RP, Thomas MA, Lauer C, Moir D. Afferent arteriolar C3 disease— a distinct pathological entity. Am J Kidney Dis 1989; 14:31–8. 11. DeWolf WC, Fraley EE. Renal pain. Urology 1975; 6:403–8. 12. Cervero F. Visceral hyperalgesia revisited. Lancet 2000; 356:1127–8. 13. Sarkar S, Aziz Q, Woolf CJ, Hobson AR, Thompson DG. Contribution of central sensitisation to the development of non-cardiac chest pain. Lancet 2000; 356:1154–9. 14. Talley NJ, Spiller R. Irritable bowel syndrome: a little understood organic bowel disease? Lancet 2002; 360:555–64. 15. Leaker BR, Gordge MP, Patel A, Neild GH. Haemostatic changes in the loin pain and haematuria syndrome: secondary to renal vasospasm? Q J Med 1990; 76:969–79. 16. Siegler RL, Brewer ED, Hammond E. Platelet activation and prostacyclin supporting capacity in the loin pain hematuria syndrome. Am J Kidney Dis 1988; 12:156–60. 17. Parbtani A, Cameron JS. Platelet involvement in loin-pain/haematuria syndrome. Lancet 1979; 1:1413. 18. Smellie SW, Lambert M, Lavenne E, van Cangh PJ. Factor XII deficiency associated with loin pain/haematuria syndrome. Lancet 1987; 2:1330. 19. Hanington E, Jones RJ, Amess JA, Wachowicz B. Migraine: a platelet disorder. Lancet 1981; 2:720–3. 20. Crassard I, Conard J, Bousser MG. Migraine and haemostasis. Cephalalgia 2001; 21:630–6. 21. Jones K, Naish PF, Aber GM. Oestrogen-associated disease of the renal microcirculation. Clin Sci Mol Med 1977; 52:33–42. 22. Bell GM, Williams P, Thomson D. Is the loin pain and haematuria syndrome a renal manifestation of hypersensitivity? Lancet 1984; 1:340. 23. Lewis CA, Coptcoat MJ, Carter SS, Hilson AJ, Wickham JE, Shah PJ. Radionuclide imaging of ureteric peristalsis. Br J Urol 1989; 63:144–8. 24. Wilcox CS, Roddis S, Peart WS, Gordon D, Lewis GP. Intrarenal prostaglandin release: effects of arachidonic acid and hyperchloremia. Kidney Int 1985; 28:43–50. 25. Woolfson RG, Hilson AJ, Lewis CA, Hill PD, Shah PJ, Neild GH. Scintigraphic evidence of abnormal ureteric peristalsis following urological surgery. Br J Urol 1994; 73:142–6. 26. Woolfson RG, Lewis CA, Hilson AJ, Hill PD, Neild GH. Ureteric peristalsis studies in loin pain and haematuria syndrome—another diagnostic disappointment. Br J Urol 1993; 72:291–2. 27. Dietl J. Wanderende Nieren und deren Einklemmung. Wien Med Wochenschr 1864; 14:563–600. 28. McWhinnie DL, Hamilton DN. The rise and fall of surgery for the “floating” kidney. Br Med J (Clin Res Ed) 1984; 288:845–7. 29. Ghanem AN. Features and complications of nephroptosis causing the loin pain and hematuria syndrome. A preliminary report. Saudi Med J 2002; 23:197–205. 30. O’Reilly PH, Pollard AJ. Nephroptosis: a cause of renal pain and a potential cause of inaccurate split renal function determination. Br J Urol 1988; 61:284–8. 31. Barber NJ, Thompson PM. Nephroptosis and nephropexy—hung up on the past? Eur Urol 2004; 46:428–33. 32. Higgins PM, Aber GM. Renal pain and haematuria. Br J Urol 1974; 46:601–8. 33. Fletcher P, Al Khader AA, Parsons V, Aber GM. The pathology of intrarenal vascular lesions associated with the loin-pain–haematuria syndrome. Nephron 1979; 24:150–4. 34. Aber GM, Higgins PM. The natural history and management of the loin pain/haematuria syndrome. Br J Urol 1982; 54:613–5. 35. Bultitude M, Young J, Bultitude M, Allan J. Loin pain haematuria syndrome: distress resolved by pain relief. Pain 1998; 76:209–13.

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36. Lucas PA, Leaker BR, Murphy M, Neild GH. Loin pain and haematuria syndrome: a somatoform disorder. Q J Med 1995; 88:703–9. 37. McBeth J, Silman AJ. Unraveling the association between chronic widespread pain and psychological distress: an epidemiological approach. J Psychosom Res 1999; 47:109–14. 38. Page LA, Wessely S. Medically unexplained symptoms: exacerbating factors in the doctor–patient encounter. J R Soc Med 2003; 96:223–7. 39. Kelly B. Psychiatric issues in the “loin pain and haematuria syndrome”. Aust NZ J Psychiatry 1994; 28:302–6. 40. Bass C, Murphy M. Somatisation, somatoform disorders and factitious illness. In: Creed F, Guthrie E, eds. Seminars in Liaison Psychiatry. London: Gaskell Press, 1996:150. 41. Winterowd C, Beck AT, Gruener D. Monitoring pain and activity levels and activity scheduling. In: Winterowd C, Beck AT, Gruener D, eds. Cognitive Therapy with Chronic Pain Patients. New York: Springer, 2003. 42. Portenoy RK, Foley KM. Chronic use of opioid analgesics in non-malignant pain: report of 38 cases. Pain 1986; 25:171–86. 43. Max MB. Improving outcomes of analgesic treatment: is education enough? Ann Intern Med 1990; 113:885–9. 44. Smith GR, Jr., Rost K, Kashner TM. A trial of the effect of a standardized psychiatric consultation on health outcomes and costs in somatizing patients. Arch Gen Psychiatry 1995; 52:238–43. 45. Bass C, Jack T. Current approaches in chronic pain. Clin Med 2002; 2:505–8. 46. Sheil AG, Chui AK, Verran DJ, Boulas J, Ibels LS. Evaluation of the loin pain/hematuria syndrome treated by renal autotransplantation or radical renal neurectomy. Am J Kidney Dis 1998; 32:215–20. 47. Chin JL, Kloth D, Pautler SE, Mulligan M. Renal autotransplantation for the loin pain–hematuria syndrome: long-term followup of 26 cases. J Urol 1998; 160:1232–5. 48. Armstrong T, McLean AD, Hayes M, Morgans BT, Tulloch DN. Early experience of intra-ureteric capsaicin infusion in loin pain haematuria syndrome. BJU Int 2000; 85:233–7. 49. Playford D, Kulkarni H, Thomas M, et al. Intra-ureteric capsaicin in loin pain haematuria syndrome: efficacy and complications. BJU Int 2002; 90:518–21. 50. Greenwell TJ, Peters JL, Neild GH, Shah PJ. The outcome of renal denervation for managing loin pain haematuria syndrome. BJU Int 2004; 93:818–21. 51. Andrews BT, Jones NF, Browse NL. The use of surgical sympathectomy in the treatment of chronic renal pain. Br J Urol 1997; 80:6–10. 52. Bretlau P, Thomsen J, Tos M, Johnsen NJ. Placebo effect in surgery for Meniere’s disease: nine-year follow-up. Am J Otol 1989; 10:259–61. 53. Karvelas JP, Ramsey EW. Renal autotransplantation in patients with loin pain–hematuria syndrome. Can J Surg 1996; 39:121–5. 54. Spitz A, Huffman JL, Mendez R. Autotransplantation as an effective therapy for the loin pain– hematuria syndrome: case reports and a review of the literature. J Urol 1997; 157:1554–9. 55. Talic RF, Parr N, Hargreave TB. Anephric state after graft nephrectomy in a patient treated with renal autotransplantation for bilateral metachronous loin pain/hematuria syndrome. J Urol 1994; 152:1194–5. 56. Hutchison SM, Doig A, Jenkins AM. Recurrence of loin pain/haematuria syndrome after renal autotransplantation. Lancet 1987; 1:1501–2. 57. Dimski DS, Hebert LA, Sedmak D, et al. Renal autotransplantation in the loin pain–hematuria syndrome: a cautionary note. Am J Kidney Dis 1992; 20:180–4. 58. Harney J, Rodgers E, Campbell E, Hickey DP. Loin pain–hematuria syndrome: how effective is renal autotransplantation in its treatment? Urology 1994; 44:493–6. 59. Blacklock AR, Raabe AL, Lam FT. Renal auto-transplantation with interposed PTFE arterial graft: not necessarily a cure for loin pain/haematuria syndrome. J R Coll Surg Edinb 1999; 44:134. 60. Parnham AP, Low A, Finch P, Perlman D, Thomas MA. Recurrent graft pain following renal autotransplantation for loin pain haematuria syndrome. Br J Urol 1996; 78:25–8. 61. Mesmer FA. Me´moire sur la De´couverte du Magne´tisme Animal. Paris: P. Fr. Didot le jeune, 1779.

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Bladder Pain Syndrome/Interstitial Cystitis Etiology and Animal Research C. A. Tony Buffington

Department of Veterinary Clinical Sciences, The Ohio State University Veterinary Hospital, Columbus, Ohio, U.S.A.

INTRODUCTION Bladder pain syndrome/interstitial cystitis (BPS/IC) is a chronic clinical syndrome of unknown cause and no generally accepted treatment. The diagnosis of BPS/IC is established based on the presence of urinary frequency, nocturia, pain referable to the bladder, and characteristic (nonspecific) cystoscopic signs in the absence of objective evidence of other diseases that could cause these symptoms. Symptoms associated with idiopathic BPS/IC often appear acutely, and generally progress rapidly to a final severity with little worsening thereafter. Additionally, symptoms often wax and wane, being exacerbated by stress. BPS/IC patients also may be at increased risk for a wide variety of other unexplained clinical conditions, including irritable bowel syndrome, fibromyalgia, panic disorder (1). Patients with BPS/IC also were much more likely than controls to have had prior pelvic surgery (44.1% vs. 17.5%) (2). Unfortunately, many of the bladder abnormalities identified in patients with IC are not specific for this disease; they have been reported in patients with other bladder diseases. And although there is no generally effective treatment, a spontaneous remission rate of up to 50% has been reported (3). Chapters describing the causes of disorders of unknown etiology create challenges, this one is no exception. Part of the challenge is semantic. The name bladder pain syndrome seems to imply that the pain results from nociception, and that the bladder has been unambiguously identified as the source of the problem, despite the rather compelling evidence to the contrary in most cases. Similar limitations apply to the term IC, coined by AJC Skene in 1887. This term suggests the etiology of the problem to be inflammation of the bladder interstitium, again despite rather compelling evidence to the contrary in most cases. Another part of the challenge is that the disease is defined by the presence of variable combinations of clinical signs, and evidence of absence of alternative explanations. Unfortunately, the lower urinary tract has only a limited repertoire of responses to insult, which include frequency, urgency, and pain. These responses may be activated by insults external to the bladder, such as microbial infection, those intrinsic to the bladder, such as cancer, and disorders of other body systems that secondarily affect the bladder, such as viral disease, spinal cord injury or diabetes mellitus. Two subtypes of “IC” currently are recognized based on cystoscopic evaluation of the bladder. Only submucosal petechial hemorrhages (glomerulations) are observed in “Type I” IC. Unfortunately, these lesions, once thought to be an important diagnostic criterion, have been reported to be present in healthy women after bladder distention (4). In contrast, “Hunner’s ulcers,” with or without glomerulations, are identified in patients with “Type II” IC. These ulcers were described by Guy Hunner in 1914 (although they had been reported before) as located within the dome and lateral walls of the bladder in the presence of areas of mucosal congestion (5). In most studies, Type II IC occurs in approximately 10% of patients, although some investigators have reported an incidence as high as 50%. The two types also appear to differ in patient demographics, histological findings, and response to treatment, further suggesting that they may be distinct entities (6). Patients with Type II IC appear to obtain significant symptomatic relief after supratrigonal cystectomy and cystoplasty, whereas the pain in patients with Type I IC is not usually diminished by this procedure (7). The differences between the two identified forms of IC suggest that Type II may be an inflammatory disease

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intrinsic to the bladder that results in pain of nociceptive origin. Pain of nociceptive origin results from persistent stimulation of sensory afferent fibers, and is relieved by removal of the stimulus. Examples include the pain of toothache, which is relieved by extraction of the affected tooth, and that of osteoarthritis of the hip, which is relieved by hip replacement (8). In contrast, the symptoms of patients with Type I IC may be neuropathic in origin. Neuropathic pain is caused or initiated by a primary lesion in the peripheral or central nervous system (CNS) (9), and although generally attributed to a body structure, can remain after removal of that structure (10). Unfortunately, the nervous system lesion(s) associated with IC, if they exist, have yet to be undefined. For the interested reader, many excellent reviews of pain in general (11,12), and visceral pain in particular (13) have been published in recent years. In addition to the two forms of IC currently recognized, others may well exist. Despite our current limited etiologic understanding of IC, extension of the descriptive term to include painful bladder syndrome has been an important step forward (14). Moreover, recent research appears to support the view that abnormalities of many (15), probably most, body systems are present in some patients with BPS/IC (1), whereas this does not appear to be the case to nearly the same extent in other chronic bladder disorders such as urinary tract infection or transitional cell carcinoma. Thus, BPS/IC may be most appropriately categorized as an idiopathic body pain syndrome.

ANIMAL MODELS Data from both acute and chronic nociceptive and neuropathic injuries of healthy animals, and from animals with naturally occurring chronic pain states have contributed importantly to our current understanding of pain in animals and humans. My introduction to BPS/IC occurred during the course of investigations of the etiopathogenesis of a lower urinary tract signs (LUTS) in domestic cats. During the course of investigating this syndrome, it became apparent that it shared many features in common with BPS/IC (16). We termed the syndrome in cats feline interstitial cystitis (FIC) (16), since the cats seemed to share a comparable disease history and course, and to meet all the applicable inclusion and exclusion criteria for diagnosis of IC that have been established by the National Institutes of Arthritis, Diabetes, Digestive and Kidney Diseases (17) that can reasonably be applied to animals. The utility of animal models of human disease depends on how closely the model resembles the condition to which it is compared. Willner (18) has suggested criteria for considering the usefulness of animal models: 1. Face validity: the degree of phenomenological similarity between the model and the disease modeled. Although necessary, this criterion is not sufficient due to the limited repertoire of responses to noxious stimuli available to most organ systems. 2. Construct validity: the extent to which the model has a sound theoretical rationale. This criterion first requires a good theoretical understanding of the etiopathogenesis of the condition modeled, then evidence of congruency of the model with this understanding. 3. Predictive validity: the similarity in response of the model and naturally occurring disease to clinically proven disease-modulating interventions. In the case of BPS/IC, these criteria have yet to be met by any animal model. The two most common types of animal models of human disease are those of induced disease (or signs of disease) in otherwise healthy animals, and investigation of spontaneously occurring disease in animals that bear some resemblance to the human disease of interest. A variety of injuries have been inflicted on healthy animals of various species to study the responses of the bladder and other visceral tissues to different types of noxious stimuli of acute and persistent duration. These studies have revealed important differences in nociceptive responses based on the location, type and duration of the nociceptive stimulus, as well as on the species, strain, age, sex, context and environmental history of the animal to which it is applied (19).

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INDUCED MODELS Noxious Intravesical Stimuli Many models of acute bladder injury in healthy animals have been investigated for their potential relevance to BPS/IC. The potential presence of some toxic constituent in the urine of IC patients has been investigated by instillation of their urine into the bladder of healthy rabbits, which resulted in some histological changes compatible with IC (20). Subsequent studies using a similar protocol, but filling the bladder to only 10% to 20% of capacity, could not reproduce the differences (21). The authors concluded that disruption of the urothelial barrier by distention, rather than any toxic principle in the urine, was the most likely cause of the observed changes. Another study also documented that filling the bladder to R90% of capacity resulted in significant increases in dye penetration through the urothelium (22). These (and other) studies demonstrate that distention per se may mimic some bladder abnormalities present in patients with BPS/IC. A variety of toxins have been instilled into the bladder of animals to study IC. For example, varying concentrations of acetone have been used to induce cystitis in a variety of species (23–25). Instillation of 30% acetone decreased time to micturition without altering threshold or micturition pressures, whereas 50% acetone completely abolished the micturition reflex, resulting in incontinence (23). Inflammation was observed histologically in bladders treated with 30% and 50% acetone; 50% resulted in more severe desquamation of the urothelium, but the severity of inflammatory cell infiltrate was not different from the 30% group. In Green monkeys, 50% acetone decreased bladder compliance and voiding volumes, and increased bladder permeability and animal discomfort after instillation. All parameters returned to normal by four weeks after the study except for bladder compliance (25). Acid instillation also has been used to induce cystitis with some similarities to the ulcer form of BPS/IC. Acidic phosphate-buffered saline (pHZ4.5) instilled into the bladders of healthy female rabbits increased neutrophil chemotactic activity by 70%, and resulted in extensive neutrophil accumulation and edema (26). Increased neutrophil chemotactic activity in urine from IC patients compared to normal patients and patients with other lower urinary tract diseases also was reported (26), but other investigators were unable to detect any neutrophil chemotactic effect of urine from IC patients (27). Instillation of 25% turpentine, 2.5% mustard oil or 2% croton oil into the bladder of decerebrate rats (28) resulted in plasma extravasation that resolved within 72 hours, but increased numbers of leukocytes still were present at that time. Cystometric evaluation identified bladder hyperreflexia for variable periods that had resolved or begun to subside by 72 hours. Interestingly, responses to noxious somatic stimuli also were increased after irritant administration. Immune sensitization also has been used to characterize features of the acute response of the bladder to noxious luminal stimuli. Sensitizing the bladder of healthy guinea pigs to ovalbumin (OVA) resulted in a generalized increase in plasma extravasation (29), and bladder histology that was somewhat similar to the ulcer form of BPS/IC. Instillation of the immune system-activating compounds lipopolysaccharide (LPS) or polyinosinic–polycytidylic acid rapidly also was shown to induce an inflammation that was maintained for at least seven days, and decreased the bladder content of immunoreactive Substance P by approximately 50%, suggesting enhanced release (30). Despite the presence of acute inflammation, no change in the urinary frequency was observed. Administration of an neurokin-1 (NK-1) receptor antagonist did not block the inflammation produced by polyinosinic–polycytidylic acid, suggesting that Substance P was not responsible for the observed inflammatory response. In contrast, NK-1 receptor knockout mice did not develop an inflammatory cell infiltrate or edema in response to intravesical infusion of dinitrophenyl4-OVA after dinitrophenyl4human serum albumin sensitization, despite the presence of increased numbers and percentage of degranulated bladder mast cells compared with wild-type mice (31). These results provided evidence that NK-1 receptors were required for development of the inflammation observed in this model of cystitis. Although these and many other studies have investigated the effects of intravesically administered agents, the absence of a demonstrated toxin in the urine of IC patients, the acute

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time course, and the histological and functional alterations induced by toxins make these studies difficult to relate to patients with naturally occurring disease, particularly the more common nonulcer form. Moreover, similar effects have been produced by other routes, suggesting that some of the identified lesions may be the nonspecific reaction of the bladder to noxious stimuli. Noxious Systemic Stimuli In addition to local instillation of irritants, the bladder also is known to respond to systemic challenges. For example, intravenous injection of Substance P or LPS induced cystitis and increased plasma extravasation in normal, but not in mast cell-deficient mice, indicating that mast cells participate in the inflammatory response of the bladder to systemically administered Substance P and LPS in these mice (32). Whether these compounds acted from the basal or luminal surface of the urothelium, or if they affected bladder function, was not determined. In another study, a toxin from bracken fern reportedly caused a hemorrhagic cystitis even when urine was not allowed to reach the bladder, demonstrating that toxins may result in bladder lesions without having direct contact with the urothelium (33). Infection with animals with viruses at remote sites also can inflame the bladder. In one model, injection of pseudorabies virus (PRV) into the tail base of healthy rats resulted in inflammation of the bladder, colon and prostate gland by activation of CNS circuits (34). Further studies described a role for mast cells in this form of neurogenic cystitis (35). More recently, PRV injection into the kidney for retrograde transneuronal mapping of the spinal cord and brain stem resulted in signs of neurogenic inflammation of the bladder, but not other organs. It was concluded that the effect was due to increased sympathetic nerve activity (36). [In humans, BK virus also has been associated with acute hemorrhagic and nonhemorrhagic cystitis (37), and viruses have been suggested to be associated with LUTS in cats (38).] In addition to virally mediated injury, irritation of other pelvic organs also affects bladder function by a phenomenon called viscero-visceral hyperalgesia (39). This term describes the observation that injury to one visceral organ can affect function of the others. Examples include ureteral (39) and bladder (40) injury affecting uterine function, and bidirectional crosssensitization of the colon and lower urinary tract following either acute bladder irritation or colorectal distention pressures (41). Although the pathway(s) mediating this phenomenon remain to be identified, they may help explain the commonly observed presence of comorbid pelvic organ disorders in patients with BPS/IC. Spinal cord injury also is known to adversely affect the urothelium (42). Apodaca et al., recently reported that spinal cord injury altered several indicators of urothelial barrier function, including decreased continuity of the surface umbrella cell layer and transepithelial resistance, and increased urea and water permeability. These changes were prevented by pretreatment with hexamethonium (an autonomic ganglion transmission blocker), indicating involvement of sympathetic or parasympathetic input to the urinary bladder. Prior treatment with capsaicin exacerbated the change in permeability, suggesting that capsaicin-sensitive afferent neurons may have played a protective role. These results suggest that some balance between afferent and efferent nerve traffic influences normal urothelial integrity. Noxious Environmental Stimuli Stressful circumstances seem to aggravate symptoms of BPS/IC (43), and the effects of some external stressors on bladder function have been studied in animal models. External psychological and physical stressors can result in injury to the urothelium in experimental animals. In healthy rats, 30 minutes of restraint stress resulted in activation of 75% of bladder mast cells (44), whereas the stressor activated 49% of mast cells in animals treated with capsaicin as neonates, suggesting that the stress-induced bladder mast cell activation was partially mediated in part by capsaicin-sensitive neurons, as occurs in many other tissues (45). The procedure also activated bladder mast cells in approximately one-third of control animals, suggesting that the stress of the experimental procedure itself might have been adequate to induce these changes in some individuals.

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Three hours of acute cold (48C) stress was found to induce mucosal edema, leukocyte infiltration, and mast cell degranulation in the bladder (46) and gastrointestinal tract (47) of healthy rats. The stress-induced changes were prevented by treating neonates with capsaicin, or by administering it around the vagus or celiac nerves before exposure to cold immobilization stress (48). These studies demonstrated that the inflammatory changes in response to external stimuli were not specific to the bladder, and support the suggestion that activation of capsaicin sensitive afferent neurons may be involved in responses to stressors at many epithelial surfaces. Urothelial abnormalities similar to those found in some patients with IC also have been found in healthy rodents exposed to 378C temperature (49), or constant illumination (49,50). Electron microscopic evaluation of the urothelium of animals exposed to these conditions revealed abnormal cytoplasmic detail and loss of subapical vesicles. Disruption of tight junctions between superficial urothelial cells and desquamation of superficial cells also occurred, which exposed the underlying intermediate cells to the bladder lumen. Desquamation of superficial urothelial cells thus appears to be a nonspecific bladder defense mechanism, also occurring after Escherichia coli adherence (51), administration of LPS (50), ischemia (52), systemic administration of hydrocortisone or norepinephrine (NE), or removal of calcium (49,53). Moreover, epithelial desquamation also occurs in the colon (54), intestine (55), lung (56), and skin (57) in response to a variety of noxious stimuli. Desquamation may increase epithelial permeability, permitting increased access of external stimuli to neurons and inflammatory cells, which may mediate part of the organism’s response to threatening environmental stimuli. These studies of the role of external stimuli on urothelial (and other epithelial) integrity suggest that complex mechanisms mediate CNS activation of local inflammation during stressful circumstances. The inflammatory response to acute external stressors may partially explain the observation of glomerulations in healthy women undergoing tubal ligation because they may have perceived this procedure as stressful (4). Increased numbers of mast cells have been observed in biopsy specimens from about 65% of IC patients with ulcers and in 20% of specimens from patients without ulcers (58). Since these biopsies were taken during surgical procedures conducted in patients that may have been in an active phase of the disease when they were collected, the increase in mast cells may have been due to the context at the time of collection as well as to the disease itself. Corticotropin releasing factor (CRF) appears to mediate a range of stress responses to internal and external stimuli, including alterations of the gastrointestinal and urinary motor functions (59). The effects of a chronically activated stress response system to additional stressors on visceral function are not known. CRF over expressing (CRF-OE) mice show a number of physiologic and behavioral features that parallel those seen in chronically stressed animals (60). We recently reported on the effects of restraint stress (60 minutes), a novel environment (placed in individual novel cage, 60 minutes) or brief handling (two minutes) in adult female wild type and CRF-OE mice. Compared to wild-type mice, frequency of both defecation and micturition was similar (and high) during restraint stress. However, CRF-OE had significantly increased frequency of defecation and urination in response to novel environment exposure and brief handling, and spent more time in grooming and rearing in response to novel environment. The data suggest that CRF-OE mice display enhanced pelvic visceral motor function in response to a novel environment, and provide evidence that chronically increased stress reactivity can increase responsiveness to additional mild stressors, whereas the response to more severe stimuli (restraint) is similar (61). Studies of healthy animals have thus provided an essential description of the complexity of responses of the normal bladder to a variety of insults, and have demonstrated that both local and distant factors can result in bladder pathology. The relevance of these models to the cause(s) of IC, however, is less clear. The identified responses usually are not specific to the bladder, and when the stimulus is removed, the bladder of healthy animals appears to return to normal rather quickly (46). Naturally Occurring Lower Urinary Tract Disease in Cats A spontaneously occurring disease somewhat analogous to IC also occurs in domestic cats. This disorder sometimes has been referred to as FIC to distinguish it from IC in humans (16,62,63). It is distinguished from idiopathic cystitis in cats only by the requirement for

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cystoscopic evaluation of the bladder and identification of compatible lesions. As in humans, many cats with chronic recurrent LUTS in the absence of an alternative diagnosis are not evaluated cystoscopically. comparison of the two syndromes is presented in Table 1. The syndrome of IC in cats and humans is remarkably similar. Patients of both species have abnormalities of local bladder factors, as well as a multiple comorbidities, and involvement of the afferent, central, and efferent limbs of the nervous system (1). Cats with FIC meet all of the inclusion criteria, and all of the exclusion criteria for diagnosis of IC published by National Institute of Diabetes and Digestive and Kidney that can be applied to animals. Exclusion criterion five (absent nocturia) is difficult to apply to cats because they are nondiurnal animals, but client reports of increased frequency of urination are common. TABLE 1 Comparison of Results of Studies in Humans and Cats with Bladder Pain Syndrome/Interstitial Cystitis Parameter Patient features Gender Bladder symptoms Nonbladder symptoms Clinical course Meet NIDDK criteria Local bladder abnormalities Petechial hemorrhages (cystoscopy) Urothelial permeability Urothelial cell abnormalities Mast cells Total glycosaminoglycan excretion Glycosaminoglycan GP-51 expression Vasodilatation and edema without inflammatory infiltrate Antiproliferative factor Sensory abnormalities Bladder SPIR Sensory neuron abnormalities Dorsal root ganglia abnormalities Sacral cord SPIR Bladder substance P receptors Central abnormalities Response to stress Startle responsiveness Locus coeruleus tyrosine hydroxylase IR Hormonal abnormalities Adrenocortical Gonadal Sympathetic efferent abnormalities Plasma catecholamine concentrations Urine NE excretion Bladder neuropeptide Y-IR Bladder tyrosine hydroxylase IR Alpha-2 adrenoceptor function Bladder NE content Comorbid disorders Gastrointestinal Cardiovascular Neurological Psychological/behavioral Response to treatment Amitriptyline Psychological/behavioral

Human beings (5)

Cats

Females and males Frequency, urgency, pain Yes (1) Waxes and wanes Most

Females and males (16) Frequency, urgency, pain (16) Yes (64) Waxes and wanes (16) Most (16)

Present Increased Yes GIncreased Variable Decreased Present

Present (16) Increased (65) Yes (65) GIncreased (62,66) Decreased (67) Decreased (68) Present (16)

Increased

ND

Increased in some, (69) but not all (70,71) studies ND ND ND ND

GIncreased (72) Yes (73) Yes (74,75) Increased Increased (76)

Exacerbation of signs Increased (by pt. report) ND

Exacerbation of signs Increased (77,78) Increased

Yes (1) Yes (1)

Yes (79) Yes (80)

ND Increased (82) Increased (13) Increased (12,13) ND ND

Increased (81) ND ND Increased (83) Yes (84) Increased (85)

Yes (86) Yes (87) Yes (1) Yes (1)

Yes (64) Yes (88) Yes (75,89) Yes (64)

Yes Yes (90)

Yes Yes (91)

Abbreviations: IR, immunoreactivity; ND, not determined; NE, norepinephrine; NIDDK, National Institute of Diabetes and Digestive and Kidney Diseases; pt., patient; SPIR, substance P-immunoreactivity.

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Exclusion criterion 18 restricts subjects to adults, and FIC most commonly (although not always) is seen in adult cats. Thus, making allowances for species differences, cats with FIC meet the National Institute of Health criteria for IC. The FIC primarily resembles nonulcer IC in humans, although ulceration and inflammatory infiltrates occasionally have been reported in cats (92). Abnormalities of the urothelium, sensory (afferent) neurons, the CNS, and sympathetic (efferent) neurons occur in cats as they do in humans (93). Most (94,95), but not all (96), studies of human patients with IC have found increased bladder permeability. Bladder permeability to sodium salicylate was increased in an in vivo study of cats with FIC (97). Additionally, in vitro bladder epithelial urea permeability was significantly increased from normal in both undistended and distended bladders, water permeability was significantly increased in distended bladders, and transitional cell desquamation was identified in cats with FIC (65). Increased neuronal Substance P immunoreactivity (IR) has been reported in the bladder of humans with IC in some (69) but not all studies (70,71), and has been observed in the bladder of cats with FIC (72). Significant increases in the density of NK-1 receptors in the bladder of humans and cats with IC also have been reported (76,98). Similar increases in both peripheral and spinal NK-1 receptor density have been reported in a variety of other chronic inflammatory processes (99–103), so these findings may represent nonspecific responses to tissue injury. A significant increase in tyrosine hydroxylase (TH) IR, the rate-limiting enzyme of catecholamine synthesis, has been found in the locus coeruleus (LC) of cats with FIC (104). Bladder distention stimulates neuronal activity in the LC, and the LC (Barrington’s nucleus) is the origin of the descending excitatory pathway to the bladder (105). Chronic stress also can increase TH activity in the LC (106), with accompanying increases in autonomic outflow, so the stimulus for the increase in targeted external heavy ion beam irradiation (THIR) is unclear (107,108). The LC contains the largest number of noradrenergic neurons, and is the most important source of NE, in the mammalian nervous system. It is involved in such global brain functions as arousal, vigilance, and analgesia, and appears to mediate visceral responses to stress (109). The increased THIR observed in the LC of cats with FIC may provide a clue to the observation that the clinical symptoms of IC follow a waxing and waning course in both cats and human beings, and are aggravated by environmental stressors (43,110,111). CRF containing projections from the amygdala that are activated as part of the stress response innervate the hypothalamus and LC (112,113), which may increase hypothalamic-mediated CRF release in the LC. These connections have been proposed to stimulate the increased activity of the LC during stressful circumstances, and provide one link between the environment and bladder function (109). If the nociceptive input resulting from an abnormal input somehow primes this circuit, it might become more sensitive to external activation. Alternatively, an unusually sensitive stress response system may result in benign external stimuli being misperceived as threatening. Recent studies have found increased permeability in cats with FIC compared to controls when subjected to a mild stressor (78), and a recent case-control study found that owners of cats with idiopathic cystitis perceived their cats as being more nervous, fearful and aggressive than did owners of healthy cats (114). In addition to increased LC activity, cats with FIC also have increased plasma NE concentrations (115), enhanced stimulus-induced local NE release from the bladder (116) and functional desensitization of central alpha-2 adrenoceptors (a-2 AR) (84). In the LC, a-2 agonists inhibit NE release, whereas in the spinal cord they inhibit transmission of nociceptive input to the brain (117,118). The spinal receptors appear to be located on the central processes of sensory neurons (119–121). Although spinal a-2 AR activation can inhibit nociceptive input acutely, the receptors can become desensitized or downregulated after chronic stimulation (120,122). Increased sympathoneural activity also may release inflammatory mediators associated with pain. For example, NE reportedly can induce local release of prostaglandins, which can in turn excite nociceptive afferent fibers (123), and a recent study has suggested the existence of synaptic contacts between primary sensory afferents and neurons regulating sympathetic outflow to corresponding dorsal root ganglia (124). Conversely, inhibition of sympathetic efferent activity appears to decrease inflammation in some circumstances. For example, sympathectomy reduced the severity of experimentally induced urethral inflammation (125), arthritis (126), and colitis (127), in rats. In both humans

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and cats with IC, amitriptyline, a tricyclic antidepressant with some sympatholytic activity (128), has been shown to reduce symptom severity in some patients (129,130). Although autonomic function has not yet been thoroughly evaluated in humans with IC, stressor-induced increases in heart rate (87) and sympathetic activity have been reported (131), and increased density of bladder sympathetic fibers and THIR have been observed (70,71). Evidence for increased spinal sympathetic neuron activity also has been presented (132), and increased urine NE excretion has been reported (82). In contrast to the activation of the sympathoneural system in cats with FIC, abnormalities of the hypothalamic–pituitary–adrenal axis were not initially identified when responses to CRF challenge were measured in unstressed cats (81). When evaluated in stressed cats, however, the cortisol response to adrenocorticotropic (ACTH) stimulation was reduced, and adrenal gland size was smaller in cats with FIC than in healthy cats (79). Microscopic examination of the glands revealed a reduction in size of the fasciculata and reticularis zones of the adrenal cortex. No evidence of hemorrhage, inflammation, infection, or necrosis that might have caused the reduction in size was identified. These results, when combined with our observations of increased concentrations of CRF (133,134) and ACTH (135), and activity of the sympathoneural system in response to stress in the absence of a comparable increase in plasma cortisol concentrations suggest the presence of an exaggerated stress response in the absence of adrenocortical restraint in cats with FIC. Some evidence for decreased adrenocortical function in human beings with IC also is available (1,136,137), but this aspect of the disease has not yet been comprehensively evaluated. Holstege (138) has described the relationships between neuronal control of micturition and the “emotional motor system”—the set of parallel motor pathways governing somatic, autonomic and endocrine responses to emotionally significant input. The connections between the emotional, nervous, endocrine and epithelial systems of the individuals with chronic pelvic pain may be further understood by additional studies of these systems in cats with FIC. Like the induced models of bladder injury, FIC also has limitations as a model of IC. One is the seemingly different gender distribution between affected males and females of the two species. In cats, both genders are affected roughly equally, whereas in humans, previous studies have suggested that 90% of patients are women (139). Recent reports, however, suggest that the gender difference in humans may not be as large as originally thought (140,141). Additionally, men with IC symptoms are more likely to be diagnosed with “nonbacterial prostatitis” rather than with IC. Miller et al. recently reported that 8 out of 20 men evaluated for “nonbacterial prostatitis” had cystoscopic findings compatible with IC, and “perhaps.should be given the diagnosis of IC” (142). If only half of the cases of “nonbacterial prostatitis” are the same disease as IC, the difference in gender distribution between humans and cats would disappear. Another limitation to using cats with FIC to investigate etiologic mechanisms of IC is that affected animals are not easy to acquire without veterinarian and owner cooperation. Additionally, cats are more expensive to maintain in laboratory animal facilities than are rodents. Despite these limitations, studies of cats with FIC have duplicated many results obtained in humans with IC. Moreover, a wealth of bladder and stress neuroscience research conducted in cats is available to compare anatomic and functional alterations in the CNS caused by IC in ways that would not be possible in humans or induced models.

ANIMAL WELFARE CONSIDERATIONS Although models rarely recreate all the features of the disease they resemble, they still can contribute significantly to a better understanding of the condition in humans (143). In light of this benefit, it also must be remembered that when healthy animals are used as experimental subjects, they are compelled to serve as a means to our ends. Whether the end is alleviation of suffering in other animals and humans, or elucidation of basic biological mechanisms, the result is the same for the animal. Many societies have concluded that it may be ethical to use one group of individuals as the means to the ends of another group. When such a decision is made, as with military conscripts for example, it carries with it the responsibility to treat the burdened

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group as humanely as possible. Mann et al. (144) have argued that use of an appropriate experimental design is an integral part of laboratory animal welfare. For example, if more animals than necessary are used to adequately test a hypothesis, the extra animals used will have been wasted. In contrast, inadequate power to avoid a type II statistical error may prevent appropriate interpretation if too few animals are used, and all will have been wasted. A variety of experimental design strategies are available to reduce the number of animals used in research (144,145), including increasing effect size, reducing variability (146), appropriate use of controls, repeated measures from animals, using interim data analyses, applying one-tailed rather than two-tailed tests, using trend analysis and careful examination of the (blinded) data in addition to computer-based statistical analysis as appropriate. Judicious use of such designs permits appropriate experimental designs to complement efforts to safeguard research animal welfare. Concern for animal welfare is particularly important during studies of stress and pain physiology. Many studies have shown the effects of housing and the laboratory environment of animals used for such studies on key experimental variables, including body weight (147), hypothalamic-pituitary (148), and autonomic function (149), and even such potentially unexpected processes as angiogenesis (150). Choice of diet offered to the animals also may affect results. Shir et al. (151) have shown that the phytoestrogen content of diets may influence nociceptive behaviors in rodents. Since the amount of these compounds in diets may vary significantly between manufacturers and batch, this may be an additional source of experimental variation in studies of visceral pain (152).

CONCLUSIONS AND FUTURE DIRECTIONS A major difficulty in defining IC is that the symptoms represent an exaggeration of normal bladder function (58). An important distinction, however, is that they rarely occur under normal circumstances. Frequency, urgency, and suprapubic pain may occur in normal individuals in response to stressful circumstances (153), which also might explain the observation of glomerulations in patients in the absence of complaints referable to the bladder (4). The participation of the bladder in the stress response identified in rodents may thus model some features of the stress response of healthy humans. In this case, the symptoms may be an effect rather than a cause, and suggest that the bladder may be the victim rather than the instigator of BPS/IC. In contrast to the response of the normal bladder to stressful circumstances, both feline (154) and human patients (155) can have significant reductions in symptoms of IC in the presence of ongoing bladder abnormalities. Moreover, symptoms may remain in humans after removal of the bladder (156). Thus, models that focus only on the response of the healthy bladder to noxious agents cannot be valid models of IC, although they have improved our understanding of the range of responses of the bladder to injury. These observations suggest that the bladder lesions identified in some patients with IC are more likely the result of some disease process, rather than the cause. From this perspective, IC may be one of a number of chronic pain syndromes that have been named and studied based on the medical specialty from which they seek care (157,158). Until an identified etiology, specific pathogenesis, or pathognomonic symptom complex is identified in patients with IC, the relevance of induced animal models can only be evaluated in the context of a bladder injury and the body’s response to whatever “threat” was imposed on it. The relevance of these models to chronic pain syndromes may not be as strong (159). The naturally occurring disease in domestic cats may be more useful to evaluate these aspects of BPS/IC. REFERENCES 1. Buffington CAT. Comorbidity of interstitial cystitis with other unexplained clinical conditions. J Urol 2004; 172:1242–8. 2. Koziol JA. Epidemiology of interstitial cystitis. Urol Clin North Am 1994; 21:7–20.

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Bladder Pain Syndrome/Interstitial Cystitis Clinical Considerations Philip Hanno

Department of Surgery, Division of Urology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, U.S.A.

PROBLEMS IN EPIDEMIOLOGY Epidemiology studies of painful bladder syndrome/interstitial cystitis (IC), now commonly referred to as bladder pain syndrome (BPS)/IC, are hampered by many problems (1). The lack of an accepted definition, the absence of a validated diagnostic marker, and questions regarding the etiology and pathophysiology make much of the literature difficult to interpret. This is most apparent when one looks at the variation in incidence reports. These range from 1.2 per 100,000 population and 4.5 per 100,000 females in Japan (2), to a questionnaire-based study that suggests a figure in American women of 20,000 per 100,000 (3). There is probably a high rate of misdiagnosis (4). Descriptive epidemiologic studies demonstrate the patterns of disease occurrence in human populations. They provide general observations relating the disease to basic characteristics including age, sex, race, occupation, and social class. They help to alert the medical community as to who is most likely to be affected by a disease and where and when it may occur. They can assist in medical planning, provide clues to etiology, and suggest strategies for future research (5). Most epidemiologic information about BPS/IC has historically come from anecdotal reports and reviews of series of patients from physicians or medical centers that have accumulated large numbers of patients with the disease. Clinic-based studies are commonly published in the literature, but suffer from distortions based on who is seen in clinics. As an example, in the early 1990s, almost all studies on the newly described “chronic fatigue syndrome” (CFS) were clinic-based. As a result, CFS was characterized as a disease that primarily affected white women in their 40s and 50s, who were in the middle to upper socioeconomic groups. The women were well-educated professionals who developed sudden onset of symptoms. The Center for Disease Control in Atlanta, Georgia eventually conducted community studies, which estimated that the minority population has twice the prevalence of CFS as had been estimated. CFS was determined to be more common in the lower socioeconomic strata. Slow onset of illness was noted as often as acute onset. The importance of population-based studies is emphasized by these findings (6). Another potential drawback of clinic-based studies is that each study may use a different definition of a symptom-based illness, and self-reported symptoms may not be uniformly assessed. Diagnostic criteria to be used for research studies of BPS/IC were established in 1987 at a workshop held at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) in Bethesda, Maryland (Table 1) (8). The purpose of the criteria was to allow comparison of the data from published clinic research studies conducted throughout the world. These diagnostic criteria were intended only to be applied to research studies for the purpose of obtaining uniformity in the patient population studied. Over time, they were mistakenly used to fill the void of the lack of established uniform clinical criteria for the diagnosis of BPS/IC, a purpose for which they were neither developed nor intended. The cohort of persons who meet these criteria excludes many who would routinely be diagnosed as having BPS/IC in a clinical setting (9). They cannot be used for population-based

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TABLE 1 NIDDK Diagnostic Criteria for Interstitial Cystitis To be diagnosed with interstitial cystitis, patients must have either glomerulations on cystoscopic examination or a classic Hunner’s ulcer, and they must have either pain associated with the bladder or urinary urgency. An examination for glomerulations should be undertaken after distention of the bladder under anesthesia to 80 cm to 100 cm of water pressure for one to two minutes. The bladder may be distended up to two times before evaluation. The glomerulations must be diffuse present in at least three quadrants of the bladder and there must be at least 10 glomerulations per quadrant. The glomerulations must not be along the path of the cystoscope (to eliminate artifact from contact instrumentation). The presence of any one of the following excludes a diagnosis of interstitial cystitis: Bladder capacity of greater than 350 cc on awake cystometry using either a gas- or liquid-filling medium Absence of an intense urge to void with the bladder filled to 100 cc of a gas- or 150 cc of liquid-filling medium The demonstration of phasic involuntary bladder contractions on cystometry using the fill rate described above Duration of symptoms less than nine months Absence of nocturia Symptoms relieved by antimicrobials, urinary antiseptics, anticholinergics, or antispasmodics A frequency of urination while awake of less than eight times per day A diagnosis of bacterial cystitis or prostatitis within a three-month period Bladder or ureteral calculi Active genital herpes Uterine, cervical, vaginal, or urethral cancer Urethral diverticulum Cyclophosphamide or any type of chemical cystitis Tuberculous cystitis Radiation cystitis Benign or malignant bladder tumors Vaginitis Age less than 18 years Abbreviation: NIDDK, National Institute of Diabetes and Digestive and Kidney Diseases. Source: From Ref. 7.

epidemiologic studies. A usable clinical definition of BPS/IC is an essential prerequisite for epidemiologic research. CURRENT DEFINITION OF BPS/IC IC is a clinical diagnosis primarily based on symptoms of pain related to the urinary bladder, usually accompanied by urinary frequency and/or nocturia, in the absence of other diagnosable conditions that may cause those symptoms. The International Continence Society (ICS) prefers the term BPS, defined as “the complaint of suprapubic pain related to bladder filling, accompanied by other symptoms such as increased daytime and nighttime frequency, in the absence of proven urinary infection or other obvious pathology” (10). ICS reserves the diagnosis of IC to patients with “typical cystoscopic and histological features,” without further specifying these. Peeker and colleagues have described such features (11), but they are still somewhat controversial and vague (12–14). In the absence of clear criteria for “IC,” it is perhaps reasonable to refer to this syndrome as BPS/IC. All but recent literature term the syndrome “IC.” The most recent taxonomy suggests that the term bladder pain syndrome (BPS) is preffered. There are data to suggest that true urinary frequency in women can be defined as regularly having to void at intervals of less than three hours, and that of women older than 40 years, 25% have nocturia at least once (15,16). Whereas bladder capacity tends to fall in women by the eighth and ninth decades of life, bladder capacity at first desire to void tends to rise as women age (17). Based on a 90th percentile cutoff to determine the ranges of normality, the highest “normal” frequency in the fourth decade varies from 6 for men to 9 for women (18). Large variation in the degree of bother with differing rates of frequency (19) makes a symptomatic diagnosis of BPS/IC based on an absolute number of voids subject to question. Frequency per volume of intake or even the concept of “perception of frequency” as a problem may be more accurate than an absolute number. DIAGNOSIS OF BPS/IC The diagnosis of BPS/IC is, by its very nature, based upon the definition. Urinary frequency and pelvic pain, pressure, or discomfort of long duration related to the bladder and unrelated

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to other known causes establishes a working diagnosis (12,20). Diagnostic approaches vary widely and general agreement on a diagnostic algorithm remains a future goal (21–23). The disorder can be very difficult to diagnose until symptoms become well established, unless one has a high level of suspicion (24). One must rule out infection and less common conditions including but not limited to carcinoma (25,26), eosinophilic cystitis (27,28), malakoplakia, schistosomiasis, scleroderma (29), and detrusor endometriosis (30,31). In men under the age of 50, videourodynamics are useful to rule out vesical neck obstruction, “pseudo” dyssynergia, or impaired contractility (32). Musculoskeletal dysfunction may also play a role in causation or increasing symptom severity and should be looked for in the diagnostic phase of evaluation (33). A complete history, physical examination, and appropriate cultures can usually suffice to make a presumptive diagnosis. The finding of hematuria would necessitate its own evaluation to include imaging of the urinary tract and cystoscopic examination. Urine cytology is essential if bladder carcinoma in situ is in the differential, as in those with microhematuria or a history of tobacco use. The diagnosis is generally subject to more rigorous testing in Europe than in North America, where symptoms in the absence of other obvious causes seem to be the gold standard (12,20,22,23). EPIDEMIOLOGIC STUDIES An NIDDK epidemiology task force (6) concluded that epidemiologic studies of BPS/IC are hampered by confusion among the population between the terms “IC” and “cystitis” related to acute bladder infections. Thus, asking subjects about whether or not they have ever been given a diagnosis of IC overestimates prevalence, as many will misinterpret the designation of IC to include all episodes of cystitis. However, the prevalence of symptoms consistent with a diagnosis of BPS/IC is much higher than the rate of clinician diagnosis. Studies using subjects identified through clinician offices will tend to underestimate prevalence, when compared with studies sampling the general population with questions related to symptoms rather than diagnosis. The task force concluded that epidemiology studies should be grounded in certain principles which are as follows: 1. IC is a symptomatic diagnosis based on the presence of three key symptoms: pain, urgency, and frequency, as well as exclusion of a short list of other conditions that cause the same symptoms. 2. Pain is the most consistent and disabling symptom for BPS/IC patients. Some will not use the term pain, but will rather describe a sense of pressure or discomfort. Typically, but not always, the pain is worse with filling of the bladder and is relieved by emptying the bladder. 3. There is no “gold standard” for diagnosis, and criteria used by experienced clinicians will need standardization for use in epidemiology studies. 4. Questions to subjects about whether or not they have ever been given the diagnosis of IC are not useful, because subjects frequently confuse the term “IC” with acute bacterial cystitis. 5. The prevalence of symptoms consistent with diagnosis is much higher than the rate of clinician diagnosis. Subjects identified through clinician offices will differ from subjects identified through population sampling strategies. With the above caveats in mind, we can better understand, and keep in some perspective, the epidemiologic work on BPS/IC that has been published in the literature. Case Series It has been estimated that the prevalence of chronic pain due to benign causes in the population is at least 10% (34). Numerous case series have, until recently, formed the basis of epidemiologic information regarding BPS/IC. Farkas and associates (35) discussed BPS/IC in adolescent girls. Hanash and Pool (36) reviewed their experience with BPS/IC in men. Geist and Antolak (37) reviewed and added to reports of disease occurring in childhood. A childhood presentation is

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extremely rare and must be differentiated from the much more common and benign-behaving extraordinary urinary frequency syndrome of childhood, a self-limited condition of unknown etiology (38,39). Nevertheless, there is a small cohort of children with chronic symptoms of bladder pain and urinary frequency in the absence of infection who have been evaluated with urodynamics, cystoscopy, and bladder distention and have findings consistent with the diagnosis of BPS/IC. In Close and colleagues review of 20 such children (40), the median age of onset was younger than five years, and the vast majority of patients had longterm remissions with bladder distention. A study conducted at the Scripps Research Institute (41) included 374 patients at Scripps as well as some members of the Interstitial Cystitis Association, the large patient support organization. A more recent, but similar study in England (42) concurred with the Scripps findings of frequency, and pain in the vast majority of these patients, devastating effects on quality of life, and often unsuccessful attempts at therapy with a variety of treatments. Although such reviews provide some information, they would seem to be necessarily biased by virtue of their design. The Interstitial Cystitis Database cohort of patients has been carefully studied, and the findings seem to bear out those of other epidemiologic surveys (43). Patterns of change in symptoms with time suggest regression to the mean and an intervention effect associated with the increased follow-up and care of cohort participants. Although all symptoms fluctuated, there was no evidence of significant long-term change in overall disease severity. The data suggest that BPS/IC is a chronic disease and no current treatments have a significant impact on symptoms over time in the majority of patients. Quality of life studies suggest that BPS/IC patients are six times more likely than individuals in the general population to cut down on work time owing to health problems, but only half as likely to do so as patients with arthritis (44). There is an associated high incidence of comorbidity including depression, chronic pain, and anxiety and overall mental health (12,45,46). There seems to be no effect on pregnancy outcomes (47). Population-Based Studies Several population-based studies have been reported in the literature, and these studies tend to support the reviews of selected patients or from individual clinics and the comprehensive follow-up case-control study by Koziol (48). The first population-based study (49) included “almost all the patients” with BPS/IC in the city of Helsinki. This superb, brief report from Finland surveyed all diagnosed cases in a population approaching one million. The prevalence of the disease in women was 18.1 per 100,000. The joint prevalence in both sexes was 10.6 cases per 100,000. The annual incidence of new female cases was 1.2 per 100,000. Severe cases accounted for about 10% of the total. Ten percent of cases were in men. The disease onset was generally subacute rather than insidious, and full development of the classic symptom complex occurred over a relatively short time. BPS/IC does not progress continuously, but usually reaches its final stage rapidly [within five years in the Koziol study (41)] and then continues without significant change in symptomatology. Subsequent major deterioration was found by Oravisto to be unusual. The duration of symptoms before diagnosis was three to five years in the Finnish study. Analogous figures in a classic American paper a quarter of a century earlier were 7 to 12 years (50). Another early population study, in the United States, first demonstrated the potential extent of what had been considered a very rare disease (51). The following population groups were surveyed: (i) random survey of 127 board-certified urologists, (ii) 64 BPS/IC patients selected by the surveyed urologists and divided among the last patient with BPS/IC seen, and the last patient with BPS/IC diagnosed, (iii) 904 female patients belonging to the Interstitial Cystitis Association, and (iv) random phone survey of 119 persons from the U.S. population. This 1987 study reached the following conclusions: 1. 43,500 to 90,000 diagnosed cases of BPS/IC in the United States (twice the Finnish prevalence) 2. Up to a fivefold increase in BPS/IC prevalence if all patients with painful bladder, sterile urine had been given the diagnosis, yielding up to half million possible cases in the U.S.

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3. 4. 5. 6. 7. 8.

Median age of onset 40 years Late deterioration in symptoms unusual Fifty percent temporary spontaneous remission rate, mean duration eight months Ten times higher incidence of childhood bladder problems in BPS/IC patients versus controls Two times the incidence of a history of urinary tract infection versus controls Fourteen percent of BPS/IC patients Jewish [15% in Koziol sample (48)] versus 3% Jewish in general population sample 9. Lower quality-of-life than dialysis patients 10. Costs, including lost economic production in 1987, of $427 million Other population studies followed. Jones et al. (52) obtained their data from self-report of a previous diagnosis of IC in the 1989 National Household Interview Survey. The survey estimated that 0.5% of the population or O1,000,000 people in the United States reported having a diagnosis of IC. There was no verification of this self-report by medical records. Bade et al. (53) did a physician questionnaire-based survey in the Netherlands yielding an overall prevalence of 8 to 16 per 100,000 females, with diagnosis heavily dependent on pathology and presence of mast cells. This prevalence in females compares with 4.5 per 100,000 in Japan (2). The Nurses Health Study I and II (54) showed a prevalence of BPS/IC between 52 and 67 per 100,000 in the U.S.A., twice the prevalence in the Held study (51) and threefold greater than that in the Netherlands (53). It improved on previous studies by using a large sample derived from a general population and careful ascertainment of the diagnosis. If the 6.4% confirmation rate of their study was applied to the Jones et al. National Health Interview Survey data, the prevalence estimates of the two studies would be nearly identical. Leppilahti et al. (55,56) used the O’Leary-Sant IC symptom and problem index (never validated for making a diagnosis per se) to select persons with BPS/IC symptoms from the Finnish population register. They calculated an incidence, based on an index score of 12 or greater, of 450 per 100,000. Roberts (57), using a physician diagnosis as the arbiter of BPS/IC, found annual incidence in Olmsted County, Minnesota of 1.6 per 100,000 in women and 0.6 per 100,000 in men, a figure remarkably similar to that of Oravisto in Helsinki. The cumulative prevalence by age O80 years in the Minnesota study was 114 per 100,000, a figure comparable to that in the Nurses Health Study if one takes into account the younger age group in the Curhan data. Clemens calculated a prevalence of diagnosed disease in a managed care population of 197 per 100,000 women and 41 per 100,000 men, but when the diagnosis was tested by eliminating those who had not been evaluated with endoscopy or in whom exclusionary conditions existed, the numbers dropped considerably. Whether the considerable variability in prevalence in studies within the United States and around the world is related to methodology or true differences in incidence is an important question yet to be answered. Familial occurrence of BPS/IC has been reported (58). A hereditary aspect to incidence has been suggested by Warren in a pioneering study. He found that adult female first-degree relatives of patients with BPS/IC may have a prevalence of the syndrome 17 times that found in the general population. This, together with previously reported evidence showing a greater concordance of BPS/IC among monozygotic than dizygotic twins, suggests, but does not prove, a genetic susceptibility that could partially explain the discord in prevalence rates in different populations (59,60). Most studies show a female-to-male preponderance of 5:1 or greater (12,61). In the absence of a validated marker, it is often difficult to distinguish BPS/IC from the chronic pelvic pain syndrome (CPPS; nonbacterial prostatitis, prostatodynia) that affects males (62), and the percentage of men with BPS/IC may actually be higher (56,63,64). Men tend to be diagnosed at an older age and have a higher percentage of Hunner’s ulcer in the case series reported (57,64).

ASSOCIATED DISORDERS Knowledge of associated diseases is relevant for the clues it engenders with regard to etiology and possible treatment of this enigmatic pain syndrome. In a case-control study Erickson found that patients with BPS/IC had higher scores than controls for pelvic discomfort, backache,

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dizziness, chest pain, aches in joints, abdominal cramps, nausea, palpitations, and headache (65). An association between persistent post-hysterectomy chronic pelvic pain and BPS/IC can readily be explained on the basis of a misdiagnosis of the cause of pelvic pain symptoms leading to ineffective treatment by hysterectomy (66). Buffington theorizes that a common stress response pattern of increased sympathetic nervous system function in the absence of comparable activation of the hypothalamic–pituitary–adrenal axis may account for some of these related symptoms (67). It has recently been hypothesized that panic disorder may sometimes be a part of a familial syndrome that includes IC, thyroid disorders, and other disorders of possible autonomic or neuromuscular control (68). Newly diagnosed patients are most concerned with the possibility that BPS/IC could be a forerunner of bladder carcinoma. No reports have ever documented a relationship to suggest that BPS/IC is a premalignant disorder. Utz and Zincke discovered bladder cancer in 12 of 53 men treated for BPS/IC at the Mayo Clinic (69). Three of 224 women were eventually diagnosed with bladder cancer. Four years later additional cases were reported (70). Tissot (25) reported that 1% of 600 patients previously diagnosed as having BPS/IC were found to have transitional cell carcinoma as the cause of symptoms. Somewhat ominously, two of these patients had no hematuria. In all patients, storage symptoms resolved after treatment of the malignancy. From this experience has come the dictum that all patients with presumed BPS/IC should undergo cystoscopy, urine cytology, and bladder biopsy of any suspicious lesion to be sure that a bladder carcinoma is not masquerading as BPS/IC. It would seem that in the absence of microhematuria, and with a negative cytology, the risk of missing a cancer is negligible, but not zero. There is no evidence that BPS/IC itself is associated with a higher risk of bladder cancer, or transitions to cancer over time (71). A large-scale survey of 6783 individuals diagnosed by their physicians as having BPS/IC studied the incidence of associated disease in this population (72). Data from the 2405 responders were validated by comparison with 277 nonresponders. Allergies were the most common association with over 40% affected. Allergy was also the primary association in Hand’s study (50). Thirty percent of patients had a diagnosis of irritable bowel syndrome, a finding confirming that of Koziol (48). Altered visceral sensation has been implicated in irritable bowel syndrome in that these patients experience intestinal pain at intestinal gas volumes that are lower than those that cause pain in healthy persons (73), strikingly similar to the pain on bladder distention in BPS/IC. Fibromyalgia, another disorder frequently considered functional because no specific structural or biochemical cause has been found, is also overrepresented in the BPS/IC population. This is a painful, nonarticular condition predominantly involving muscles; it is the commonest cause of chronic, widespread musculoskeletal pain. It is typically associated with persistent fatigue, nonrefreshing sleep, and generalized stiffness. As in BPS/IC, women are affected at least 10 times more often than men (74). The association is intriguing as both conditions have nearly identical demographic features, modulating factors, associated symptoms, and response to tricyclic compounds (75). Generalized vulvar pain syndrome, migraine headaches, endometriosis, CFS, incontinence, and asthma had similar prevalence as in the general population. Several publications have noted an association between BPS/IC and systemic lupus erythematosis (SLE) (76–80). The question has always been as to whether the bladder symptoms represent an association of these two disease processes, or rather are a manifestation of lupus involvement of the bladder or even a myelopathy with involvement of the sacral cord in a small group of these patients (81). The beneficial response of the cystitis of SLE to steroids (79) tends to support the latter view. No association with discoid lupus has been demonstrated (82). While the actual numbers are small, the Alagiri study demonstrated a 30 to 50 times greater incidence of SLE in the BPS/IC group compared with the general population. Overall, the incidence of collagen vascular disease in the BPS/IC population is low. Parsons found only two of 225 consecutive patients to have a history of autoimmune disorder (83). Inflammatory bowel disease was found in over 7% of the BPS/IC population Alagiri studied, a figure 100-times higher than in the general population. While unexplained at this time, abnormal leukocyte activity has been implicated in both conditions (84,85).

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Other mysterious disorders that have been associated with BPS/IC include localized vulvar pain syndrome and vestibular pain syndrome. Vestibular pain syndrome is a constellation of symptoms and findings involving and limited to the vulvar vestibule consisting of (i) severe pain on vestibular touch to attempted vaginal entry, (ii) tenderness to pressure localized within the vulvar vestibule, and (iii) physical findings confined to vulvar erythema of various degrees (86). McCormack (87) reported on 36 patients with vestibular pain syndrome, 11 of whom also had IC. Fitzpatrick (88) has added three more cases. The concordance of these noninfectious inflammatory syndromes involving the tissues derived from the embryonic urogenital sinus and the similarity of the demographics argue for a common etiology. An association has been reported between BPS/IC and Sjo¨gren’s syndrome (SS), an autoimmune exocrinopathy with a female preponderance manifested by dry eyes, dry mouth, and arthritis, but which can also include fever, dryness, gastrointestinal, and lung problems. Van De Merwe (89) investigated 10 BPS/IC patients for the presence of SS. Two patients had both the keratoconjunctivitis sicca and focal lymphocytic sialoadenitis allowing a primary diagnosis of SS. Only two patients had neither finding. He later reported an incidence of 28% of Sjo¨gren’s in patients with IC (90). The incidence of symptoms of BPS/IC in patients with Sjo¨gren’s has been estimated to be up to 5% (91). A negative correlation with diabetes has been noted (48,83).

ONGOING EPIDEMIOLOGIC RESEARCH Aside from providing potentially important clues as to treatment and prevention of BPS/IC, studies of the epidemiology of the syndrome have some much more mundane, but just as important implications in the long-term goal of bringing this problem under control. From the perspective of government, the incidence and prevalence of the disorder may well determine to a large extent how much money will be spent to support studies on the etiology, pathophysiology, and treatment of BPS/IC. From the perspective of the pharmaceutical industry, such studies will help to determine how much of an effort should be made, to target the development of treatments for the syndrome, given the projected market size for such treatments and given the natural history of the disorder. If the natural history is one of a chronic, lifelong process, the market expands considerably, as it would if the prevalence is much higher than generally supposed. The medical profession itself has a great stake in the answers to these questions in helping the profession to rationally allocate scarce medical resources and personnel for the treatment and care of these often desperate patients. The epidemiology task force of the NIDDK in the United States recently made the following recommendations (6): 1. Use a population-based sampling strategy to identify persons who are symptomatic. 2. Perform more intensive evaluation on a sample of symptomatic subjects and on control subjects. 3. Draw a sample for intensive study from a region close to sites of investigation. 4. Consider a national strategy for telephone surveys. 5. Include persons with early symptoms of the illness in the study, i.e., persons with symptoms greater than four weeks that cannot be attributed to urinary tract infection. 6. Limit surveys to persons with bladder symptoms, rather than confounding them with persons who have vulvodynia or chronic pelvic pain. 7. Perform prospective studies to identify risk factors for the syndrome. 8. Perform a longitudinal study of symptomatic subjects and controls to provide information on natural history of early symptoms and long-term prognosis. 9. Collect biosamples to evaluate sensitivity and specificity of antiproliferative factor (APF) and enable future research projects. Naturally, studies like those noted are extremely expensive, and one must use available resources in a way that maximizes the marginal value of available funding.

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ANTIPROLIFERATIVE FACTOR The finding that cells from the bladder lining of normal controls grow significantly more rapidly in culture than cells from BPS/IC patients (92) led Keay and associates at the University of Maryland to the discovery of an APF produced by the urothelium of BPS/IC patients. Normal bladder cells were cultured in the presence of urine from patients with BPS/IC, asymptomatic controls, bacterial cystitis, and vulvovaginitis. Only urine from BPS/IC patients inhibited bladder cell proliferation (93). The presence of APF was found to be a sensitive and specific biomarker for BPS/IC (94). It was found in bladder urine but not in renal pelvic urine of IC patients, indicating its production by the bladder urothelial cells (95). Subsequent studies indicated that APF is associated with decreased production of heparin-binding epidermal growth factor-like growth factor (HB-EGF) (96,97). APF activity was related to increased production of EGF, insulin-like growth factor-1, and insulin-like growth factor binding protein-3 by the bladder cells from BPS/IC patients but not by the cells from healthy bladders. Studies of BPS/IC patients and asymptomatic controls showed urine levels of APF, HB-EGF, and EGF to reliably separate out BPS/IC from controls (94,98). APF levels in the urine were found to discriminate between men with BPS/IC versus those with CPPS or nonbacterial prostatitis (99). APF activity dropped significantly in BPS/IC patients within two hours after hydrodistention (100) and after five days of sacral neuromodulation (101). Cell culture studies showed that APF actually caused decrease in HB-EGF and increase in EGF, mirroring the differences in urine levels of these growth factors between BPS/IC patients and controls, and suggesting that APF is the primary abnormality (97). While APF may prove to be a useful marker for BPS/IC, it may also unlock the etiology of the syndrome. It has been hypothesized by Keay and colleagues that BPS/IC may result from an inhibition of bladder epithelial cell proliferation caused by the APF, which is mediated by its regulation of growth factor production from bladder cells (102). Conceivably, any of a variety of injuries to the bladder (infection, trauma, and overdistention) in a susceptible individual may result in BPS/IC if APF is present and suppresses production of HB-EGF (103). Theoretically, if production of APF could be “turned off” by genetic techniques, or its effects were nullified by exogenous HB-EGF growth factor, the clinical syndrome might be prevented. APF has been purified and proved to be a frizzled 8 protein that belongs to a newly discovered family of proteins which seem to be important in the development of nerve tissues, skin, and the lining of organs (104). Studies are ongoing to confirm the research by Dr. Keay and colleagues and expand on its significance in diagnosis and development of a rational treatment approach (105). CONCLUSION An accurate country-by-country determination of BPS/IC prevalence and incidence is difficult to perform at the present time. Until specific diagnostic markers are verified and/or a set of agreed upon diagnostic criteria based on well-designed published data are established, it seems most appropriate to use a more inclusive symptom-specific definition of BPS/IC to permit an assessment of the population burden. Specifically, a validated questionnaire that can be administered in person or by telephone and that has been compared to a gold standard (disease marker in the future; expert opinion and diagnosis at present) is required to estimate within a given range the true extent of disease in populations around the world. If APF proves to have the superb sensitivity and specificity it seems to have in initial studies, it will become an important epidemiologic tool and may lead the way to rational development of therapy. REFERENCES 1. Bernardini P, Bondavalli C, Luciano M, et al. Interstitial cystitis: epidemiology. Arch Ital Urol Androl 1999; 71:313. 2. Ito T, Miki M, Yamada T. Interstitial cystitis in Japan. BJU Int 2000; 86:634. 3. Parsons CL, Tatsis V. Prevalence of interstitial cystitis in young women. Urology 2004; 64:866.

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Gynecol Obstet Invest 2003; 56:160. 48. Koziol JA. Epidemiology of interstitial cystitis. Urol Clin North Am 1994; 21:7. 49. Oravisto KJ. Epidemiology of interstitial cystitis. Ann Chir Gynaecol Fenn 1975; 64:75. 50. Hand JR. Interstitial cystitis: report of 223 cases (204 women and 19 men). J Urol 1949; 61:291. 51. Held PJ, Hanno PM, Wein AJ. Epidemiology of interstitial cystitis: 2. In: Hanno PM, Staskin DR, Krane RJ, Wein AJ, eds. Interstitial Cystitis. London: Springer, 1990:29–48. 52. Jones CA, Nyberg L. Epidemiology of interstitial cystitis. Urology 1997; 49:2. 53. Bade JJ, Rijcken B, Mensink HJ. Interstitial cystitis in The Netherlands: prevalence, diagnostic criteria and therapeutic preferences. J Urol 1995; 154:2035. 54. Curhan GC, Speizer FE, Hunter DJ, Curhan SG, Stampfer MJ. Epidemiology of interstitial cystitis: a population based study. J Urol 1999; 161:549. 55. Leppilahti M, Tammela TL, Huhtala H, Auvinen A. Prevalence of symptoms related to interstitial cystitis in women: a population based study in Finland. J Urol 2002; 168:139. 56. Miller JL, Bavendam TG, Berger RE. Interstitial cystitis in men. In: Sant GR, ed. Interstitial Cystitis. Philadelphia, PA: Lippincott-Raven, 1997:165–8. 57. Roberts RO, Bergstralh EJ, Bass SE, Lightner DJ, Lieber MM, Jacobsen SJ. Incidence of physiciandiagnosed interstitial cystitis in Olmsted County: a community-based study. BJU Int 2003; 91:181. 58. Dimitrakov JD. A case of familial clustering of interstitial cystitis and chronic pelvic pain syndrome. Urology 2001; 58:281. 59. Warren JW, Keay SK, Meyers D, Xu J. Concordance of interstitial cystitis in monozygotic and dizygotic twin pairs. Urology 2001; 57:22. 60. Warren JW, Jackson TL, Langenberg P, Meyers DJ, Xu J. Prevalence of interstitial cystitis in firstdegree relatives of patients with interstitial cystitis. Urology 2004; 63:17. 61. Clemens J, Meenan R, Rosetti M, Calhoun E. Prevalence and incidence of interstitial cystitis in a managed care population. J Urol 2005; 173:98. 62. Forrest JB, Schmidt S. Interstitial cystitis, chronic nonbacterial prostatitis and chronic pelvic pain syndrome in men: a common and frequently identical clinical entity. J Urol 2004; 172:2561. 63. Miller JL, Rothman I, Bavendam TG, Berger RE. Prostatodynia and interstitial cystitis: one and the same? Urology 1995; 45:587. 64. Novicki DE, Larson TR, Swanson SK. Interstitial cystitis in men. Urology 1998; 52:621. 65. Erickson DR, Morgan KC, Ordille S, Keay SK, Xie SX. Nonbladder related symptoms in patients with interstitial cystitis. J Urol 2001; 166:557. 66. Chung MK. Interstitial cystitis in persistent posthysterectomy chronic pelvic pain. J Soc Laparoendosc Surg 2004; 8:329. 67. Buffington CA. Comorbidity of interstitial cystitis with other unexplained clinical conditions. J Urol 2004; 172:1242. 68. Weissman MM, Gross R, Fyer A, et al. Interstitial cystitis and panic disorder: a potential genetic syndrome. Arch Gen Psychiatry 2004; 61:273. 69. Utz DC, Zincke H. The masquerade of bladder cancer in situ as interstitial cystitis. Trans Am Assoc Genitourin Surg 1973; 65:64. 70. Lamm DL, Gittes RF. Inflammatory carcinoma of the bladder and interstitial cystitis. J Urol 1977; 117:49.

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71. Murphy DM, Zincke H, Utz DC. Interstitial cystitis. J Urol 1982; 128:606. 72. Alagiri M, Chottiner S, Ratner V, Slade D, Hanno PM. Interstitial cystitis: unexplained associations with other chronic disease and pain syndromes. Urology 1997; 49:52. 73. Lynn RB, Friedman LS. Irritable bowel syndrome. N Engl J Med 1993; 329:1940. 74. Consensus document on fibromyalgia: the copenhagen declaration. J Musculoskeletal Pain 1993; 1:295. 75. Clauw DJ, Schmidt M, Radulovic D, Singer A, Katz P, Bresette J. The relationship between fibromyalgia and interstitial cystitis. J Psychiatr Res 1997; 31:125. 76. Boye E, Morse M, Huttner I, Erlanger BF, MacKinnon KJ, Klassen J. Immune complex-mediated interstitial cystitis as a major manifestation of systemic lupus erythematosus. Clin Immunol Immunopathol 1979; 13:67. 77. de la Serna AR, Alarcon-Segovia D. Chronic interstitial cystitis as an initial major manifestation of systemic lupus erythematosus. J Rheumatol 1981; 8:808. 78. Fister GM. Similarity of interstitial cystitis (Hunner ulcer) to lupus erythematosus. J Urol 1938; 40:37. 79. Meulders Q, Michel C, Marteau P, et al. Association of chronic interstitial cystitis, protein-losing enteropathy and paralytic ileus with seronegative systemic lupus erythematosus: case report and review of the literature. Clin Nephrol 1992; 37:239. 80. Weisman MH, McDanald EC, Wilson CB. Studies of the pathogenesis of interstitial cystitis, obstructive uropathy, and intestinal malabsorption in a patient with systemic lupus erythematosus. Am J Med 1981; 70:875. 81. Sakakibara R, Uchiyama T, Yoshiyama M, Yamanishi T, Hattori T. Urinary dysfunction in patients with systemic lupus erythematosis. Neurourol Urodyn 2003; 22:593. 82. Jokinen EJ, Lassus A, Salo OP, Alfthan O. Discoid lupus erythematosus and interstitial cystitis. The presence of bound immunoglobulins in the bladder mucosa. Ann Clin Res 1972; 4:23. 83. Parsons CL. Interstitial cystitis: clinical manifestations and diagnostic criteria in over 200 cases. Neurourol Urodyn 1990; 9:241. 84. Bhone AW, Hodson JM, Rebuck JW, et al. An abnormal leukocyte response in interstitial cystitis. J Urol 1962; 88:387. 85. Kontras SB, Bodenbender JG, McClave CR, Smith JP. Interstitial cystitis in chronic granulomatous disease. J Urol 1971; 105:575. 86. Marinoff SC, Turner MLC. Vulvar vestibulitis syndrome: an overview. J Obstet Gynecol 1991; 165:1228. 87. McCormack WM. Two urogenital sinus syndromes. Interstitial cystitis and focal vulvitis. J Reprod Med 1990; 35:873. 88. Fitzpatrick CC, DeLancey JO, Elkins TE, McGuire EJ. Vulvar vestibulitis and interstitial cystitis: a disorder of urogenital sinus-derived epithelium? Obstet Gynecol 1993; 81:860. 89. Van de MJ, Kamerling R, Arendsen E, Mulder D, Hooijkaas H. Sjogren’s syndrome in patients with interstitial cystitis. J Rheumatol 1993; 20:962. 90. van de Merwe JP, Yamada T, Sakamoto Y. Systemic aspects of interstitial cystitis, immunology and linkage with autoimmune disorders. Int J Urol 2003; 10(Suppl.):S35. 91. Leppilahti M, Tammela TL, Huhtala H, Kiilholma P, Leppilahti K, Auvinen A. Interstitial cystitis-like urinary symptoms among patients with Sjogren’s syndrome: a population-based study in Finland. Am J Med 2003; 115:62. 92. Keay S, Zhang CO, Trifillis AL, et al. Decreased 3H-thymidine incorporation by human bladder epithelial cells following exposure to urine from interstitial cystitis patients. J Urol 1996; 156:2073. 93. Keay S, Zhang CO, Hise MK, et al. A diagnostic in vitro urine assay for interstitial cystitis. Urology 1998; 52:974. 94. Keay SK, Zhang CO, Shoenfelt J, et al. Sensitivity and specificity of antiproliferative factor, heparinbinding epidermal growth factor-like growth factor, and epidermal growth factor as urine markers for interstitial cystitis. Urology 2001; 57:9. 95. Keay S, Warren JW, Zhang CO, Tu LM, Gordon DA, Whitmore KE. Antiproliferative activity is present in bladder but not renal pelvic urine from interstitial cystitis patients. J Urol 1999; 162:1487. 96. Keay S, Kleinberg M, Zhang CO, Hise MK, Warren JW. Bladder epithelial cells from patients with interstitial cystitis produce an inhibitor of heparin-binding epidermal growth factor-like growth factor production. J Urol 2000; 164:2112. 97. Keay S, Zhang CO, Shoenfelt JL, Chai TC. Decreased in vitro proliferation of bladder epithelial cells from patients with interstitial cystitis. Urology 2003; 61:1278. 98. Erickson DR, Xie SX, Bhavanandan VP, et al. A comparison of multiple urine markers for interstitial cystitis. J Urol 2002; 167:2461. 99. Keay S, Zhang CO, Chai T, et al. Antiproliferative factor, heparin-binding epidermal growth factorlike growth factor, and epidermal growth factor in men with interstitial cystitis versus chronic pelvic pain syndrome. Urology 2004; 63:22.

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100. Chai TC, Zhang CO, Shoenfelt JL, Johnson HW, Jr., Warren JW, Keay S. Bladder stretch alters urinary heparin-binding epidermal growth factor and antiproliferative factor in patients with interstitial cystitis. J Urol 2000; 163:1440. 101. Chai TC, Zhang C, Warren JW, Keay S. Percutaneous sacral third nerve root neurostimulation improves symptoms and normalizes urinary HB-EGF levels and antiproliferative activity in patients with interstitial cystitis. Urology 2000; 55:643. 102. Keay S, Seillier-Moiseiwitsch F, Zhang CO, Chai TC, Zhang J. Changes in human bladder epithelial cell gene expression associated with interstitial cystitis or antiproliferative factor treatment. Physiol Genomics 2003; 14:107. 103. Keay S, Warren JW. A hypothesis for the etiology of interstitial cystitis based upon inhibition of bladder epithelial repair. Med Hypotheses 1998; 51:79. 104. Keay SK, Szekely Z, Conrads TP, et al. An antiproliferative factor from interstitial cystitis patients is a frizzled 8 protein-related sialoglycopeptide. Proc Natl Acad Sci USA 2004; 101:11803. 105. Rashid HH, Reeder JE, O’Connell MJ, Zhang CO, Messing EM, Keay SK. Interstitial cystitis antiproliferative factor (APF) as a cell-cycle modulator. BMC Urol 2004; 4:3.

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Bladder Pain Syndrome/Interstitial Cystitis Treatment Options Magnus Fall and Ralph Peeker

Department of Urology, Sahlgrenska University Hospital, Gçteborg, Sweden

INTRODUCTION Interstitial cystitis (IC) is a chronic disease of as yet unknown etiology. The lack of a universally accepted definition and the fact that this syndrome does not represent one well-defined entity has recently favored the use of bladder pain syndrome (BPS) as a general term, the denomination IC preferably to be reserved for cases with cystoscopically and/or histologically defined findings (1–4). (See also glossary in Chapter 1.) BPS/IC commonly affects females, presenting with symptoms of pain on bladder filling and urinary frequency. Since the etiologies and pathophysiologies of the various syndromes included under the umbrella term BPS are largely unknown, treatment has had to be founded on a trial and error principle. The symptom complex includes two separate entities, the classic Hunner-type of disease, displaying a genuine and characteristic inflammatory bladder wall reaction as seen in the cystoscope, as well as histologically, and a less well-defined subtype that has been denominated non-ulcer IC (Figs. 1–3) (5–8). Various hypotheses to explain BPS/IC and, in consequence, numerous treatment modalities have been presented, including measures as different as hydrodistension of the bladder, intravesical instillation therapy, varying oral medications, electrical stimulation techniques, transurethral resection of diseased bladder tissue, supratrigonal cystectomy with enterocystoplasty and urinary diversion.

NONMEDICAL AND NONSURGICAL TREATMENTS Fluid Intake and Diet Most patients with BPS will soon find out that reduction of fluid intake will reduce urine volumes with associated frequent urinations and pain related to bladder filling. The other side of this coin is, however, that by reduction of fluid intake the urine becomes more concentrated with the risk of increased bladder irritation. Therefore, some BPS subjects prefer not to decrease fluid consumption. It is common experience that spicy or acid drinks like coffee, citrus juice or wine can make symptoms worse. Dietary restrictions are reported among the many physical self-care strategies that BPS patients develop (9). In an analysis of the Interstitial Cystitis Data Base cohort study, special diets rank in the five most commonly used therapies (10). Bade investigated the nutritional habits of BPS patients and found that they consume significantly less calories, fat and coffee, but more fibers (11). Comprehensive instructions on how to identify individual trigger foods are given in the IC-Network Patient Handbook (12). Scientific data on a rationale for such diets are not available. According to Gillespie the concentration of certain metabolites and amino acids appears to be changed in patients with BPS (13). A study of the metabolism of the arylalkylamines (tryptophan, tyrosine, tyramine, and phenylalanine) in 250 patients revealed an inability to synthesize normal amounts of serotonin and a noradrenaline metabolite. In this study, dietary restriction of acid foods and arylalkylamines lessened the symptoms but did not alter specific abnormalities in dopamine metabolism.

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FIGURE 1 (See color insert .) Cystoscopic appearance of Hunner lesion before bladder distension. Note radiating vascular reaction and central scar with fibine deposit. Source: From Ref. 5.

FIGURE 2 (See color insert .) Cystoscopic appearance of Hunner lesion after bladder distension in general anesthesia. Note rupture of the mucosa at the scar site and waterfall-like bleeding. Source: From Ref. 6.

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FIGURE 3 (See color insert .) Bladder pain syndrome, cystoscopic changes of the so-called non-ulcer type; multiple mucosal cracles small and punctuate submucosal bleedings following bladder distension. Perfectly normal bladder mucosa before distension. Source: From Ref. 5.

In another non-randomized prospective study with nutrition-related exacerbations, calcium glycerophosphate was reported to ease food-related flares (14). The observed efficacy seems little better than would be expected with placebo. Overall, dietary management is a common self-care strategy in BPS but scientific data are limited and dietary restriction alone will not result in complete relief of symptoms. For a general review on diet and food supplements, see Chapter 47 of this book. Bladder Retraining For BPS patients with predominant symptoms of frequency/urgency but less pain, behavioral bladder training techniques are attractive. Parsons (15) included 21 selected BPS patients on a protocol which focused on progressively increasing micturition intervals. Fifteen patients reported a 50% decrease in urgency, frequency, and nocturia and there was a moderate increase in bladder capacity. Chaiken (16) retrospectively analyzed 42 patients who were instructed in diary keeping, timed voiding, controlled fluid intake, and pelvic floor muscle training. After twelve weeks, voiding intervals increased by a mean of 93 minutes and daily micturitions were on average reduced by nine voids. Overall, 88% of the patients reported that their symptoms had markedly improved. MEDICAL TREATMENT OF BPS/IC Analgesic Drugs Since pain is a dominating symptom, commonly used analgesics are tested by most patients at some stage of the disease. Unfortunately, the result is generally discouraging, since visceral pain of the kind experienced in BPS does not respond very well to analgesics. Long-term treatment with opioids for nonmalignant conditions is difficult. Because of the chronic nature

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of the condition such drugs should be used only exceptionally, with great care and under close surveillance. No systematic studies on analgesics have been presented. Immunoregulators Corticosteroids have been tried; reports on outcome have been both promising (17) and discouraging (18). The side effects of systemic steroids can be very serious so there is little justification for chronic use in BPS. Hydroxyzine is a histamine H1-receptor antagonist that can block neuronal activation of mast cells. These cells are considered to play a pivotal role in BPS. Among the substances released by mast cells is histamine. Hydroxizine is thought to inhibit serotonin secretion from thalamic mast cells and neurons, too (19). Usually, hydroxyzine hydrochloride is used, starting with 25 mg at bedtime, increasing the dose to 50 mg/day or even 75 mg, if tolerable. The most common side effects are sedation and generalized weakness, effects that usually resolve after some period of treatment. In the first trial using this drug, more than 90% of patients responded with an improvement of the whole range of symptoms and, interestingly, also noted an improvement of associated symptoms like migraine, irritable bowel syndrome, and allergies (20). In a further presentation these promising results were corroborated (21). Recently, however, in a large placebo controlled study no significant effect could be demonstrated (22). Cimetidine, a H2-blocker has been reported to improve symptoms in BPS (23). Thilagarajah enrolled 36 patients with painful bladder diseases into a double-blind clinical study with oral cimetidine versus placebo for three months. Those receiving cimetidine had a significant improvement in symptom scores, pain, and nocturia. However, histologically the bladder mucosa showed no qualitative changes in either group (24). Another principle is to use immune suppressive chemotherapeutic agents. Azathioprin was tried as a treatment of IC by Oravisto and Alftan (25). They gave 50 to 100 mg daily to 38 patients. Pain disappeared in 22 and urinary frequency in 20 of the subjects. Side effects were not reported. Controlled trials are not available, and published data are not sufficient to assess the value of this treatment in BPS/IC. More recently, cyclosporine (26) and methotrexate (27) have been on trial in open studies with good effect on pain but with limited effect on urinary frequency. Cyclosporine A was recently evaluated in a placebo study on 23 patients by Sairanen et al. (28). Efficacy and tolerability of this medication was good. Relapse occurred when the drug was withdrawn. Suplatast Tosilate (IPD-1151T) is an oral immunoregulator that suppresses helper T-cell mediated allergic processes. Ueda et al. (29) examined the efficacy in 14 women with BPS/IC. After one year of treatment, a significantly increased bladder capacity and decreased symptoms were reported. No major side effects occurred and therapeutic effects correlated with a reduction in blood eosinophils, IgE, and urinary T cells. Comparative controlled data are not available. Misoprostol is a prostaglandin that regulates various immunologic cascades. Kelly treated 25 BPS/IC patients with 600 mg of misoprostol daily for three months. Upon response, patients continued therapy for another six months. At three months, 14 were significantly improved, and after a further six months, 12 had a sustained response. However, the incidence of adverse drug effects was 64%, although minor and seldom resulting in withdrawal (30). Quercetin is a bioflavinoid suggested to be effective in pelvic pain syndromes, having an anti-inflammatory action also inhibiting activation of mast cells. It was tested in two limited, open label studies with promising results (31,32). Drugs Affecting Neural Transmission The tricyclic antidepressant amitriptyline has been reported to alleviate symptoms in BPS/IC. The drug acts via a number of mechanisms such as blockade of acetylcholine receptors, inhibition of reuptake of released serotonin and norepinephrine and blockade of the histamine H1 receptor (33). Several reports have indicated amelioration after oral treatment with amitriptyline (34,35). Generally, 25 mg are administered before bedtime, when needed with gradual increase to

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75 mg over a three-week period. In a recent randomized, placebo-controlled study the therapeutic benefit from this drug was corroborated (36). The antiepileptic drug gabapentin is a new agent also used in the adjunctive treatment of painful disorders. Gabapentin may reduce opioid medication. Two patients with BPS showed improved functional capacity and received adequate pain control with the addition of gabapentin to their medication regimen (37). In a subsequent uncontrolled dose escalation protocol on 21 chronic genitourinary pain patients (38), 10 improved with gabapentin at six months. The study included eight BPS patients, of whom five responded to gabapentin. Oral treatment with L-arginine, the substrate for nitric oxide synthase (39), has been reported to result in a decrease in BPS related symptoms (40–42). In other studies neither symptomatic relief nor change in nitric oxide production after treatment could be demonstrated (43,44). Nitric oxide has been shown to be elevated in patients with BPS (45) yet this appears to be true only for the classic Hunner subtype of disease (46). Glycosaminoglycane Replacement Sodium pentosanpolysulfate (PPS) is thought to substitute for a defect in the glycosaminoglycane (GAG) layer, a pathogenetic explanation to BPS that has been proposed by Parsons and co-workers (47). Sodium PPS has been tested in double blind, placebo-controlled studies. Subjective improvement of pain, urgency, frequency but not nocturia was reported in patients taking the drug as compared to placebo (48,49). In an open multicenter study, Fritjofsson et al. demonstrated that PPS had a more favourable effect in classic than in non-ulcer disease (50). The normal dose is 150 to 200 mg twice daily between meals. Absorption is incomplete. Data are contradictory, though. In a recent multicenter placebo controlled study, low global response rates for sodium PPS as well as hydroxyzine suggest that neither provided benefit for the majority of patients with BPS (22). Antibiotics Antibiotics have a limited role in the treatment of BPS. Warren conducted a prospective, randomized, double-blinded, and placebo-controlled pilot study of sequential oral antibiotics among 50 patients. Twelve out of 25 patients in the antibiotic and 6 of 25 in the placebo group reported overall improvement, while 10 and 5, respectively, noticed improvement in pain and urgency. The authors conclude that antibiotics alone or in combination may be associated with decreased symptoms in some patients but do not represent a major advance in therapy for BPS/IC (51). It is worth noting that a recent study using various techniques for microbe detection negated any evidence for infection as cause of BPS/IC (52).

INTRAVESICAL TREATMENT OF BPS/IC Intravesical application of medications establishes high concentrations at the target site with few systemic side effects. The need for intermittent catheterization, which is often painful in BPS patients, the costs, and the risk of infection are drawbacks. Various intravesical treatments have been proposed and investigated. Local Anesthetics Sporadic reports of successful treatment with intravesical lidocaine can be found in the literature (53,54). Lidocaine provides a local anesthetic effect but absorption is poor. Although the initial response to instillation may be excellent, a drawback with this method is that very frequent instillations are needed, sometimes three or four times a day. Since catheterizations may be painful in this group of patients this mode of treatment is often difficult to perform. According to Henry et al. (55) superior pharmacokinetics can be achieved by alkalization of lidocaine prior to intravesical application.

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Dimethyl Sulfoxide The chemical solvent dimethyl sulfoxide (DMSO) is a lipid and water-soluble liquid that penetrates cell membranes and is claimed to have analgesic, anti-inflammatory, collagenolytic, and muscle relaxant effects. It is also a scavenger of the intracellular OH radical believed to be an important trigger of the inflammatory process. It has been tested empirically and found to alleviate symptoms in BPS/IC and is now a standard treatment. In a crossover trial (56), 33 patients were randomly allocated to receive instillations with a 50% DMSO solution and placebo (saline). All patients received both regimens, which were administered intravesically every two weeks for two sessions of four treatments each. Subjective improvement was noted in 53% versus 18% and objective improvement in 93% versus 35%, following DMSO and placebo treatment, respectively. Other uncontrolled trials with DMSO report response rates of 50% to 70% for a period between one and two months (57). DMSO in contraindicated during urinary tract infections or shortly after bladder biopsy and it temporarily causes a garlic-like odor. It is also noteworthy that a case was reported (58) in which DMSO treatment may have caused pigmented eye lens deposits, so that ophthalmic review should be considered during DMSO treatment. The rate of side effects is tolerable, though, and maintenance treatment is an option in good responders (59). Urologists may also consider offering multiagent intravesical therapy in BPS patients who do not respond to single-agent therapy. Ghoneim et al. reported on a favorable response to a combination of DMSO, methylprednisolone, and heparin sulfate (60). Another combination is with heparin and bicarbonate for local application. GAG Replacement PPS is a glycoprotein aimed at replenishing the GAG layer in BPS/IC bladders. The bioavailability of PPS is poor after oral administration, hence the intravesical application. A double-blind placebo-controlled study (61) reported on 20 patients of whom 10 received intravesical PPS (300 mg in 50 mL of 0.9% saline) twice a week for three months and the other 10 got placebo. At three months, four and two patients gained significant symptomatic relief from PPS and placebo, respectively. However, the only parameter showing a statistically significant increase in patients treated with PPS was the urodynamic bladder capacity (pZ0.047). It was noted that at 18 months, symptoms were relieved in eight patients while still receiving PPS instillations and in four without treatment. Intravesical heparin has been proposed as a coating agent. In an open prospective uncontrolled trial (62), 48 patients received instillations of 10,000 units in 10 mL sterile water, three times per week for three months. In over half of the patients studied, intravesical heparin controlled the bladder symptoms with continued improvement even after one year of therapy. Kuo (63) reported another uncontrolled trial of intravesical heparin (25,000 units twice a week for three months) used in women with frequency-urgency syndrome with a positive potassium test. The study included 10 patients with BPS/IC of whom eight reported symptomatic improvement. Hyaluronic acid (HA) and Chondroitin sulfate are proteoglycans aimed at GAG layer defect repair, recently introduced as instillation therapy. Morales (64) treated 25 BPS patients and reported a 56% (week 4) and 71% (week 7) response rate. Beyond week 24, effectiveness decreased but there was no significant toxicity. Nordling (65) reported a three-year follow-up to a three months prospective, non-randomized study evaluating the effect of intravesical HA on bladder pain and urinary frequency. Eleven of the 20 patients chose to continue treatment beyond the initial trial and modest beneficial long-term effects were noted in about two-thirds of patients. Bacillus Calmette-Gue´rin Immunomodulatory properties of the tuberculosis vaccine bacillus Calmette-Gue´rin (BCG) are employed for intravesical treatment of superficial bladder carcinoma. In 1997, a prospective, double-blind pilot study on intravesical BCG demonstrated a 60% BCG versus 27% placebo response rate in 30 BPS/IC patients who received six weekly instillations of Tice strain BCG

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or placebo (66). In a subsequent 24- to 33-month follow-up report, eight of the nine responders reported favorable outcome and BCG did not worsen symptoms in nonresponders (67). These results are contradictory to a prospective, double-blind crossover trial of BCG and DMSO (68), in which BCG treatment failed to demonstrate any benefit. The negative results were corroborated in a large placebo study including 265 subjects. Although treatment was tolerable the response rate was quite low and did not warrant recommendation of this potentially harmful treatment in BPS/IC (69). Vanilloids Vanilloids disrupt C-fiber sensory neurons. Resiniferatoxin (RTX) is a substance derived from a cactus named Euphorbia resinifera and is an ultra potent analogue of the chili pepper extract capsaicin, causing less pain on instillation. In a randomized, placebo-controlled trial on 18 patients with hypersensitive bladder disorder and pain (70), RTX significantly reduced mean frequency, nocturia, and pain scores by approximately 50%. Despite a physiologically logic concept and the promising initial data, in a recently concluded, randomized, double blind, placebo-controlled trial RTX was not found to be effective in BPS/IC (71). Electromotive Drug Administration Electromotive drug administration (EMDA) enhances tissue penetration of ionized drugs by iontophoresis. When used to reinforce bladder instillation therapy, a transurethral anode and a suprapubic skin cathode are utilized. Gurpinar (72) treated six patients with EMDA using lidocaine (1.5%) and the ratio of 1:100,000 epinephrine in aqueous solution while dilating the bladder to maximum tolerance. Significant bladder enlargement was achieved and voiding symptoms and pain decreased. In four patients, the results were reported as “durable.” Rosamilia (73) treated 21 women with BPS/IC with EMDA of lidocaine and dexamethasone, followed by cystodistension. Eighty-five percent had a good response at two weeks, with 63% still responding at two months. Complete resolution of pain was present in 25% of patients reviewed at six months. Using a similar technique, Riedl (74) noted complete resolution of bladder symptoms in 8 of 13 patients lasting 1 to 17 months. Partial or short-term improvement was observed in three patients. Two patients experienced aggravation of pain for several days after therapy. A 66% increase in bladder capacity was observed. Upon symptom recurrence, treatment was repeated with equal efficacy in 11 patients. EMDA is expensive and the subject of uncontrolled studies only. NERVE STIMULATION Suprapubic Transcutaneous Electrical Nerve Stimulation Transcutaneous electrical nerve stimulation (TENS) is proposed to relieve pain in BPS by stimulation of myelinated afferents in order to activate segmental inhibitory circuits according to the theory of Melzack and Wall (75) of blockade of afferent impulses by a gate control mechanism. By stimulating more easily excitable afferents from the painful area, the artificial stimulus competes with and blocks the pain impulses. The stimulus may simultaneously elicit autonomic nerve effects like inhibition of detrusor activity (76). Another mechanism is the release of opiates, especially endorphins. TENS is administered by means of carbon rubber electrodes positioned 10 cm apart immediately above the pubic bone. The electrodes are applied with a broad tape to enable the patient to be ambulant during treatment for one to two hours twice daily. Treatment is initiated using intensity as high as possible starting with high frequency stimulation (50–100 Hz). If the effect is inadequate or lacking, low frequency stimulation is tested as well (2–10 Hz). The trial should go on for at least two months before evaluation. The outcome of therapy differs markedly between the two main categories of the disease. In a long-term follow-up study, 33 patients with classic Hunner-type lesions and 27 with the so called non-ulcer disease were treated by means of suprapubic, high or low frequency TENS for one to two hours twice daily at maximum, non-painful intensity. The response to treatment was clearly better in the classic subtype. Interestingly and remarkably,

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in some cases of classic IC, chronic Hunner lesions disappeared during treatment and there was also a total remission of symptoms (77). Sacral Nerve Electrical Stimulation Sacral nerve electrical stimulation often termed as neuromodulation, implies application of electrodes within the sacral foramina three or four. The method includes two steps. First, an electrode is inserted into a relevant sacral foramen and correct positioning is checked by observing anal contractions and bladder/urethral sensations during electrode positioning. If a good subjective effect is achieved during some days to weeks of stimulation by means of an external pulse generator, the patient is a candidate for a permanent implant. Then, the sacral nerve electrode is connected to a subcutaneously implanted pulse generator (IPG) for longterm use. This modality was evaluated in an open study by Maher. Of their patients 73% had benefit of a test procedure which was followed by implantation of an IPG (78). Long-term treatment has been demonstrated to reduce symptoms and also narcotic requirement in refractory BPS patients (79). Acupuncture Chang performed urodynamics before and after acupuncture in 52 women with frequency, urgency, and dysuria and reported a significant increase in capacity. Depending on the acupuncture site, symptomatic improvement was noted in up to 85% (80). In a follow-up investigation after one and three years these effects where no longer detectable and the authors concluded that repeated acupuncture was necessary to maintain beneficial effects (81). In contrast, in a prospective study on the effect of acupuncture in BPS (82) no differences in frequency, voided volumes, or symptom scores were noted and only one patient improved for a short period of time. In summary, the few low-evidence reports on acupuncture in the treatment of BPS/IC are contradictory and the effects appear to be very limited or temporary. A comprehensive review of the theories behind acupuncture is found in Chapter 47.

INVASIVE TREATMENTS OF BPS/IC Bladder Distension As BPS relates to abnormal sensory function, various surgical and nonsurgical approaches have been tried in order to interrupt neural transmission. The long-term results for most measures are, however, disappointing. Hydrodistension is one method suggested to alleviate symptoms in BPS (83). It is postulated that the mechanism of action is destruction of the submucosal nerve plexus and tension receptors in the bladder wall (84). A frequently cited report by Bumpus (85) claims imprecisely that hydrodistension achieved symptom improvement in 100% of the patients over several months. Neither the patient population nor symptoms were defined. The method description is scarce. In 1957, an uncontrolled retrospective study was presented by Franksson (86) who treated 33 patients with repeated, up to 10 distensions. Twelve patients improved symptoms for up to four weeks, 14 for up to six months and seven for up to one year. Dunn (83) claimed to have achieved complete absence of symptoms in 16 of 25 patients during a mean follow-up of 14 months using the Helmstein method (87), where an intravesical balloon is distended at the level of systolic blood pressure for three hours. Bladder ruptures occurred in two cases. These reports are contradicting Badenoch (17) who failed to notice any improvement in 44 of 56 patients after hydrodistension. Twenty years later, McCahy (88) rejected balloon hydrodistension because of inefficacy and a complication rate of 20%. Although hydrodistension of the bladder is a common treatment in BPS scientific justification is lacking. It represents a diagnostic tool but has only a temporary therapeutic value.

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Nerve Blockades and Epidural Pain Pumps These are specialist procedures that may be performed for diagnostic reasons and also therapeutic benefit. Nerve blocks should be performed as part of a pain specialist management and not in isolation. Neurolytic blocks are rarely indicated for benign conditions; to embark upon such strategies in a chronic, non-malignant condition may induce catastrophic consequences. Transurethral Resection and Laser Endourological ablation of involved bladder tissue aims to eliminate focal bladder wall lesions of the Hunner type. These lesions contain mast cells, lymphocytes and plasma cells (5,89,90), cells being repositories of a number of inflammatory mediators which are removed together with the local intramural sensory nerves. Greenberg et al. reported on 77 patients with Hunner lesions treated over a 40-year period, 42 of which were managed conservatively, seven underwent fulguration and 28 received transurethral resection (TUR) in a non-randomized fashion. All had symptom of recurrence in less then one year and efficacy was not superior to nonsurgical treatment (91). In our first series of 30 classic (Hunner) IC patients (92) complete TUR of visible lesions including the peripheral edema zone resulted in initial disappearance of pain in all and a decrease in urinary frequency in 21 patients. A relapse was noted in onethird of patients after 2 to 20 months while the remaining two-thirds were still pain-free after 2 to 42 months. We recently reported the hitherto largest series of patients with classic IC treated by complete TUR of all visible ulcers (6). Altogether 259 TURs were performed on 103 patients: 92 experienced amelioration, and in 40% symptom relief lasted more than three years. The majority of remaining patients responded well to repeat TUR. Transurethral application of the neodymium (Nd)-YAG (neodymium-doped yttrium aluminum garnet) laser is suggested as an alternative to TUR for endoscopic treatment. Initially, Shanberg (93) treated five therapy refractory BPS/IC patients, four of whom demonstrated cessation of pain and frequency within several days. At 3 to 15 months of follow-up there was no relapse except mild recurrent voiding symptoms. This series was extended to 76 patients treated at two institutions (94). Twenty one out of 27 patients with Hunner lesions noted symptom improvement; however 12 experienced relapse within 18 months. In the group without circumscript Hunner lesions only 20 of 49 patients improved, of which 10 required further therapy within one year. Recently, Rofeim (95) investigated 24 patients with therapy refractory disease undergoing ablative Nd-YAG laser ablation of Hunner lesions. All patients had symptom improvement within days without complications. At 23 months, mean pain and urgency scores, nocturia, and voiding intervals improved significantly. Relapse in 11 patients required up to four additional treatments. Endourological resections/coagulations are not applicable to non-ulcer IC. These techniques may provide long-term alleviation of symptoms but none of them will cure the TABLE 1 Level of Evidence and Grade of Recommendation Level 1a 1b 2a 2b 3 4 Grade A B C Source: From Ref. 2.

Type of evidence Meta-analysis of randomized trials At least one randomized trial One well-designed controlled study without randomization One other type of well-designed quasi-experimental study Nonexperimental study (comparative study, correlation study, case reports) Expert committee, expert opinion Basis for recommendation Clinical studies of good quality and consistency including at least one randomized trial Well-conducted clinical studies without randomized trials Absence of directly applicable clinical studies of good quality

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TABLE 2 Medical Treatment of BPS/IC Level of evidence

Grade of recommendation

Analgesics

4

C

Corticosteroids

3

C

2b 1b 3 1b 3 3 3 1b 3 3 1a 1b

B A C A C C C A C C A A

Hydroxyzine Cimetidine Azathioprin Cyclosporine Suplatast Tosilate Misoprostol Quercetin Amitriptyline Gabapentin L-arginine Sodium pentosanpolysulfate Antibiotics

Comment Indications limited to cases awaiting further treatment Corticosteroids not recommended as long-term treatment Standard treatment Preliminary data so far Insufficient data on IC, adverse effects Side effects to be considered Preliminary data so far Insufficient data on IC, high rate of adverse effects Preliminary data so far Standard treatment Preliminary data so far Data contradictory Standard treatment Limited role in the treatment of IC

Abbreviation: IC, interstitial cystitis. Source: From Ref. 2.

TABLE 3 Intravesical Treatment of BPS/IC

Intravesical anesthetics Intravesical dimethyl sulfoxide Intravesical pentosanpolysulfate Intravesical heparin Intravesical hyauronic acid Intravesical bacillus Calmette-GuØrin Intravesical resineferatoxin Electromotive drug administration

Type of evidence

Nature of recommendation

3 1b 1b 3 3 1b 1b 3

C A A C C A A B

Comment

Limited role in the treatment of IC Limited role in the treatment of IC

Abbreviation: IC, interstitial cystitis. Source: From Ref. 2.

TABLE 4 Invasive, Alternative, and Surgical Treatment of BPS/IC

Bladder distension Nerve blockades/epidural pain pumps Transcutaneous electrical nerve stimulation Sacral neuromodulation Bladder training Diet Acupuncture Transurethral resection and laser Surgical treatment Abbreviation: NA, not applicable. Source: From Ref. 2.

Type of evidence

Nature of recommendation

3 3 2b

C C B

3 3 3 3 NA NA

B B C C A/B A

Comment For crisis intervention, effect on pain only Not recommended beyond clinical trials Patients with little pain Data contradictory Hunner’s lesions only Ultima ratio, experienced surgeons

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disease. Controlled studies are still lacking. When all efforts fail to relieve disabling symptoms, especially in end-stage classic Hunner disease, subtotal cystectomy represents a good option. Methods and considerations are presented in Chapter 46 of this monograph. CONCLUSIONS Many strategies used in BPS/IC have low levels of evidence and grade of recommendation. The most commonly used treatments are summarized in Tables 1–4, including assessment of levels of evidence (2). In addition, many studies suffer from confusion as to classification and lack of detailed description of patients included. Although therapies essentially have been established on a trial and error basis it is hoped that, by continuous research, the etiology and pathogenesis of conditions included in the BPS/IC group of diseases will eventually be revealed. Then, the ultimate goal can be reached, i.e., to find rational treatment strategies. ACKNOWLEDGMENTS Supported by Sahlgrenska University Hospital project number ALF Gbg-2887 and the Swedish Research Council project number K 2004-73X-15058-01A. REFERENCES 1. Abrams P, Cardozo L, Fall M, et al. The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-Committee of the International Continence Society. Neurourol Urodyn 2002; 21(2):167–78. 2. Fall M, Baranowski AP, Fowler CJ, et al. EAU guidelines on chronic pelvic pain. Eur Urol 2004; 46(6):681–9. 3. Hanno PM, Baranowski AP, Fall M, et al. Painful bladder syndrome (including interstitial cystitis). In: Abrams P, Cardozo L, Khoury S, Wein A, eds. Incontinence. 2005 ed. Paris: Health Publication Ltd., 2005:1455–520. 4. Nordling J, Anjum FH, Bade JJ, et al. Primary evaluation of patients suspected of having interstitial cystitis (IC). Eur Urol 2004; 45(5):662–9. 5. Johansson SL, Fall M. Clinical features and spectrum of light microscopic changes in interstitial cystitis. J Urol 1990; 143(6):1118–24. 6. Peeker R, Aldenborg F, Fall M. Complete transurethral resection of ulcers in classic interstitial cystitis. Int Urogynecol J 2000; 11:290–5. 7. Fall M, Johansson SL, Aldenborg F. Chronic interstitial cystitis: a heterogeneous syndrome. J Urol 1987; 137(1):35–8. 8. Peeker R, Fall M. Toward a precise definition of interstitial cystitis: further evidence of differences in classic and nonulcer disease. J Urol 2002; 167(6):2470–2. 9. Webster DC, Brennan T. Use and effectiveness of physical self-care strategies for interstitial cystitis. Nurse Pract 1994; 19(10):55–61. 10. Rovner E, Propert KJ, Brensinger C, et al. Treatments used in women with interstitial cystitis: the interstitial cystitis data base (ICDB) study experience. The Interstitial Cystitis Data Base Study Group. Urology 2000; 56(6):940–5. 11. Bade JJ, Peeters JMC, Mensink HJA. Is the diet of patients with interstitial cystitis related to their disease? Eur Urol 1997; 32(2):179–83. 12. Osborne JH, Manhattan D, Laumn B. IC and diet. In: Osborne JH, ed. The Interstitial Cystitis Network Patient Handbook. Santa Rosa, CA: The Interstitial Cystitis Network, 1999:43–62. 13. Gillespie L. Metabolic appraisal of the effects of dietary modification on hypersensitive bladder symptoms. Br J Urol 1993; 72(3):293–7. 14. Bologna RA, Gomelsky A, Lukban JC, Tu LM, Holzberg AS, Whitmore KE. The efficacy of calcium glycerophosphate in the prevention of food-related flares in interstitial cystitis. Urology 2001; 57(6 Suppl. 1):119–20. 15. Parsons CL, Koprowski PF. Interstitial cystitis: successful management by increasing urinary voiding intervals. Urology 1991; 37(3):207–12. 16. Chaiken DC, Blaivas JG, Blaivas ST. Behavioral therapy for the treatment of refractory interstitial cystitis. J Urol 1993; 149(6):1445–8. 17. Badenoch AW. Chronic interstitial cystitis. Br J Urol 1971; 43:718–21. 18. Pool TL. Interstitial cystitis: clinical considerations and treatment. Clin Obstet Gynecol 1967; 10:185–91. 19. Lambracht-Hall M, Konstantinidou AD, Theoharides TC. Serotonin release from rat brain mast cells in vitro. Neuroscience 1990; 39(1):199–207.

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Oral gabapentin (neurontin) treatment of refractory genitourinary tract pain. Tech Urol 2001; 7(1):47–9. 39. Moncada S, Higgs A. The L-arginine–nitric oxide pathway. N Engl J Med 1993; 329:2002–12. 40. Korting GE, Smith SD, Wheeler MA, Weiss RM, Foster H, Jr. A randomized double-blind trial of oral L-arginine for treatment of interstitial cystitis. J Urol 1999; 161(2):558–65. 41. Smith SD, Wheeler MA, Foster HE, Jr., Weiss RM. Improvement in interstitial cystitis symptom scores during treatment with oral L-arginine. J Urol 1997; 158(3 Pt 1):703–8. 42. Wheeler MA, Smith SD, Saito N, Foster HE, Jr., Weiss RM. Effect of long-term oral L-arginine on the nitric oxide synthase pathway in the urine from patients with interstitial cystitis. J Urol 1997; 158(6):2045–50. 43. Cartledge JJ, Davies AM, Eardley I. A randomized double-blind placebo-controlled crossover trial of the efficacy of L-arginine in the treatment of interstitial cystitis. BJU Int 2000; 85(4):421–6. 44. Eigner EB, Freiha FS. The fate of the remaining bladder following supravesical diversion. J Urol 1990; 144(1):31–3. 45. Lundberg JO, Ehren I, Jansson O, et al. Elevated nitric oxide in the urinary bladder in infectious and noninfectious cystitis. Urology 1996; 48(5):700–2. 46. Logadottir YR, Ehren I, Fall M, Wiklund NP, Peeker R. Intravesical nitric oxide production discriminates between classic and nonulcer interstitial cystitis. J Urol 2004; 171(3):1148–50 (discussion 50–1). 47. Parsons CL, Lilly JD, Stein P. Epithelial dysfunction in nonbacterial cystitis (interstitial cystitis). J Urol 1991; 145(4):732–5. 48. Mulholland SG, Hanno P, Parsons CL, Sant GR, Staskin DR. Pentosan polysulfate sodium for therapy of interstitial cystitis. A double-blind placebo-controlled clinical study. Urology 1990; 35(6):552–8. 49. Hwang P, Auclair B, Beechinor D, Diment M, Einarson TR. Efficacy of pentosan polysulfate in the treatment of interstitial cystitis: a meta-analysis. Urology 1997; 50(1):39–43. 50. 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51. Warren JW, Horne LM, Hebel JR, Marvel RP, Keay SK, Chai TC. Pilot study of sequential oral antibiotics for the treatment of interstitial cystitis. J Urol 2000; 163(6):1685–8. 52. Al-Hadithi HN, Williams H, Hart CA, et al. Absence of bacterial and viral DNA in bladder biopsies from patients with interstitial cystitis/chronic pelvic pain syndrome. J Urol 2005; 174(1):151–4. 53. Asklin B, Cassuto J. Intravesical lidocaine in severe interstitial cystitis. Case report. Scand J Urol Nephrol 1989; 23(4):311–2. 54. Giannakopoulos X, Champilomatos P. Chronic interstitial cystitis. Successful treatment with intravesical idocaine. Arch Ital Urol Nefrol Androl 1992; 64(4):337–9. 55. Henry R, Patterson L, Avery N, et al. Absorption of alkalized intravesical lidocaine in normal and inflamed bladders: a simple method for improving bladder anesthesia. J Urol 2001; 165(6 Pt 1):1900–3. 56. Perez-Marrero R, Emerson LE, Feltis JT. A controlled study of dimethyl sulfoxide in interstitial cystitis. 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Br J Urol 1994; 73(5):504–7. 63. Kuo HC. Urodynamic results of intravesical heparin therapy for women with frequency urgency syndrome and interstitial cystitis. J Formos Med Assoc 2001; 100(5):309–14. 64. Morales A, Emerson L, Nickel JC, Lundie M. Intravesical hyaluronic acid in the treatment of refractory interstitial cystitis. J Urol 1996; 156(1):45–8. 65. Nordling J, Jorgensen S, Kallestrup E. Cystistat for the treatment of interstitial cystitis: a 3-year followup study. Urology 2001; 57(6 Suppl. 1):123. 66. Peters K, Diokno A, Steinert B, et al. The efficacy of intravesical tice strain bacillus Calmette-Guerin in the treatment of interstitial cystitis: a double blind, prospective, placebo controlled trial. J Urol 1997; 157(6):2090–4. 67. Peters KM, Diokno AC, Steinert BW, Gonzales JA. The efficacy of intravesical bacillus CalmetteGuerin in the treatment of interstitial cystitis: long-term followup. J Urol 1998; 159(5):1483–7. 68. Peeker R, Haghsheno M, Holma¨ng S, Fall M. Intravesical bacillus Calmette-Guerin and dimethyl sulfoxide for treatment of classic and nonulcer interstitial cystitis: a prospective, randomized doubleblind study. J Urol 2000; 169:1912–6. 69. Mayer R, Propert KJ, Peters KM, et al. A randomized controlled trial of intravesical bacillus CalmetteGuerin for treatment refractory interstitial cystitis. J Urol 2005; 173(4):1186–91. 70. Lazzeri M, Beneforti P, Spinelli M, Zanollo A, Barbagli G, Turini D. Intravesical resiniferatoxin for the treatment of hypersensitive disorder: a randomized placebo controlled study. J Urol 2000; 164(3 Pt 1):676–9. 71. Payne CK, Mosbaugh PG, Forrest JB, et al. Intravesical resiniferatoxin for the treatment of interstitial cystitis: a randomized, double-blind, placebo controlled trial. J Urol 2005; 173(5):1590–4. 72. Gurpinar T, Wong HY, Griffith DP. Electromotive administration of intravesical lidocaine in patients with interstitial cystitis. J Endourol 1996; 10(5):443–7. 73. Rosamilia A, Dwyer PL, Gibson J. Electromotive drug administration of lidocaine and dexamethasone followed by cystodistension in women with interstitial cystitis. Int Urogynecol J Pelvic Floor Dysfunct 1997; 8(3):142–5. 74. Riedl CR, Knoll M, Plas E, Pfluger H. Electromotive drug administration and hydrodistention for the treatment of interstitial cystitis. J Endourol 1998; 12(3):269–72. 75. Melzack R, Wall PD. Pain mechanisms: a new theory. Science 1965; 150:971–9. 76. Fall M, Carlsson CA, Erlandson BE. Electrical stimulation in interstitial cystitis. J Urol 1980; 123:192–5. 77. Fall M, Lindstrom S. Transcutaneous electrical nerve stimulation in classic and nonulcer interstitial cystitis. Urol Clin North Am 1994; 21(1):131–9. 78. Maher CF, Carey MP, Dwyer PL, Schluter PL. Percutaneous sacral nerve root neuromodulation for intractable interstitial cystitis. J Urol 2001; 165(3):884–6. 79. Peters KM, Konstandt D. Sacral neuromodulation decreases narcotic requirements in refractory interstitial cystitis. BJU Int 2004; 93(6):777–9. 80. Chang PL. Urodynamic studies in acupuncture for women with frequency, urgency and dysuria. J Urol 1988; 140(3):563–6. 81. Chang PL, Wu CJ, Huang MH. Long-term outcome of acupuncture in women with frequency, urgency and dysuria. Am J Chin Med 1993; 21(3–4):231–6.

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82. Geirsson G, Wang YH, Lindstrom S, Fall M. Traditional acupuncture and electrical stimulation of the posterior tibial nerve. A trial in chronic interstitial cystitis. Scand J Urol Nephrol 1993; 27(1):67–70. 83. Dunn M, Ramsden PD, Roberts JBM, Smith JC, Smith PJB. Interstitial cystitis, treated by prolonged bladder distension. Br J Urol 1977; 49:641–5. 84. Hanno PM, Wein AJ. Conservative therapy of interstitial cystitis. Semin Urol 1991; 9(2):143–7. 85. Bumpus HC. Interstitial cystitis: its treatment by over-distension of the bladder. Med Clin North Am 1930; 13:1495–8. 86. Frankson C. Interstitial cystitis: a clinical study of 59 cases. Acta Chir Scand 1957; 113:51–62. 87. Helmstein K. Treatment of bladder carcinoma by a hydrostatic pressure technique. Report on 43 cases. Br J Urol 1972; 44(4):434–50. 88. McCahy PJ, Styles RA. Prolonged bladder distension: experience in the treatment of detrusor overactivity and interstitial cystitis. Eur Urol 1995; 28(4):325–7. 89. Aldenborg F, Fall M, Enerba¨ck L. Proliferation and transepithelial migration of mucosal mast cells in interstitial cystitis. Immunology 1986; 58:411–6. 90. Fall M, Johansson SL, Vahlne A. A clinicopathological and virological study of interstitial cystitis. J Urol 1985; 133(5):771–3. 91. Greenberg E, Barnes R, Stewart S, Furnish T. Transurethral resection of Hunner’s ulcers. J Urol 1974; 111:764–6. 92. Fall M. Conservative management of chronic interstitial cystitis: transcutaneous electrical nerve stimulation and transurethral resection. J Urol 1985; 133:774–8. 93. Shanberg AM, Malloy T. Treatment of interstitial cystitis with neodymium: YAG laser. Urology 1987; 29(Suppl. 4):31–3. 94. Malloy TR, Shanberg AM. Laser therapy for interstitial cystitis. Urol Clin North Am 1994; 21(1):141–4. 95. Rofeim O, Hom D, Freid RM, Moldwin RM. Use of the neodymium: YAG laser for interstitial cystitis: a prospective study. J Urol 2001; 166(1):134–6.

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Prostate Pain Syndrome Etiology, Epidemiology, and Research Michel A. Pontari and Brett Lebed

Department of Urology, Temple University School of Medicine, Philadelphia, Pennsylvania, U.S.A.

INTRODUCTION The most recent National Institutes of Health (NIH) classification of prostatitis adopted in 1995 (Table 1) includes acute or chronic bacterial infections, chronic pelvic pain syndrome, and even asymptomatic inflammation of the prostate (1). Category III is known as chronic prostatitis/ chronic pelvic pain syndrome (CP/CPPS). The current NIH definition of CP/CPPS includes genitourinary pain with or without voiding symptoms in the absence of uropathogenic bacteria detected by standard microbiological methods or other identifiable causes such as a malignancy (1). The accepted research definition is that of chronic pelvic pain for at least three of the preceding six months in the absence of other identifiable causes (2). The symptom that distinguishes CP/CPPS from other voiding dysfunction is the presence of pain (3). Category III is divided into IIIA and IIIB. IIIA refers to the presence of any number of white blood cells (WBCs) in either semen, post-prostate massage urine specimen (VB3), or expressed prostatic secretions (EPS). This corresponds to the previously used classification of nonbacterial prostatitis (4). Category IIIB is comparable to the formerly used term prostatodynia, and refers to patients with pelvic pain but no evidence of inflammation in either semen, VB3, or EPS. EPIDEMIOLOGY Prevalence It has become evident that prostatitis is widely prevalent in male populations throughout the world. In the United States alone, an estimated two million physician visits per year are attributed to prostatitis, a total of 1% and 8% of all family practitioner and urologist visits, respectively (5). Urologists and family practice–based physicians see an average of 25 patients with a diagnosis of prostatitis per month (6). Categories I and II, acute prostatitis, and chronic bacterial prostatitis account for no more than 5% to 10% of all cases of prostatitis (7). By far the most common type presenting with symptoms is category III or CP/CPPS (1). The prevalence among individual populations in the United States, Canada, Europe, and Asia has differed among published studies (Table 2). This is likely a result of variable questionnaires, differences in patient selection, methods of reporting and diagnosis, and differences in definitions of prostatitis or prostatitis-like symptoms. In North America, prevalence estimates range from 2.2% to 16%. A retrospective study on a cohort of 2115 patients in Minnesota showed a 9% overall prevalence of acute or chronic prostatitis based on physician diagnosis. A 2.2% incidence of prostatitis-like symptoms was found using questions similar to the National Institute of Health Chronic Prostatitis Symptom Index (NIH-CPSI) in select patients from the same cohort of men (9,10). An incidence of 5% of prostatitis was found in younger men in the Wisconsin National Guard (8). A study of selfreported history of prostatitis among 31,681 health professionals revealed a prevalence of 16% (15). Lastly, Nickel et al. used the NIH-CPSI to evaluate the prevalence of chronic prostatitis– like symptoms in 868 Canadian men, with a total prevalence of 9.7% (11). European studies from Finland and Italy and an Asian study from Korea had prevalence ranges from 6% to 14%. A study of Italian urology practices found 1148 patients with suspected or diagnosed

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TABLE 1 National Institutes of Health Classification of Prostatitis Category I II III IIIA IIIB IV

Acute bacterial prostatitis Chronic bacterial prostatitis Chronic prostatitis/chronic pelvic pain syndrome Inflammatory Noninflammatory Asymptomatic inflammatory prostatitis

Source: From Ref. 1.

prostatitis, and a prevalence of 12.8% within that patient population (12). Using the NIH-CPSI, Ku et al. reported a 6% prevalence of chronic prostatitis-like symptoms among 16,321 men within their Korean community (13). A population-based cross-sectional study in Northern Finland of 1832 men reported a 14% lifetime prevalence of prostatitis (14). Demographics Traditionally, prostatitis has been suggested to be a disease of younger men; however, more recent data indicate that prostatitis affects men across a wide range of ages. Prostatitis is the most common urological diagnosis in men younger than 50 years old, and the third most common diagnosis in men over age 50 years, after benign prostatic hyperplasia (BPH) and prostate cancer (5). The mean age of patients with prostatitis has been reported to be from 42.8 to 47.1 years (12,16). Whether prostatitis increases or decreases with age is unclear. In the study of physician visits in the United States, there was a significant increase in the incidence of chronic prostatitis from the second to third decade of life, with the highest prevalence in men aged 35 to 50 years. Compared with the age group older than 66 years, there was a 2.5- and 2-fold greater risk of chronic prostatitis in men aged 36 to 50 and 50 to 65 years, respectively (5). However, a population-based study of Finnish men by Mehik et al. demonstrated an increased risk of prostatitis with age. In comparison to men aged 20 to 39 years, there was a 1.7 and 3.1 greater incidence of prostatitis in men aged 40 to 49 years and 50 to 59 years, respectively (14). Overall there does not appear to be any correlation between age and severity of genitourinary pain (9,11). The effect of socioeconomic status and education on the epidemiology of prostatitis has been examined. Lower income was associated with higher NIH-CPSI score in the NIH chronic prostatitis cohort study, and the NIH-CPSI was also inversely related to level of education (16). These findings were similar in a study of Korean men, with middle school and high school graduates having 1.8- and 1.4-fold higher odds of prostatitis-like symptoms than men graduating college (13). There was no evidence of a correlation between level of education or profession and prostatitis incidence in a cohort of Finnish men using an alternative questionnaire (14). There does not appear to be evidence for racial or ethnic predisposition to the development of prostatitis or chronic pelvic pain. One limitation however to the available TABLE 2 Prevalence of Chronic Prostatitis Study

Country

Method of assessment

Prevalence of CP/CPPS (%)

Collins et al. (3) Moon et al. (8) Roberts et al. (9) Roberts et al. (10) Nickel et al. (11) Rizzo et al. (12) Ku et al. (13) Mehik et al. (14)

U.S.A. U.S.A. U.S.A. U.S.A. Canada Italy Korea Finland

Self-report of history Symptom score Symptom score Symptom score Symptom score Physician diagnosis Symptom score Symptom score

16 5 9 2.2 9.7 12.8 6 14.2

Abbreviation: CP/CPPS, chronic prostatitis/chronic pelvic pain syndrome.

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data is that many studies have evaluated relatively racially uniform populations, and has little available data directly comparing racial and ethnic influences on prostatitis (11–15). In studies looking at mixed populations, the likelihood for a diagnosis of prostatitis at a given visit in a study of U.S. physician visits did not vary by race (5), and there was no significant difference in NIH-CPSI score for white and nonwhite participants in the NIH chronic prostatitis cohort study (16). Environment The southern United States has a 1.7-fold greater frequency for prostatitis diagnosis than the northeastern areas of the country. This is presumed to be secondary to higher temperatures in the southern states (5). Contrary to these findings, a Finnish questionnaire–based population study in 1832 men found 63% of men with their worst symptoms in the winter months, while only 3% reported worse prostatitis symptoms in the summer months (14). A study of Korean men showed no statistically significant increase in prostatitis for lower temperatures in a multivariate analysis of the data, but the average duration of sunlight was statistically significant in both univariate and multivariate analyses (13). Family History and Comorbid Conditions Rizzo et al. recorded a family history of prostatitis in 20.4% of patients with a physician diagnosis of prostatitis. Similarly, Mehik et al. found that 48% of men had a family history of prostatitis. When compared with men with no evidence of prostatitis, family history was a statistically significant risk factor for the development of the disease (14). Data from the NIH chronic prostatitis cohort study also had 10% and 3% of chronic prostatitis patients reporting family history of prostatitis and interstitial cystitis, respectively (16). There are several other medical conditions that are associated with CP/CPPS. Common comorbid conditions in patients diagnosed with prostatitis include other genitourinary diseases, particularly BPH. Concurrent genitourinary diseases were reported in 55% of patients in the NIH prostatitis cohort (16). A diagnosis of BPH determined by digital rectal examination was found in 65% of Italian men with prostatitis (12), and as defined by prior transurethral resection (TUR) of the prostate or physician diagnosis of enlargement on examination in 57% of the health professionals followed in the United States. In this latter group, patients with a diagnosis of BPH had 7.7-fold greater odds of developing prostatitis (12). Prostatic surgery was performed in approximately one-third of patients prior to development of prostatitis symptoms in the NIH chronic prostatitis cohort study (16). Psychiatric disorders and psychological stressors are also prevalent in the chronic prostatitis population. Over 60% of men in one study had an associated psychosocial or depressive disorder, while others reported much lower rates of concurrent depression and psychiatric illness, at 6.8% and 28% (12–14,16,17). Stress at home and work lead to 1.5- and 1.2-fold greater odds of having a history of prostatitis, although it was unclear whether this reflected the cause or outcome of prostatitis (15). Diabetes mellitus and allergies were also common coexisting diagnoses with prostatitis (12,16). The NIH chronic prostatitis cohort study compared self-reported medical history in 463 men with CP/CPPS and 121 age-matched controls. After multivariable analysis to control for differences between cases and controls, a history of cardiovascular disease was nearly six times more likely in CP/CPPS cases than controls; a history of neurological disease was nearly five times more likely; a history of psychiatric disease was more than 2.5 times more likely; and a history of hematopoetic, lymphatic, and infectious diseases, particularly sinusitis, was almost twice as common in CP/CPPS participants than among controls (18). Recurrent Symptoms and Quality of Life CP/CPPS is a disabling disease with an impact on quality of life, often related to the chronic nature of the symptoms. Once a man has an initial episode of prostatitis, he is more likely to develop chronic episodes of symptoms than a man without a diagnosis (10). In one study of 1832 men with chronic prostatitis symptoms, 27% of patients had symptoms at least once per year, while 16% had persistent symptoms (14). The distress caused by the symptoms of voiding

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dysfunction, pelvic, and perineal pain, and sexual disorders is significant. An Italian study reported 57.7% of all patients diagnosed with prostatitis were dissatisfied or very dissatisfied with their quality of life (12). Assessing quality of life with the 12-item short form instrument (19), the mental component summary score for CPPS patients is lower than that observed in the most severe subgroups of congestive heart failure and diabetes (20). ETIOLOGY AND RESEARCH The etiology of CP/CPPS is unknown. Many different theories and mechanisms for the pathogenesis of prostatitis have been proposed in the current literature. One question to start is whether the prostate is actually a source of symptoms in men with CP/CPPS. True et al. found prostatic inflammation in only 33% of patients with CP/CPPS who underwent transperineal prostate biopsy (21). These findings raise the question of whether the prostate is even actually involved in the symptoms of CP/CPPS. The name chronic pelvic pain syndrome recognizes that the prostate may not be the sole source of discomfort, and that there may be other factors or anatomic sites involved. The epidemiological data looking at other associated medical conditions (18) suggest a possible role for immunological, neurological, and psychological factors in the development of the disease process. A model has been proposed in which there is an initial inciting event, such as infection, or trauma that then sets up an injury with inflammation which then persists. It may be modified by other factors, and likely sets up neurogenic inflammation and end in a final common pathway of pain (22). Infection The symptoms of pelvic pain and voiding dysfunction are similar to those that occur with a true bacterial infection. Therefore, it is not surprising that one of the most common theories of etiology is that of an occult infection. This idea has been bolstered by the discovery of fastidious microbes as the cause of other previously poorly characterized conditions such as Helicobacter pylori for stomach ulcers and Tropheryma whippelii for Whipple’s disease (23). Studies to date have failed to identify an ongoing infection in these men from any sexually transmitted organisms including Chlamydia trachomatis, Ureaplasma urealyticum, Mycoplasma hominis, or Trichomonas vaginalis (24,25). Newer studies have also increasingly used molecular techniques to try to answer the question of infection in these patients. Shoskes et al. (26) found that performing polymerase chain reaction (PCR) on EPS detected the presence of bacterial DNA in category IIIA patients in 23 (70%) of 33 specimens, whereas culture was positive (for grampositive bacteria) in only 17 (51%) of 33. Only two of 14 category IIIB patients had bacterial DNA. Nevertheless, 13 (57%) of the total patients with bacterial DNA improved with antibiotics while patients who lacked bacterial DNA by PCR did not improve with antibiotics. Although sexual contact has been thought to play a role in the development of symptoms, the data do not indicate significant differences in sexual practices in men with CPPS compared with controls. A population-based study (14) of Finnish men reported a 60% lower risk for divorced men compared with married men independent of age. Single men in the cohort had a 15% lower risk of prostatitis. The authors speculated that this difference might be due to the exposure of married men to potential pathogens from their wives’ genital tract. However, an internet-based study of chronic prostatitis evaluated the number of sexual contacts prior to the development of prostatitis. Sixtynine percent of patients reported zero or one sexual partner prior to onset of prostatitis-like symptoms (16). In the NIH Chronic Prostatitis Collaborative Research Network (CPCRN) study, there were no differences between men with CPPS and age-matched controls in number of sexual partners, types of sexual partners and types of sexual contact including oral and anal intercourse, and use of spermicides (18). However, the CPCRN study did show significantly greater selfreported history of an sexually transmitted disease (STD) in men with CPPS compared with asymptomatic controls (18). A history of sexually transmitted diseases has been reported to produce a 1.8-fold greater risk of developing prostatitis (15). In the Boston Area Community Health survey, men with a history of a urinary tract infection had a 3.8 times greater likelihood of having symptoms of prostatitis (27) There is the possibility that men with CP/CPPS have symptoms of a remote infection that is no longer active but which has caused tissue damage or inflammation that

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may be producing symptoms Thus, lack of evidence of an ongoing infection does not rule out the possibility that an infection was the inciting event for the symptoms. Another possible role for bacteria is that men with CPPS may be having an abnormal reaction to prostatic or genitourinary tract bacteria that are not otherwise normally pathogenic. Considerable data have accumulated to indicate that the genitourinary (GU) tract of asymptomatic men harbors bacteria. Cultures localize uropathogenic bacteria to the prostate in 8% of asymptomatic men and what are considered to be non-uropathogens in 74% of asymptomatic men (28). Direct comparison of PCR performed in prostate tissue taken at the time of radical prostatectomy for prostate cancer in men with and without symptoms of chronic pelvic pain have shown no differences in product for herpes simplex virus, cytomegalovirus, papillomavirus nor bacterial DNA (29,30). Using PCR on perineal biopsies from men with and without pelvic pain and no prostate cancer showed no differences in rates of positive findings for bacteria (31). There may be an abnormal immune response to otherwise normal prostate bacteria. Another marker of inflammation besides leukocytes is reactive oxygen species (ROS). Neutrophils release ROS free radicals (O$2 , HO%, H2O2), in response to antigenic stimulation. Shahed and Shoskes (32) studied the premise that infection by gram-positive bacteria in category IIIA, and not just prostatic colonization, results in oxidative stress, since tissue injury by definition follows infection and not colonization. Elevated concentrations of ROS were found in the EPS of their CPPS patients, less subsequently detected after clinically successful treatment with oral antibiotics or the antioxidant quercetin. The conclusion was that after antibiotic treatment for infection, oxidative stress is reduced, which minimizes tissue injury and pain, supporting the hypothesis that gram-positive bacteria can be true pathogens. Immune Factors Inflammation Traditionally, WBCs in the prostatic fluids have been studied and thought to be markers for an inflammatory process that contributes to the symptoms of prostatitis. The use of WBCs as markers of inflammation is limited for several reasons. WBCs can be found in the prostatic fluid or seminal plasma of asymptomatic men as well as those with pelvic pain (28,33). Also, in symptomatic men, none of the measures of the NIH-CPSI, including subsets for pain, urinary, and quality of life show any correlation with WBCs in either EPS, VB3, or seminal plasma (34). Another argument against the association between inflammation and symptoms is that category IIIB patients have symptoms but no inflammation, and conversely category IV patients have inflammation but no symptoms. Given the lack of correlation between WBCs and symptoms, other inflammatory markers and mediators have been studied. Cytokines are soluble signaling molecules that are produced from leukocytes as well as endothelial, epithelial, and several other cell types. They act locally over short cellular distances as initiators and modulators of immune and inflammatory responses. Comparison of proinflammatory interleukins (ILs) between men with and without CPPS reveals no clear patterns or differences (35). More recently studied are the proinflammatory cytokines macrophage inflammatory protein-1a, which is chemotactic for macrophages and T lymphocytes, and monocyte chemoattractant protein-1, which has selective chemoattraction for monocytes. Both of these have been found to be elevated in the EPS of patients with category IIIA CP/CPPS when compared with category IIIB and asymptomatic controls (36). Differences have been detected between IIIA and IIB in elastase with patients in category IIIA having significantly more elastase in their seminal plasma than patients in category IIIB (37). Instead of elevations of proinflammatory cytokines, another proposed mechanism is low concentrations of endogenous cytokine inhibitors. Recent evidence points to dysregulation of IL-10 as a potential contributing factor in CPPS. IL-10 is produced by monocytes; macrophages; T0, T1, T2, and B lymphocytes; mast cells; eosinophils; keratinocytes; and various tumor cells. IL-10 has immunosuppressive effects such as decreased tumor necrosis factor a (TNF-a), IL-1a, IL-2, IL-6, IL-8, and interferon gamma (IFN-g). IL-10 also has some immunostimulatory effects such as increased B-cell proliferation and antibody production, increased proliferation, activation, and chemotaxis of CD8CT cells, and increased IL-2-induced natural killer cell cytotoxicity (38).

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One study looked at differences in the DNA sequence (polymorphisms) of the genes for cytokines in patients with CP/CPPS. Polymorphisms have been identified in the promoter regions of several cytokines. These differences in DNA sequence of the promoter region result in different degrees of cytokine production in response to a given stimulus (39,40). Shoskes et al. determined the genotype for high production and low production alleles for two proinflammatory cytokines: TNF-a and IL-6 and two antiinflammatory cytokines: transforming growth factor b (TGF-b) and IL-10. The frequency of these genotypes were compared between 36 men with CPPS and a control population including 252 samples from transplant donors and recipients (41). All IIIA patients had the low TNF-a production genotype. There was no difference in the TNF-a genotype in IIIB versus controls. None of the category III patients had low IL-6 genotype. However, significantly more of men with CPPS expressed the IL-10 AA genotype which is associated with low IL-10 production (42) compared with controls (30.6% vs. 12.1%; pZ0.007). The cytokine polymorphisms also correlated with response to treatment with quercetin, an antioxidant: all of those who failed therapy had the GG TNF-a genotype (low cytokine expression) versus 29.4% of patients with a favorable clinical response to quercetin therapy (pZ0.0003). Only 10% of the treatment failure group had the low IL-10 genotype versus 47.1% of patients who had a beneficial therapeutic response to quercetin therapy (pZ0.04). Given these findings, some men with CPPS may have a blunted IL-10 production capacity. TNF-a induces production of IL-10 (43), so in men with category IIIA prostatitis, low concentrations of TNF-a may lead to decreased IL-10 which would lead to less inhibition of IL-8 and thus increased WBC chemotaxis. Some men may have low IL-10 primarily on the basis of the allele for IL-10, irrespective of the TNF-a levels. Low systemic IL-10 concentrations may have several effects. There may be failure to suppress inflammation if IL-10 concentrations are low. Sustained proinflammatory cytokines could lead to tissue injury. IL-10 is a powerful suppressant of monocyte–macrophage function, inhibiting the production of proinflammatory cytokines such as TNF-a, IL-1, IL-6, IL-8, and downregulating macrophage production of nitric oxide (38). The concept of lack of immune suppression leading to chronic inflammation and pain in these men is supported by the observation that a man with CP/CPPS who was immunosuppressed after transplant experienced resolution of his pelvic pain (44). Other genetic mutations may contribute to the ongoing inflammation and oxidative stress. Patients with CPPS were found to have a higher frequency of an allele of the manganese superoxide dismutase gene that contributes to lower enzyme activity, causing mitochondrial damage and dysfunction, contributing to oxidative stress (45). Autoimmunity The possibility of an autoimmune basis for prostatic inflammation has been examined in both humans and animal models. Markers for cytotoxic Tcells have been found in the EPS from patients with CPPS, a cell type not typical of antimicrobial immunity, but more consistent with autoimmune inflammation or secondary remodeling of injured tissue (32). prostate specfic antigen (PSA) was proposed as a candidate self-antigen by Ponniah et al. (46). CD4 T cells from category III patients had a proliferative response to PSA more than double than in controls, yet no response was found to two other seminal proteins, prostatic acid phosphatase, and b-microseminoprotein. Another candidate protein is MAD-PRO-34, a nucleolar autoantigen that was recognized in the sera of 6 of 62 patients with CP/CPPS but in 0 of 71 asymptomatic controls (47). Possible autoimmunity may in part explain the chronic and relapsing nature of chronic prostatitis, resembling other relapsing autoimmune disorders such as multiple sclerosis and lupus. Endocrine Another important factor in the development of prostatitis may be sex hormones. Male Wistar and Lewis rats develop spontaneous autoimmune inflammation of the lateral prostate with age whereas Sprague–Dawley rats do not. However, development of prostatitis (as defined in this model histologically by inflammatory infiltrates of the lateral prostate) is also hormone dependent. In this model, all of the old Wistar rats treated with estrogen for 30 days had histological evidence of lateral prostate inflammation (48). Studies have also noted that coadministration of testosterone with estradiol prevented estrogen-induced prostatitis, while

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dihydrotestosterone (DHT) was less effective (48,49). This suggests that testosterone must exert an independent role on the prostate aside from conversion to DHT. Steroid hormones may be also be affected locally by the inflammation. In models of autoimmunity there is evidence for chemotactic cytokines such as TNF-a and IFN-g altering the surface of endothelial cells favoring mononuclear cell homing and infiltration, thus leading to decreased steroid hormone production (50). In the rat model of autoimmune prostatitis, inflammation impairs 5-a-reductase activity and lowers the intraprostatic levels of DHT relative to testosterone (51). Given the effects of testosterone on prostate inflammation, this may be a mechanism to limit prostatic inflammation. This observation may be the basis for the possible beneficial clinical effect seen with the use of finasteride in CPPS, which inhibits the conversion of testosterone to DHT, and may raise local levels of testosterone (52). Recent findings on the genetics of patients with CPPS bolster the theory that there may be an underlying problem with androgens in prostatitis. Krieger and Riley (53) found differences in frequency of three alleles near the phosphoglycerate kinase (PGK) gene, between CPPS patients and controls. The alleles differed in the number of short tandem repeats. The PGK1 gene in the region assessed has been found to be associated with familial prostate cancer, hypospadias, and androgen insensitivity. Another gene in the same region of the X chromosome, Xq11–Xq13, is the androgen receptor. This finding raises the possibility of androgen insensitivity or dysfunction in the pathogenesis of CPPS. Further work by this group indicates that the tandem repeats found in men with CP/CPPS function frequently in other systems encoding membrane-associated proteins. Whether there is a defect in the interaction between the androgen receptor and the nuclear envelope in these men remains to be determined (54). Overall these findings lead to the possibility that if testosterone levels protect against inflammation as seen in animal models, then androgen insensitivity may lead to prostatic inflammation. Nervous System The nervous system itself may be the source of the symptoms. Pain is the symptom that separates men with CP/CPPS from other men with voiding symptoms alone, such as with lower urinary tract symptoms (LUTS)/BPH (3). This indicates some neurological involvement, either on a local level or in the CNS. The pain of chronic prostatitis may also be a result of neurogenic inflammation in the peripheral and central nervous systems. Experimental evidence for central remodeling is provided by the finding that chemical irritation of rat prostate and bladder causes c-fos expression at spinal cord levels L6 and S1 along with plasma extravasation at the identical L6 and S1 dermatomes, underscoring the overlap of afferent nerve fiber distribution (55). One of the hallmarks of such remodeling or “windup” is neurogenic inflammation. In the Wistar rat model of prostatitis, an increased density of nerve fibers, the sensory neuropeptide calcitonin gene–related peptide, and evidence of progressive mast cell degranulation are noted at progressive time points (56). One of the products released from activated mast cells is nerve growth factor (NGF) (57). The importance of NGF is that it is one of the few factors that correlate with the pain in CP/CPPS (58). NGF is a neurotrophin that has been found to play a role in the regulation of nociceptive nerves and as a mediator and amplifier of neurogenic inflammation. NGF is a survival factor for both sympathetic and sensory neurons during development (59). The concentrations of NGF in damaged or inflamed tissue have been shown to increase many fold above normal (60). NGF regulates the sensitivity of adult sensory neurons to capsaicin, which excites C-mechano-heat receptors (61). These C fibers are sensory nerves associated with pain transmission and also innervate mast cells (57). NGF is also a potent stimulator of mast cells and can cause their degranulation (62). The released substances lead to neurogenic inflammation and then sensitize C fibers. There is evidence that increased concentrations of NGF in a peripheral target can also sensitize central neurons to afferent barrages from that target (59). This can lead to sensitization of central neurons by enhanced neurotransmission mediated by the N-methyl-D-aspartate (NMDA) receptor that produces long-lasting depolarizations (63). Human data to further support a neurological hypothesis are given by Zermann et al. (64). They found significant abnormalities in the coordination of voiding and activity in the

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pelvic floor/external urethral sphincter in over 80% of their men with symptoms of pelvic pain. This kind of dysfunction is classically found in patients with a suprasacral spinal cord lesions, such as patients with a full spinal cord injury, or men with spinal cord plaques from multiple sclerosis (MS). This raises the question as to whether these men have a subclinical neural injury in the spinal cord which would contribute to such dyssynergy, and thus pelvic pain. The presence of central sensitization in patients with CPPS was also demonstrated by Yang et al. (65) who compared thermal algometry in men with CPPS versus asymptomatic controls. Sensitivity to noxious heat stimuli is thought to be a reflection of central sensitization The men with CPPS reported a higher visual analog scale to short bursts of noxious heat stimuli to the perineum but no difference to the anterior thigh. Thus these patients have altered sensation in the perineum compared with controls. This is similar to other chronic pain syndromes such as reflex sympathetic dystrophy and fibromyalgia where patients also have heightened responses to noxious heat stimuli in areas of chronic pain compared with controls. Psychological Factors Psychological factors also appear to be involved in producing symptoms in men with CP/CPPS, or may affect how the patient perceives the pain. Psychological stress is a common finding in men with CPPS (17). Self-assessment of personality showed that these men reported being more nervous and busy than healthy controls. Men with prostatitis were likely to show fear of having an STD [odds ratio (OR)Z5.9] or to have a suicidal tendency (ORZ10.5). There are cellular and molecular changes induced by psychological difficulties and stress which may play a role in these men. In addition to many other stimuli such as cytokines, bacterial toxins and hypoxia, mast cells release their contents in response to stress (66). In patients with CPPS, there appear to be some direct measurable effects of stress or stress reduction on cytokine levels. In category III prostatitis patients, the degree of spousal concern and support and effort to distract the patient correlates with lower seminal plasma IL-6 and IL-10 concentrations (58). Interaction of Immune, Nervous, Endocrine, and Psychological Factors There is also considerable interplay of immune, neurological, endocrine, and even psychiatric factors as well (35). For example, the endocrine and immune systems also can play a role in neurogenic inflammation. Testosterone can have a negative effect on NGF. All rat pelvic noradrenergic neurons express the NGF receptors trkA and p75 (67). NGF induces neurite growth in these neurons. In vitro, testosterone impedes the NGF-induced growth of long neurites from pelvic ganglia cells cultured from adult male rats (68). Mast cells may also act as antigen-presenting cells (69) that will degranulate after contact with T cells, and thus activate nearby nerve fibers and release NGF. As noted above, mast cells also release their contents in response to stress (66). The immune system also plays a role in mast cell survival. In the short term, IL-10 and IL-4 promote mast cell survival but long-term exposure of mast cells to IL-3, 4, and 10 will induce downregulation of critical mast cell proteins such as the stem cell factor receptor kit and the high affinity IgE receptor FcRI, which is followed by mast cell apoptosis (70). Thus in individuals with low IL-10, there may be decreased mast cell apoptosis, greater numbers of mast cells, and higher chance of developing neurogenic inflammation. Other Factors Intraprostatic Pressure Another local factor could be elevated intraprostatic pressure. Measuring intraprostatic tissue pressure was performed in 42 patients with chronic abacterial prostatitis under spinal anesthesia (71). After an injection of 1 mL saline, significantly higher intraprostatic pressures were recorded at all time points versus controls. The investigators felt this reflected increased tissue resistance and possibly poor tissue microcirculation. Whether this was secondary to intrinsic prostatic changes or increased sympathetic or pelvic floor activity is unknown. They speculated that poor flow may contribute to tissue rigidity and fibrosis.

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Prostate Blood Flow Inducible nitric oxide synthase levels are upregulated during prostatic inflammation, whose consequence is an increase in NO and therefore vascular dilatation and permeability. Cho et al. (72) used color Doppler ultrasonography to show marked increases in flow to the prostatic capsule and parenchyma over controls in categories IIIA and IIIB patients. This again may support the notion of a common denominator leading to pain in these different subsets. Is it vascular congestion itself that is pain generating, or the delivery of inflammatory cells, from this vascular congestion, with their resultant cytokine production and pain? CONCLUSION Recent studies show that CP/CPPS is widely prevalent throughout the world, affecting men of all ages and demographics. CP/CPPS likely represents a multifactorial syndrome that arises from multiple causes. Proposed factors involved in the symptoms of CP/CPPS include infectious, immune, neurological, and psychological processes. These may work either alone or may influence each other to create the common pathway of pelvic pain. REFERENCES 1. Krieger JN, Nyberg L, Jr., Nickel JC. NIH consensus definition and classification of prostatitis. J Am Med Assoc 1999; 282(3):236–7. 2. Nickel JC, Nyberg LM, Hennenfent M. Research guidelines for chronic prostatitis: consensus report from the first National Institutes of Health International Prostatitis Collaborative Network. Urology 1999; 54(2):229–33. 3. Krieger JN, Egan KJ, Ross SO, Jacobs R, Berger RE. Chronic pelvic pains represent the most prominent urogenital symptoms of “chronic prostatitis”. Urology 1996; 48(5):715–21 (discussion 21–2). 4. Drach GW, Fair WR, Meares EM, Stamey TA. Classification of benign diseases associated with prostatic pain: prostatitis or prostatodynia? J Urol 1978; 120(2):266. 5. Collins MM, Stafford RS, O’Leary MP, Barry MJ. How common is prostatitis? A national survey of physician visits. J Urol 1998; 159(4):1224–8. 6. Nickel JC, Nigro M, Valiquette L, et al. Diagnosis and treatment of prostatitis in Canada. Urology 1998; 52:797–802. 7. de la Rosette JJ, Hubregtse MR, Meuleman EJ, Stolk-Engelaar MV, Debruyne FM. Diagnosis and treatment of 409 patients with prostatitis syndromes. Urology 1993; 41(4):301–7. 8. Moon TD. Questionnaire survey of urologists and primary care physicians’ diagnostic and treatment practices for prostatitis. Urology 1997; 50:543–7. 9. Roberts RO, Jacobson DJ, Girman CJ, Rhodes T, Lieber MM, Jacobsen SJ. Prevalence of prostatitis-like symptoms in a community based cohort of older men. J Urol 2002; 168:2467–71. 10. Roberts RO, Lieber MM, Rhodes T, Girman CJ, Bostwick DG, Jacobsen SJ. Prevalence of a physicianassigned diagnosis of prostatitis: the Olmsted County Study of Urinary Symptoms and Health Status Among Men. Urology 1998; 51:578–84. 11. Nickel JC, Downey J, Hunter D, Clark J. Prevalence of prostatitis-like symptoms in a population based study using the National Institutes of Health chronic prostatitis symptom index. J Urol 2001; 165:842–5. 12. Rizzo M, Marchetti F, Travaglini F, Trinchieri A, Nickel JC. Clinical characterization of the prostatitis patient in Italy: a prospective urology outpatient study. World J Urol 2005; 23(1):61–6. 13. Ku JH, Kim ME, Lee NK, Park YH. Influence of environmental factors on chronic prostatitis-like symptoms in young men: results of a community-based survey. Urology 2001; 58:853–8. 14. Mehik A, Hellstrom P, Lukkarinen O, Sarpola A, Jarvelin M. Epidemiology of prostatitis in Finnish men: a population-based cross-sectional study. BJU Int 2000; 86(4):443–8. 15. Collins MM, Meigs JB, Barry MJ, Walker Corkery E, Giovannucci E, Kawachi I. Prevalence and correlates of prostatitis in the health professionals follow-up study cohort. J Urol 2002; 167:1363–6. 16. Schaeffer AJ, Landis JR, Knauss JS, et al. Demographic and clinical characteristics of men with chronic prostatitis: the National Institutes Of Health chronic prostatitis cohort study. J Urol 2002; 168(2):593–8. 17. Mehik A, Hellstrom P, Sarpola A, Lukkarinen O, Jarvelin MR. Fears, sexual disturbances and personality features in men with prostatitis: a population-based cross-sectional study in Finland. BJU Int 2001; 88(1):35–8. 18. Pontari MA, Litwin MS, O’Leary MP, et al. A case-control study of risk factors in men with chronic pelvic pain syndrome. BJU Int 2005; 96:559–65. 19. Ware JE, Kosinski M, Keller SD. A twelve item short form health survey-construction of scales and preliminary tests of reliability and validity. Med Care 1996; 34:220–3.

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20. McNaughton Collins M, Pontari MA, O’Leary MP, et al. Quality of life is impaired in men with chronic prostatitis: the Chronic Prostatitis Collaborative Research Network. J Gen Intern Med 2001; 16(10):656–62. 21. True LD, Berger RE, Rothman I, Ross SO, Krieger JN. Prostate histopathology and the chronic prostatitis/chronic pelvic pain syndrome: a prospective biopsy study. J Urol 1999; 162:2014–8. 22. Nickel CJ. Prostatitis syndromes: an update for urologic practice. Can J Urol 2000; 7(5):1091–8. 23. Relman DA, Schmidt TM, MacDermott RP, Falkow S. Identification of the uncultured bacillus of Whipple’s disease. N Engl J Med 1992; 327(5):293–301 (see comment). 24. Weidner W, Schiefer HG, Krauss H, Jantos C, Friedrich HJ, Altmannsberger M. Chronic prostatitis: a thorough search for etiologically involved microorganisms in 1,461 patients. Infection 1991; 19(Suppl. 3):S119–25. 25. Doble A, Thomas BJ, Walker MM, Harris JR, Witherow RO, Taylor-Robinson D. The role of Chlamydia trachomatis in chronic abacterial prostatitis: a study using ultrasound guided biopsy. J Urol 1989; 141(2):332–3. 26. Shoskes DA, Shahed AR. Detection of bacterial signal by 16S rRNA polymerase chain reaction in expressed prostatic secretions predicts response to antibiotic therapy in men with chronic pelvic pain syndrome. Tech Urol 2000; 6(3):240–2. 27. Daniels NA, Link CL, Barry MJ, McKinlay JB. Are urinary tract infections associated with prostatitis symptoms: results from the Boston Area Community Health (BACH) survey. J Urol 2005; 173(Suppl. 4):28 (Abstract). 28. Nickel JC, Alexander RB, Schaeffer AJ, Landis JR, Knauss JS, Propert KJ. Leukocytes and bacteria in men with chronic prostatitis/chronic pelvic pain syndrome compared to asymptomatic controls. J Urol 2003; 170:818–22. 29. Leskinen MJ, Rantakokko-Jalava K, Manninen R, et al. Negative bacterial polymerase chain reaction (PCR) findings in prostate tissue from patients with symptoms of chronic pelvic pain syndrome (CPPS) and localized prostate cancer. Prostate 2003; 55(2):105–10. 30. Leskinen MJ, Vainionp R, Syrjnen S, et al. Herpes simplex virus, cytomegalovirus, and papillomavirus DNA are not found in patients with chronic pelvic pain syndrome undergoing radical prostatectomy for localized prostate cancer. Urology 2003; 61(2):397–401. 31. Lee JC, Muller CH, Rothman I, et al. Prostate biopsy culture findings of men with chronic pelvic pain syndrome do not differ from those of healthy controls. J Urol 2003; 169(2):584–7 (discussion 7–8; see comment). 32. Shahed AR, Shoskes DA. Oxidative stress in prostatic fluid of patients with chronic pelvic pain syndrome: correlation with gram positive bacterial growth and treatment response. J Androl 2000; 21(5):669–75. 33. Schaeffer AJ, Wendel EF, Dunn JK, Grayhack JT. Prevalence and significance of prostatic inflammation. J Urol 1981; 125(2):215–9. 34. Schaeffer AJ, Knauss JS, Landis JR, et al. Leukocyte and bacterial counts do not correlate with severity of symptoms in men with chronic prostatitis: the National Institutes of Health Chronic Prostatitis Cohort Study. J Urol 2002; 168(3):1048–53. 35. Pontari MA, Ruggieri MR. Mechanisms in prostatitis/chronic pelvic pain syndrome. J Urol 2004; 174:839–45. 36. Stern JA, Koch AE, Campbell PL, Landis JR, Schaeffer AJ. MIP-1a and MCP-1: novel biomarkers for chronic prostatitis. J Urol 2005; 173(Suppl. 4):30 (Abstract). 37. Ludwig M, Vidal A, Diemer T, Pabst W, Failing K, Weidner W. Chronic prostatitis/chronic pelvic pain pyndrome: seminal markers of inflammation. World J Urol 2003; 21(2):82–5. 38. Lalani I, Bhol K, Ahmed AR. Interleukin-10: biology, role in inflammation and autoimmunity. Ann Allergy Asthma Immunol 1997; 79(6):469–83. 39. Kroeger KM, Carville KS, Abraham LJ. The K308 tumor necrosis factor-alpha promoter polymorphism effects transcription. Mol Immunol 1997; 34(5):391–9. 40. Eskdale J, Gallagher G, Verweij CL, Keijsers V, Westendorp RG, Huizinga TW. Interleukin 10 secretion in relation to human IL-10 locus haplotypes. Proc Natl Acad Sci USA 1998; 95(16):9465–70. 41. Shoskes DA, Albakri Q, Thomas K, Cook D. Cytokine polymorphisms in men with chronic prostatitis/chronic pelvic pain syndrome: association with diagnosis and treatment response. J Urol 2002; 168(1):331–5. 42. Turner DM, Williams DM, Sankaran D, Lazarus M, Sinnott P J, Hutchinson IV. An investigation of polymorphism in the interleukin-10 gene promoter. Eur J Immunogenet 1997; 24:1. 43. Wanidworanun C, Strober W. Predominant role of tumor necrosis factor-alpha in human monocyte IL-10 synthesis. J Immunol 1993; 151(12):6853–61. 44. Palapattu GS, Shoskes DA. Resolution of the chronic pelvic pain syndrome after renal transplantation. J Urol 2000; 164(1):127. 45. Buyuktuncer ED, Arisan S, Kiremitci MC, et al. MN-SOD polymorphism in chronic pelvic pain syndrome patients. J Urol 2005; 173(Suppl. 4):31 (Abstract).

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46. Ponniah S, Arah I, Alexander RB. PSA is a candidate self-antigen in autoimmune chronic prostatitis/chronic pelvic pain syndrome. Prostate 2000; 44(1):49–54. 47. Dunphy EJ, Eickhoff JC, Muller CH, Berger RE, McNeel DG. Identification of antigen-specific IgG in sera from patients with chronic prostatitis. J Clin Immunol 2004; 24(5):492–502. 48. Naslund MJ, Strandberg JD, Coffey DS. The role of androgens and estrogens in the pathogenesis of experimental nonbacterial prostatitis. J Urol 1988; 140(5):1049–53. 49. Robinette CL. Sex hormone induced inflammation and fibromuscular proliferation in the rat lateral prostate. Prostate 1988; 12:271–86. 50. Diserio GP, Nowotny E. Experimental autoimmune prostatitis: in vivo induction of the autoimmune response to lymphocytic soluble factors. Alterations at the endocrine metabolism level. Am J Reprod Immunol (Copenhagen) 1998; 39(4):226–34. 51. Diserio GP, Carrizo AE, Pacheco-Rupil B, Nowotny E. Effect of male accessory glands autoaggression on androgenic cytosolic and nuclear receptors of rat prostate. Cell Mol Biol 1992; 38(2):201–7. 52. Nickel JC, Downey J, Pontari MA, Shoskes D, Zeitlin S. Randomized placebo controlled multi-center study to evaluate the safety and efficacy of finasteride in the treatment of male chronic pelvic pain syndrome: category IIIA CPPS (chronic nonbacterial prostatitis). BJU Int 2004; 96:559–65. 53. Riley DE, Krieger JN. X Chromosomal short tandem repeat polymorphisms near the phosphoglycerate kinase gene in men with chronic prostatitis. Biochim Biophys Acta 2002; 1586(1):99–107. 54. Riley DE, Krieger JN. Diverse eukaryotic transcripts suggest short tandem repeats have cellular functions. Biochem Biophys Res Commun 2002; 298(4):581–6. 55. Ishigooka M, Zermann DH, Doggweiler R, Schmidt RA. Similarity of distributions of spinal c-fos and plasma extravasation after acute chemical irritation of the bladder and the prostate. J Urol 2000; 164(5):1751–6. 56. Keith IM, Jin J, Neal D, Jr., Teunissen BD, Moon TD. Cell relationship in a Wistar rat model of spontaneous prostatitis. J Urol 2001; 166(1):323–8. 57. Skaper SD. Nerve growth factor: a neurokine orchestrating neuroimmune-endocrine functions. Mol Neurobiol 2001; 24(1-3):183–99. 58. Miller LJ, Fischer KA, Goralnick SJ, et al. Nerve growth factor and chronic prostatitis/chronic pelvic pain syndrome. Urology 2002; 59(4):603–8. 59. Lewin GR, Mendell LM. Nerve growth factor and nociception. Trends Neurosci 1993; 16(9):353–9. 60. Varilek GW, Weinstock JV, Pantazis NJ. Isolated hepatic granulomas from mice infected with Schistosoma mansoni contain nerve growth factor. Infect Immun 1991; 59(12):4443–9. 61. Winter J, Forbes CA, Sternberg J, Lindsay RM. Nerve growth factor (NGF) regulates adult rat cultured dorsal root ganglion neuron responses to the excitotoxin capsaicin. Neuron 1988; 1(10):973–81. 62. Mazurek N, Weskamp G, Erne P, Otten U. Nerve growth factor induces mast cell degranulation without changing intracellular calcium levels. FEBS Lett 1986; 198(2):315–20. 63. Woolf CJ, Thompson SW. The induction and maintenance of central sensitization is dependent on N-methyl-D-aspartic acid receptor activation; implications for the treatment of post-injury pain hypersensitivity states. Pain 1991; 44(3):293–9. 64. Zermann DH, Ishigooka M, Doggweiler R, Schmidt RA. Neurourological insights into the etiology of genitourinary pain in men. J Urol 1999; 161(3):903–8. 65. Yang CC, Lee JC, Kromm BG, Ciol MA, Berger RE. Pain sensitization in male chronic pelvic pain syndrome: why are symptoms so difficult to treat? J Urol 2003; 170(3):823–6 (discussion 6–7). 66. Spanos C, Pang X, Ligris K, et al. Stress-induced bladder mast cell activation: implications for interstitial cystitis. J Urol 1997; 157(2):669–72. 67. Keast JR, Kepper ME. Differential regulation of trkA and p75 in noradrenergic pelvic autonomic ganglion cells after deafferentation of their cholinergic neighbours. Eur J Neurosci 2001; 13(2):211–20. 68. Meusburger SM, Keast JR. Testosterone and nerve growth factor have distinct but interacting effects on structure and neurotransmitter expression of adult pelvic ganglion cells in vitro. Neuroscience 2001; 108(2):331–40. 69. Foreman JC. Peptides and neurogenic inflammation. Br Med Bull 1987; 43(2):386–400. 70. Shelburne CP, Ryan JJ. The role of Th2 cytokines in mast cell homeostasis. Immunol Rev 2001; 179:82–93. 71. Mehik A, Hellstrom P, Nickel JC, et al. The chronic prostatitis–chronic pelvic pain syndrome can be characterized by prostatic tissue pressure measurements. J Urol 2002; 167:137–40 (see comment). 72. Cho IR, Keener TS, Nghiem HV, Winter T, Krieger JN. Prostate blood flow characteristics in the chronic prostatitis/pelvic pain syndrome. J Urol 2000; 163(4):1130–3.

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Prostate Pain Syndrome

Treatment Options

Henning Schneider and Wolfgang Weidner

Departments of Urology and Pediatric Urology, Justus-Liebig University of Giessen, Giessen, Germany

INTRODUCTION Over about 20 years, the classification of prostatitis from Drach et al. (1) was the basis in diagnostic and therapy of prostatitis. But this classification had several limitations and did not fit all facets of the complex prostatitis syndrome. So in 1999, the International Prostatitis Collaborative Network (2) developed in cooperation with the National Institutes of Health (NIH) a new classification which has been accepted worldwide (Table 1). Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a poorly understood disease. CP/CPPS (NIH III), which affects over 70% of patients with prostatitis symptoms, is a multifactorial disease of mainly unknown etiology (3). Different mechanisms have been discussed in the past, e.g., uncommon bacterial infection, inflammation (4), urodynamic abnormalities (5), such as bladder neck obstruction (6), intraprostatic reflux (5), impaired detrusor contractility (7) and autoimmune trigger mechanisms (3). The main pathogenetic pathway seems to be a mechanical or functional subprostatic obstruction, changing the laminar urine flow and providing the intraprostatic reflux of different noxious substances into the prostate (Fig. 1). The role of psychological factors like stress, depression, and hypochondriasis have also been mentioned (8). With regard to these multiple and debatable factors, the right therapy seems to be difficult. Most of the treatment suggestions are empirical and/or anecdotal; only a few well-controlled studies exist. The following overview presents the opportunities of evidence-based CP/CPPS treatment in 2005. CLASSIFICATION, SYMPTOMS, AND EVIDENCE OF CP/CPPS CP/CPPS is a multifactorial disease affecting men of all ages and demographics. Socio-epidemiological data for CP/CPPS verify the great importance of prostatitislike symptoms in the urological daily function. About 30% of all men suffer from prostatitislike symptoms at some time in their life (9). In the United States, about 8% of urological patients and 1% of patients in general are diagnosed as suffering from prostatitis, resulting in a total number of two million patients per year (10). These figures mean that CP/CPPS is the most frequently found illness in men under the age of 50 years (10). It is generally believed that CP/ CPPS symptoms reflect disorders of the prostate, although this association is not clear and has not been confirmed in all aspects (11). The diagnosis of patients suffering from CP/CPPS excludes other etiologic factors or diseases that may have similar symptoms (12). International considerations recommend categorizing the diagnostic procedures into a basic evaluation mandatory for all patients and a further stepwise evaluation in selected patients (13). Basic evaluation includes a disease history, a physical examination (including digital rectal examination) and a urinalysis/culture of midstream urine. Under suspicion of CP/CPPS, the further evaluation integrates a symptomatic evaluation, including the National Institutes of Health chronic prostatitis symptom index (14), a lower urinary tract localization test (four-glass test or pre–post massage two-glass test) and a flow rate (12). If there is a hint of another urogenital disease, a detailed evaluation in selected patients, like computerized tomography scan or cystoscopy, can be considered (12). Using such a diagnostic design, the frequency of the

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TABLE 1 The NIH Consensus Classification NIH category I II III III A III B IV

Name

Description

Acute bacterial prostatitis Chronic bacterial prostatitis Chronic nonbacterial prostatitis. Synonym: CPPS Inflammatory CPPS Noninflammatory CPPS Asymptomatic prostatitis

Acute infection of the prostate Chronic or recurrent infection of the prostate No evidence of bacteria in significant number, but symptoms Leukocytes in EPS, VB3, or semena No leukocytes in EPS, VB3, or semena No symptoms, but histological diagnosis

a Fractions of the four-glass test: EPS and VB3. Abbreviations: CPPS, chronic pelvic pain syndrome; EPS, expressed prostatic secretion; NIH, National Institutes of Health; VB3, voided bladder after prostatic massage.

different types according to the NIH classification is given in Figure 2, which shows this distribution. More than 80% of patients presenting with “prostatitis” symptoms suffer from CP/CPPS (NIH III). The symptomatology of CP/CPPS is characterized by four complexes (16): (i) pain, (ii) micturition disorder, (iii) sexual dysfunction, and (iv) general symptomatology. The main symptom of CP/CPPS is pain. The perineum, the bladder region, the testicles, the penis and the groin region can all be affected by pain in different ways (17). Voiding disturbances include dysuria, sensation of residual urine, frequent voiding, weak jet and urgency (17). Sexual disorders are characterized by painful ejaculation and erectile dysfunction (17). A set of nonspecific complaints can be summarized under general symptoms: backache, headache, pains in the neck, aching limbs, exhaustibility, fatigue, and a feeling of needing sleep (17).

TREATMENT OPTIONS Chronic Bacterial Prostatitis (NIH II) Chronic bacterial prostatitis is a chronic or recurrent infection with uropathogen microorganisms, mainly Escherichia coli; other gram-negative bacteria and enterococci species are to be considered in some cases. A four-glass test with quantitative segmental bacteriological localization cultures and an antibiogram is essential (18). Primary treatment is the use of antibiotics, which have to be lipid soluble thus reaching high concentrations in the prostatic fluid. This suggests fluoroquinolones, doxycycline, or trimethroprim–sulfametoxazol. The first choice is fluoroquinolone for four to six weeks, especially in E. coli or gram-negative infections (19,20). A dose of 500 mg ciprofloxacin two times per day is recommended by our group (18,21). If this primary therapy fails, a second course should follow. With this therapy you can

Mechanical or functional obstruction Intraprostatic reflux of urine components Local immunological reaction Chronic inflammation of the prostate Induction of pain

FIGURE 1 The hypothesis of subprostatic obstruction, laminar flow changes, intraprostatic reflux, chronic inflammation, and pain.

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NIH II 4.2%

Urethro prostatitis 14.3 %

NIH III A 31.5 %

NIH III B 50 %

FIGURE 2 Frequency of prostatitis according to the Giessen Cohort Study 2002. Abbreviation: NIH, National Institutes of Health. Source: From Ref. 15.

expect cure rates up to 70% (21,22). Cotrimoxazol is a pharmaceutic of second choice because of its longer therapy duration and lower cure rates. Table 2 gives a systematic overview of antibiotic therapy of CP. A combination of antimicrobial therapy and alpha-blockers can be recommended (23). The hypothesis that the intraprostatic reflux of bacteria, urinary constituents, and sperm induce the chronic inflammation underlines the role of alpha-blockers. The eradication of bacteria does not mean necessarily that the patient becomes asymptomatic because some patients who have no evidence of bacteria after successful antibiotic therapy remain symptomatic. So an additional treatment with alpha-blockers, analgesia, or muscle relaxants seems to be required. There are no standard guidelines to treat chronic infections with gram-positive or anaerobic germs. The antibiotic therapy should orientate to the special antibiogram, and trials with fluoroquinolones, cotrimoxazol, and macrolids are possible. Anaerobics could be treated with amoxilin/ clavulanacid or clindamycin (24). If the curative antibiotic treatment fails, a long-term suppressive, low-dose therapy over six months is debatable (Table 2). Another debatable option is the treatment with intraprostatic injection of antimicrobials like gentamycin. Previous study results do not give convincing results (25–27). TABLE 2 Therapy in Chronic Bacterial Prostatitis (National Institutes of Health II) Primary therapy (in dependence of bacterial culture) First choice Fluoroquinolones for 4 6 weeks Second choice Trimethroprim Cotrimoxazol or doxycycline for 3 months Additional an alpha-blocker for 3 6 months Suppressive therapy Long-term therapy with trimethroprim or nitrofurantoin for 3 6 months Refractory therapy Intraprostatic antibiotic injections debatable TURP not suited for younger men Abbreviation: TURP, transurethral resection.

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If pharmaceutical therapy fails, a surgical intervention, e.g., a transurethral resection (TURP), could be discussed. This is a procedure for experienced urologists because the inflammatory foci lie in the peripherical zone of the prostate and a radical procedure becomes necessary. This concept is not suited for younger men due to retrograde ejaculation. A radical prostatectomy is not suggested as a routine procedure in these cases. Chronic Prostatitis/Chronic Pelvic Pain Syndrome (NIH III A)/(NIH III B) CP/CPPS is the most common type of the prostatitis syndrome. It is estimated to be eight times more frequent than NIH II (15). The fact that no germs can be proven by conventional methods of microbiology is essential to know for diagnosis. Both forms are different only in the evidence of inflammatory parameters (Table 1), but symptoms and therapy options are the same. So in the past it was discussed if it makes sense to subdivide into an inflammatory (CP/NIH III A) and noninflammatory form (CPPS/NIH III B) (13). This division is useful for scientific questions, but at present not applicable for therapy. So in the following, therapy options are discussed for all types of CP/CPPS. Table 3 gives an overview of treatment opportunities with references to evidencebased studies. Antibiotics The positive effect of antibiotics in the treatment of acute and chronic bacterial prostatitis is proven. The use of antibiotics in CP/CPPS is controversial and debatable due to the lack of infectious origin of this entity. Nevertheless, antibiotics are widely used as an empirical firstline therapy in these patients. Krieger et al. (42) demonstrated that procaryotic RNA sequences could be found in 77% of the cases in patients with type NIH III A prostatitis. This could be a hint for a bacterial genesis in a few patients not evaluable by culture methods. So, this hypothesis could be one cause for the recommendation to treat CP/CPPS, category NIH III A with fluoroquinolones (19). Other studies also reported the association between positive PCR findings, inflammatory signs, and a questionable benefit of antibiotic treatment (43,44). Several antibiotics seem to have alternative TABLE 3 Treatment Options in Chronic Prostatitis/Chronic Pelvic Pain Syndrome Therapy Antibiotics Levofloxacin Ciprofloxacin Alpha-blockers Tamsulosin Alfuzsosin Terazosin Combinations CiprofloxacinCtamsulosin Antidepressants Sertraline Anti-inflammatory agents Rofecoxib Other agents Pentosan polysulfate sodium Finasteride Mepartricin Non-pharmaceutical Biofeedback Urethroanal electrostimulation Electromagnetic therapy Microwave thermotherapy

Treatment duration

Empirical studies

Evidence-based control studies

6 weeks 6 weeks

Nickel et al. (28) Alexander et al. (29)

6 weeks 6 weeks 24 weeks 14 weeks

Alexander et al. (29) Nickel et al. (30) Mehik et al. (31) Cheah et al. (32)

6 weeks

Alexander et al. (29)

13 weeks

Lee et al. (33)

6 weeks

Nickel et al. (34)

16 weeks 6 months 8.5 weeks

Nickel et al. (35) Nickel et al. (36)

5 weeks 4 weeks

De Rose et al. (37) Cornel et al. (38) John et al. (39) Rowe et al. (40) Nickel and Sorensen (41)

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mechanisms like modulatory, analgesic, and anti-inflammatory effects which may contribute to “positive” results (45–47). Only two studies (29,37) fulfill evidence-based criteria. Nickel (28) tested levofloxacin versus placebo for six weeks in patients with CP/CPPS. The symptoms improved in both groups, but were not significantly different (28). Alexander et al. (29) examined the effect of ciprofloxacin in a controlled six-week trial in patients with refractory, long-standing CP/CPPS. The results showed no significant symptom improvement in the ciprofloxacin group versus no therapy (29). These data verify that today antibiotic treatment cannot be recommended generally in patients with CP/CPPS. Antibiotic treatment can be discussed for first diagnosed patients with inflammatory nonbacterial prostatitis type NIH III A, who were not pre-therapied (48). If there is no symptomatic improvement during antibiotic treatment after a time of two to three weeks, therapy should be stopped. In conclusion, no general recommendation for routine use of antibiotics in CP/CPPS can be given (13). Alpha-Blockers Lower urinary tract symptoms (LUTS) are common in patients with CP/CPPS (5,49). The present knowledge suggests a functional urethral obstruction in patients with CP/CPPS, defined as “urinary dysfunction.” The bladder neck does not relax during voiding, so it results in a turbulent flow in the urethra with reflux of urine (Fig. 1). The reflux and influx of sterile urine, microorganisms, antigens, leukocytes, spermatozoa, urate metabolites, creatinine metabolites, etc., are claimed to trigger inflammation and contribute to pain activation via the appropriate receptors in the inflammatory cascade (5). Because of its high density of alphaadrenergic receptors, with the alpha-1a subtype in the prostate and the bladder neck, modern uroselective alpha-blockers are well suited to relax the bladder neck and the prostate, with low side effects (23). Some noncontrolled data suggest a symptom improvement in 50% to 80% of patients with CP/CPPS (23,50,51). Only a few well-controlled studies, fulfilling evidencedbased criteria, are available. Mehik et al. tested the effect of alfuzosin in the treatment of patients with CP/CPPS versus placebo controlled. The results show a significant improvement of pain symptoms in the alfuzosin group (31). Nickel et al. (30) compared tamsulosin to placebo. A dose of 0.4 mg tamsulosin per day over a period of six weeks demonstrated a significant effect (30). Cheah et al. could demonstrate that the alpha-antagonist terazosin was superior versus placebo (32). In contrast, the results from Alexander et al. (29) did not show a significant effect for tamsulosin in patients with CP/CPPS. This controversy must be clarified in further studies; the time of treatment may play a significant role for the efficacy (52), regarding long-term and durable treatment responses in quality of life and symptom improvement. In our opinion, the treatment with alpha-blockers over a period of at least three months can be recommended for patients with CP/CPPS. There is no recommendation for patients with CP/CPPS who have tried and failed alpha-blockers in the past. Antidepressants A number of somatic pathomechanisms have been described for CP/CPPS (53). No other phenomenon is steered to the same extent by mental factors as pain is. Fears and misgivings are known to intensify pain, whereas distractions can reduce it and even cause it to become completely forgotten. A depressive reaction may be a further psychosomatic factor in CP/CPPS symptoms. As many as 55% of patients with CP/CPPS have had depressive episodes in their lives, as was shown by increased scores in special depression questionnaires (54). So, one more starting point in the treatment of CP/CPPS symptoms could be an antidepressant therapy. Basic requirement before beginning a medical treatment is to test for depression, for example with a special questionnaire like the Beck Depression Inventory. The classic agent amitriptyline has been used for many chronic pain syndromes. Controlled data for CP/CPPS are missing, but Hanno showed in his study of the effects of amitriptyline in patients with interstitial cystitis (IC) that this agent has positive effects in symptom improvement (55). Because of similarities between IC and CP/CPPS, the use of amitriptyline might be also useful in CP/CPPS. A wellcontrolled study in the therapy of CP/CPPS exists for sertraline, a serotonin-specific reuptake inhibitor (SSRI) (33). In this study, a significant improvement for sertraline concerning prostatic

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symptom severity after a treatment duration of 13 weeks became evident (33). Another SSRI used is fluvoxamine. Fluvoxamine reduces pain intensity, but a general recommendation is not given by the authors (56). Anti-Inflammatory Agents and Analgetic Substances Nonsteroidal anti-inflammatory drugs (NSAIDs) and analgetics are widely used in the therapy of CP/CPPS, although evidenced data about their effectiveness are missing. NSAIDs inhibit the prostaglandin synthesis and block cyclooxygenase (COX) enzymes and the inflammatory response. Since 1982 prostaglandins have been discussed for their role in prostatitis (57). In an uncontrolled trial, the positive effect of nimesulid (NSAID) in patients with CPPS and nonspecific inflammation was reported (58). A first placebo-controlled study of the selective COX-2 inhibitor rofecoxib was carried out in 2003. Nickel et al. (34) treated patients with CP/CPPS (NIH III) with 50 mg of rofecoxib for six weeks. There were no significant differences in symptom severity versus placebo evaluated. Allopurinol is another agent where an ameliorative effect on CP/CPPS has been reported (59). Persson and associates (59) have described a positive, symptomatic effect of 300 mg/day of allopurinol versus placebo. The hypothesis is that the substance reduces urate concentrations in urine and EPS, tentatively inducing an inflammation in the prostate by urinary reflux (59). It is our opinion that the use of NSAIDs and analgetics has only empirical value for therapy until larger controlled trials are available (60). Other Agents (5-Alpha-Reductase Inhibitors, Pentosan Polysulfate Sodium, Mepartricin, Bioflavonoids) Many other agents like several phytotherapeutics are in use to treat CP/CPPS symptoms, but most of them have only anecdotal or empirical value. Only a few controlled studies exist for the following agents. 5-Alpha-Reductase Inhibitors

Finasteride was one of the first 5-alpha-reductase inhibitors that has demonstrated positive effects in reducing the size of the prostate and relieving symptoms in benign prostatic hyperplasia (BPH) (61,62). Finasteride inhibits the conversion of testosterone to dihydrotestosterone in the prostate gland. The hypothesis, that 5-alpha-reductase inhibitors may be considered as a therapy option for patients with CP/CPPS, is that a reduction of the glandular component, which is the primary focus of an inflammation, reduces also the inflammation itself. Second a lower tissue pressure, an improved tissue microcirculation and a reduced intraprostatic reflux should result (63,64). Besides some case reports, one group (36) tested the efficacy of finasteride for chronic CP/CPPS type NIH III A in a randomized, placebo-controlled study. The results of this six month trial showed a moderate benefit for these patients, but there is no recommendation for finasteride as monotherapy by the authors, except that the patients also suffer from LUTS. Pentosan Polysulfate Sodium

Pentosan polysulfate sodium (PPS) is a blood clot prevention agent with potential effect on mast cell release, which was tested in a placebo-controlled study in patients with CP/CPPS (35). PPS was given in a dosage of 900 mg per day for 16 weeks. The global clinical improvement was not statistically significant between PPS and the placebo group (35). At this time, there are no data to give a recommendation for or against this agent. Mepartricin

Mepartricin is a so-called estrogen reuptake inhibitor, which connects irreversibly to estrogen in the intestinal lumen. So the estrogen/testosterone ratio is one of the mechanisms that has an effect on the prostate because the estrogen level is also involved in prostate growth (65,66). Similar mechanisms, especially estrogen plasmatic levels and their concentration in the prostate, seem to play a role in the effects on CP/CPPS. In 2004, De Rose et al. (37) evaluated the role of mepartricin in a placebo-controlled trial in patients with CP/CPPS. After a treatment duration of 60 days with 40 mg mepartricin per day, the results showed a significant symptom

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improvement for pain and quality of life, but not for urinary symptoms. This interesting and hopeful treatment option must be clarified in further studies. Bioflavonoids

Bioflavonoids like quercetin are natural polyphenols that could be found in different vegetables and red wine in high concentrations. Quercetin is a phytoestrogen with anti-inflammatory, antioxidant, and antihistaminic power. Because of its low side effects, it is well suited in all kinds of therapies. Shoskes et al. tested quercetin in a placebo-controlled trial in patients with category III chronic prostatitis (67). Quercetin was given over a period of four weeks in a dose of 500 mg twice daily. The results showed a significant symptom improvement in more than 60% of the patients and was well tolerated. Non-pharmaceutical Treatment A broad spectrum of alternative, non-pharmaceutical treatment options for CP/CPPS has been described in the past, especially different kinds of thermotherapy. Due to the lack of evidence data, a general recommendation for these treatment options is not possible. In cases of refractory, long-standing symptoms, alternative treatments may be considered. Transurethral Microwave Thermotherapy

Nickel and Sorensen (41) showed in their sham-controlled study the benefit in patients with CP/CPPS. Temperatures O458C in the prostate, induced through transurethral microwave therapy, should have an anti-inflammatory effect on prostatitis patients type NIH III A. In patients of category NIH III B, temperatures !458C should be sufficient to improve symptoms (63). Urethroanal Electrostimulation

A new technique is the urethroanal high frequency electrostimulation which was tested in CP/CPPS patients by John and associates (39). A special urethroanal stimulation device was applied twice weekly for 30 minutes during five weeks, with a voltage of 6 V and a variable selfregulated current of between 1 and 10 mA. The results of this noncontrolled study demonstrated an improvement in pain and urinary symptoms. Further sham-controlled trials are necessary to give a recommendation. Electromagnetic Therapy and Biofeedback

In the past, it has been proposed that symptoms of CP/CPPS may be due to or associated with pelvic floor muscle abnormalities (68). A recent study confirmed that men with CPPS have more abnormal pelvic floor muscular findings compared with healthy controls and that these abnormalities contribute to CPPS (69). This is the starting point for biofeedback therapy and electromagnetic stimulation of the pelvic floor. Rowe et al. hypothesized that the application of electromagnetic therapy may have a neuromodulating effect on pelvic floor spasm and neural hypersensitivity (40). In a placebo-controlled double-blind study, they applied to patients with CP/CPPS active electromagnetic pelvic floor stimulation at 10 to 50 Hz twice weekly for four weeks. The results showed the greatest improvement in pain-related symptoms after four weeks (40). Biofeedback as a further option has a similar target in the treatment of CP/ CPP symptoms. Biofeedback is a training technique that enables an individual to gain voluntary control over autonomic body functions (70). Cornel and associates used the biofeedback training in patients with CPPS and demonstrated significant improvement of symptoms (38). Transurethral Needle Ablation

Transurethral needle ablation (TUNA) means to heat the prostate tissue with a special transurethral device up to 908 to 1108 over a 5-minute period with the hypothesis of a “surgical alpha-blockade” and an effect on sensory nerves in the prostate. Some uncontrolled studies described positive symptom improvement in patients with CP/CPPS (71,72). One randomized sham-controlled study by Leskinen et al. (73) showed no significant benefit of the

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TUNA to the sham-treatment, so TUNA cannot be recommended as routine treatment for CP/CPPS. Prostatic Massage

Repetitive prostatic massage is considered a treatment option and was widely used before the introduction of antibiotics. The benefit should include a better draining of occluded ducts in the prostate, a reduction of inflammatory components and a better penetration of antibiotics (74). No current data exist to support the effectiveness of repetitive prostatic massage. Surgical Therapies If all pharmaceutical and non-pharmaceutical therapies fail, then some authors recommend a surgical therapy (TURP, etc.) in refractory CP/CPPS patients. But with a lack of controlled studies, a surgical treatment for CP/CPPS patients cannot be recommended at this time. CONCLUSIONS CP/CPPS is a poorly understood disease with a multifactorial genesis of mainly unknown etiology. Different mechanisms have been discussed in the past, e.g., uncommon bacterial infections, inflammation (4), urodynamic abnormalities (5) such as bladder neck obstruction (6), intraprostatic reflux (5), impaired detrusor contractility (7) and autoimmune trigger mechanisms (3). In our opinion, the main pathogenetic pathway seems to be a mechanical or functional subprostatic obstruction, changing the laminar urine flow and providing an intraprostatic reflux of different noxious substances into the prostate. The main symptom complexes are pain and micturition disorders. There is no “gold standard” for therapy. Many empirical therapies have been mentioned in the past. Today, only a few treatment options based on evidence-based studies can be discussed for the therapy of CP/CPPS in a scientific manner. In our hands, if the patient is diagnosed with CP/CPPS with evidence of inflammation and without therapy before, a trial with antibiotics (fluorchinolones) over six weeks will be started. If there is no symptomatic improvement after two to three weeks, therapy will be stopped. Modern uroselective alphablockers can be added for a period of about three months. We do not recommended this therapy for patients who already had a failed alpha-blocker therapy in the past. For us, another hopeful option for the future is mepartricin, an estrogen reuptake inhibitor, which may improve pain symptoms and quality of life, but larger studies are still needed. Furthermore, the phytotherapeutic agent Cerniltonw was effective in a recent study (75) on patients with NIH III A prostatitis. A combination with alpha-blockers can be considered. Until more evidence studies are available, the treatment of CP/CPPS has to be focused on symptomatic improvement. If the above-mentioned treatment options are not successful, then other noninvasive therapies can be used. In this context, all kind of therapies, combinations with analgetics and antidepressants, are possible. The symptomatic improvement of the patient is the goal. REFERENCES 1. Drach GW, Fair WR, Meares EW, et al. Classification of benign diseases associated with prostatic pain: prostatitis or prostadynia. J Urol 1978; 120:266. 2. Krieger JN, Nickel JC, Nyberg L, Jr. NIH consensus definition and classification of prostatitis. J Am Med Assoc 1999; 282:236–7. 3. Mehik A, Hellstro¨m P, Leskinen MJ. Mechanisms of pain in chronic pelvic pain syndrome. Influence of prostatic inflammation. World J Urol 2003; 21:90–4. 4. Krieger JN, Riley DE, Takahashi S. Chronic prostatitis: role of uncommon organisms. Eur Urol Suppl 2003; 2:19–22. 5. Barbalias GA, Meares EM, Sant GR. Prostadynia: clinical and urodynamic characteristics. J Urol 1983; 130:514–7. 6. Hruz P, Danuser HJ, Suder UE, et al. Noninflammatory chronic pelvic pain syndrome can be caused by bladder neck hypertrophy. Eur Urol 2003; 44:106–10.

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7. Barbalias GA. Why alpha-blockers in prostatitis? Eur Urol Suppl 2003; 2:27–9. 8. Bra¨hler E. Complaint complexes and psychosomatic aspects. In: Weidner W, Madsen P O, Schiefer HG, eds. Prostatitis—Ethiopathology, Diagnosis and Therapy. Berlin: Springer, 1994:40–8. 9. Weidner W, Schiefer HG, Krauss H, et al. Chronic prostatitis: a thorough search for etiologically involved microorganisms in 1,461 patients. Infection 1991; 19:119–25. 10. McNaughton Collins M, Stafford RS, O’Leary MP, et al. How common is prostatitis? A national survey of physician visits J Urol 1998; 159:1224–8. 11. Potts JM. Chronic pelvic pain syndrome: a non-prostatocentric perspective. World J Urol 2003; 21:54–6. 12. Nickel JC. Clinical evaluation of the patient presenting with prostatitis. Eur Urol Suppl 2003; 2:11–4. 13. Schaeffer AJ, Barbalias GA, Bjerklund Johansen TE, et al. Summary consensus statement: diagnosis and management of chronic prostatitis/chronic pelvic pain syndrome. Eur Urol 2003; 2(Suppl. 2):1–4. 14. Litwin MS, McNaughton Collins M, Fowler FJ, Jr., et al. The National Institutes of Health Chronic Prostatitis Symptom Index: development and validation of a new outcome measure. J Urol 1999; 162:369–75. 15. Schneider H, Diemer T, Hossain HM, et al. The 2001 Giessen Cohort Study on patients with prostatitis syndrome—an evaluation of inflammatory status and search for microorganisms 10 years after a first analysis. Andrologia 2003; 35:258–62. 16. Weidner W, Schiefer HG. Inflammatory disease of the prostate: frequency and pathogenesis. In: Garraway M, ed. Epidemiology of Prostate Disease. Berlin/Heidelberg/New York/Tokyo: Springer, 1995:85–93. 17. Bra¨hler E, Deinhart M, Weidner W. Krankheitsverlauf bei der chronischen Prostatitis-Eine 5-Jahres Katamnese. In: Bra¨hler E, Kupfer J. (Hrsg), Mann und Medizin. Go¨ttingen, Bern: Hogrefe-Verlag, 2001. 18. Naber KG. Antimicrobial treatment of bacterial prostatitis. Eur Urol Suppl 2003; 2:23–6. 19. Bjerklund Johanson TE, Gru¨neberg RN, Guibert J, et al. The role of antibiotics in the treatment of chronic prostatitis: a consensus statement. Eur Urol 1998; 34:457–66. 20. Weidner W, Schiefer HG, Bra¨hler E. Refractory chronic bacterial prostatitis: a reevaluation of ciprofloxacin treatment after a median follow-up of 30 months. J Urol 1991; 146:350–2. 21. Weidner W, Ludwig M, Bra¨hler E, et al. Outcome of antibiotic therapy with ciprofloxacin in chronic bacterial prostatitis. Drugs 1999; 58(Suppl. 2):103–6. 22. Naber KG. Antibiotic treatment of chronic bacterial prostatitis. In: Nickel JC, ed. Textbook of Prostatitis. Oxford: ISIS Medical Media Ltd, 1999:285–92. 23. Barbalias GA, Nikiforidis G, Liatsikos EN. Alpha-blockers for the treatment of chronic prostatitis in combination with antibiotics. J Urol 1998; 159:883–7. 24. Szoke I, Torok L, Dosa E, et al. The possible role of anaerobic bacteria in chronic prostatitis. Int J Androl 1998; 21:163–8. 25. Baert L, de Ridder D. Loco Antibiotics in Chronical Bacterial Prostatitis. Berlin/Heidelberg/New York/Tokyo: Springer, 1994. 191–6. 26. Mayersak JS. Transurethral ultrasonography directed intraprostatic injection of gentamycin–xylocaine in the management of the benign painful prostate syndrome. A report of a 5 year clinical study of 75 patients. Int Surg 1998; 83:347–9. 27. Jimenez Cruz JF, Boronat F, Gallego J. Treatment of chronic prostatitis: intraprostatic injection under echography control. J Urol 1998; 139:967–70. 28. Nickel JC, Downey J, Clark J, et al. Levofloxacin for chronic prostatitis/chronic pelvic pain syndrome in men: a randomized placebo-controlled multicenter trial. Urology 2003; 62:614–7. 29. Alexander RB, Propert KJ, Schaeffer AJ, et al. Ciprofloxacin or tamsulosin in men with chronic prostatitis/chronic pelvic pain syndrome: a randomized, double-blind trial. Ann Intern Med 2004; 141:581–9. 30. Nickel JC, Narayan P, McKay J, et al. Treatment of chronic prostatitis/chronic pelvic pain syndrome with tamsulosin: a randomized double blind trial. J Urol 2004; 171:1594–7. 31. Mehik A, Alas P, Nickel JC, et al. Alfuzosin treatment for chronic prostatitis/chronic pelvic pain syndrome: a prospective, randomized, double-blind, placebo-controlled, pilot study. Urology 2003; 62:425–9. 32. Cheah PY, Liong ML, Yuen KH, et al. Initial, long-term, and durable responses to terazosin, placebo, or other therapies for chronic prostatitis/chronic pelvic pain syndrome. Urology 2004; 64:881–6. 33. Lee RA, West RM, Wilson JD. The response to sertraline in men with chronic pelvic pain syndrome. Sex Transm Infect 2005; 81:147–9. 34. Nickel JC, Pontari M, Moon T, et al. A randomized, placebo controlled, multicenter study to evaluate the safety and efficacy of rofecoxib in the treatment of chronic nonbacterial prostatitis. J Urol 2003; 169:1401–5. 35. Nickel J, Forrest JB, Tomera K, et al. Pentosan polysulfate sodium therapy for men with chronic pelvic pain syndrome: a multicenter, randomized placebo controlled study. J Urol 2005; 173:1252–5.

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36. Nickel JC, Downey J, Pontari MA, et al. A randomized placebo-controlled multicentre study to evaluate the safety and efficacy of finasteride for male chronic pelvic pain syndrome (category IIIA chronic nonbacterial prostatitis). J Urol 2004; 93:991–5. 37. De Rose AF, Gallo F, Giglio M, et al. Role of mepartricin in category III chronic nonbacterial prostatitis/chronic pelvic pain syndrome: a randomized prospective placebo-controlled trial. Urology 2004; 63:13–6. 38. Cornel EB, van Haarst EP, Schaarsberg RW, et al. The effect of biofeedback physical therapy in men with Chronic Pelvic Pain Syndrome Type III. Eur Urol 2005; 47:607–11. 39. John H, Ruedi C, Kotting S, et al. A new high frequency electrostimulation device to treat chronic prostatitis. J Urol 2003; 170:1275–7. 40. Rowe E, Smit C, Laverick L, et al. A prospective, randomized, placebo controlled, double-blind study of pelvic electromagnetic therapy for the treatment of chronic pelvic pain syndrome with 1 year follow up. J Urol 2005; 173:2044–7. 41. Nickel JC, Sorensen R. Transurethral microwave thermotherapy for nonbacterial prostatitis: a randomized double-blind sham-controlled study using new prostatitis specific assessment questionnaires. J Urol 1996; 155:1950–5. 42. Krieger JN, Riley DE, Roberts MC, et al. Procaryotic DNA sequences in patients with chronic idiopathic prostatitis. J Clin Microbiol 1996; 34:3120–8. 43. Nickel JC, Downey J, Johnston B, et al. Predictors of patient response to antibiotic therapy for the chronic prostatitis/chronic pelvic pain syndrome: a prospective multicenter clinical trial. J Urol 2001; 165:1539–44. 44. Shoskes DA, Shaded AR. Detection of bacterial signal by 16srRNA polymerase chain reaction in expressed prostatic secretions predicts response to antibiotic therapy in men with chronic pelvic pain syndrome. Tech Urol 2000; 6:240–2. 45. Galley HF, Nelson SJ, Dubbles AM, et al. Effect of ciprofloxacin on the accumulation of interleukin-6, interleukin-8 and nitrite from human endothelial cell model of sepsis. Crit Care Med 1997; 25:1392–5. 46. Yoshimura T, Kurita C, Usami E, et al. Immunmodulatory action of levofloxacin on cytokine production by human peripheral blood mononuclear cells. Chemotherapy 1996; 42:459–64. 47. Hochreiter WW, Nadler RB, Koch AE, et al. Diagnostic value of serial cytokine changes in expressed prostatic secretions. J Urol 2000; 163(Suppl. 4):24 (Abstract). 48. Lobel B, Rodriguez A. Chronic prostatitis: what we know, what we do not know, and what we should do!. World J Urol 2003; 21:57–63. 49. Meares EM, Barbalias GA. Clinical and video-urodynamic findings in prostatodynia. Semin Urol 1983; 1:146. 50. De la Rosette JJ, Karthaus HF, van Kerrebroeck PE, et al. Research in prostatitis syndrome: the use of alfuzosin (a new alpha 1-recptor-blocking agent) in patients mainly presenting with micturition complaints of an irritative nature and confirmed urodynamic abnormalities. Eur Urol 1992; 22:222. 51. Neal DE, Moon TD. Use of terazosin in prostatodynia and validation of a symptom score questionnaire. Urology 1993; 43:460–5. 52. Weidner W. Treating chronic prostatitis: antibiotics no, alpha-blockers may be? Ann Intern Med 2004; 141:639–40 (editorial). 53. Berghuis JP, Heiman JR, Rothman I, et al. Psychological and physical factors involved in chronic prostatitis. J Psychosom Res 1996; 41:313–25. 54. Keltikangas-Ja¨rvinen L, Ja¨rvinen H, Lehtonen T. Psychic disturbances in patients with chronic prostatitis. Ann Clin Res 1981; 13:45–9. 55. Hanno PM. Amitriptyline in the treatment of interstitial cystitis. Urol Clin North Am 1994; 21:89–92. 56. Turkington D, Grant JB, Ferrier IN, et al. A randomized controlled trial of fluvoxamine in prostatodynia, a male somatoform pain disorder. J Clin Psychiatry 2002; 63:778–81. 57. Bach D, Walker H. How important are prostaglandins in the prostate and kidney in man. Urol Int 1982; 237:160–71. 58. Canale D, Scaricabarozzi I, Giorgi P, et al. Use of novel non-steroidal anti-inflammatory drug nimesulide, in the treatment of abacterial prostatovesiculitis. Andrologia 1993; 25:163–6. 59. Persson BE, Ronquist G, Ekblom M. Ameliorative effect of allopurinol on nonbacterial prostatitis: a parallel double-blind controlled study. J Urol 1996; 155:961–4. 60. Pontari MA. Inflammation and anti-inflammatory therapy in chronic prostatitis. Urology 2002; 60:29–34. 61. Boyle P, Gould AL, Roehrborn CG. Prostate volume predicts outcome of treatment of benign prostatic hyperplasia with finasteride: meta-analysis of randomized clinical trials. Urology 1996; 48:398–405. 62. Tammela TLJ, Kontturi MJ. Urodynamic effects of finasteride in the treatment of bladder outlet obstruction due to benign prostatic hyperplasia. J Urol 1993; 149:342–4. 63. Nickel JC. Effective office management of chronic prostatitis. Urol Clin North Am 1998; 25:677–84. 64. Holm M, Meyhoff HH. Chronic prostatic pain: a new treatment option with finasteride? Scand J Urol Nephrol 1996; 31:213–5.

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65. Re G, Badino P, Odore R, et al. Effects of mepartricin on estradiol and testosterone serum levels an on prostatic estrogen, androgen and adrenergic receptor concentrations in adults rats. Pharmacol Res 2001; 44:141–7. 66. Denis L, Pagano F, Nonis A, et al. Double-blind, placebo controlled trial to assess the efficacy and tolerability of mepartricin in the treatment of BPH. Prostate 1998; 37:246–52. 67. Shoskes DA, Zeitlin SI, Shaded A, et al. Quercetin in men with category III chronic prostatitis: a preliminary prospective, double-blind, placebo-controlled trial. Urology 1999; 54:960–3. 68. Segura JW, Opitz JL, Greene LF. Prostatosis, prostatitis or pelvic floor tension myalgia? J Urol 1979; 122:168. 69. Hetrick DC, Ciol MA, Rothman I, et al. Musculoskeletal dysfunction in men with chronic pelvic pain syndrome type III: a case-control study. J Urol 2003; 170:828–31. 70. Potts JM. Alternative approaches to the management of prostatitis: biofeedback, progressive relaxation and the concept of functional somatic syndromes. Eur Urol 2003; 2(Suppl. 2):34–7. 71. Lee KC, Jung PB, Park HS, et al. Transurethral needle ablation for chronic nonbacterial prostatitis. BJU Int 2002; 89:226–9. 72. Chiang PH, Chiang CP. Therapeutic effect of transurethral needle ablation in non-bacterial prostatitis: chronic pelvic pain syndrome type III A. Int J Urol 2004; 11:97–102. 73. Leskinen MJ, Kilponen A, Lukkarinen O, et al. Transurethral needle ablation for the treatment of chronic pelvic pain syndrome (category III prostatitis): a randomized, sham-controlled study. Urology 2002; 60:300–4. 74. Hennenfent BR, Feliciano AE. Changes in white blood cell counts in men undergoing three-weekly prostatic massage, microbial diagnosis, and anti-microbial therapy for genitourinary complaints. Br J Urol 1998; 81:370. 75. Schneider H, Ludwig M, Weidner W, et al. The efficacy of Cerniltonw in patients with chronic pelvic pain syndrome (CP/CPPS) type NIH IIIa: a randomized, prospective, double-blind, placebo controlled study. In: AUA Annual Meeting 2006 (abstract 105). 76. Meares EM, Stamey TA. Bacteriologic localisation patterns in bacterial prostatitis and urethritris. Invest Urol 1968; 5:492–518. 77. Weidner W, Ludwig M. Common organisms in urogenital infections with special impact on prostatitis. Eur Urol Suppl 2003; 2:15–8.

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Scrotal Pain Conditions P. Granitsioti

Urology Department, Southern General Hospital, Glasgow, U.K.

INTRODUCTION Chronic pain syndromes of the urological area are often frustrating for the patients and their physicians. They can be disabling and for many patients are associated with anxiety about cancer. More often, despite extensive investigations, no etiology is found. The controversy that surrounds these syndromes ranges from questioning their existence to suggesting that they are of psychosomatic origin. The first important step for patients suffering from these pain syndromes is to find a physician who actually knows that these pain syndromes exist. For the patient, the desired goal of treatment is returning to routine activity. DEFINITIONS In the report from the Standardization Subcommittee of the International Continence Society (2002) (1) genitourinary pain syndromes are descriptions of constellations or combinations of symptoms but cannot be used for precise diagnosis. The use of the word syndrome can only be justified if there is at least one other symptom in addition to the symptom used to describe the syndrome. Genitourinary pain syndromes are all chronic in their nature. Pain is the major complaint but concomitant complaints are of lower urinary tract symptoms (LUTS) or bowel or sexual symptoms. Scrotal pain syndrome is the occurrence of persistent or recurrent episodic scrotal pain which is associated with symptoms suggestive of urinary tract or sexual dysfunction. There is no proven epididymoorchitis or other obvious pathology. Scrotal pain may or may not be localized, e.g., to the testis, epididymis, cord structures, or scrotal skin. The pain has to have lasted for a minimum of six months to qualify as chronic scrotal pain (2). It is presumed that routine assessment (history taking, physical examination, and other appropriate investigation) has excluded obvious local pathologies such as infective, neoplastic, metabolic, or hormonal sources. INCIDENCE The true incidence of scrotal pain is not known. As there are no published epidemiological studies, the prevalence of scrotal pain is not known. Urologists in general urological practice have long recognized the significant prevalence of men with chronic scrotal pain but there has never been a comprehensive study of this condition(s). There is evidence in the literature that the prevalence of neurogenic-origin pain in the U.K. population is 1% (3), but the only statistical information we have available is related to the prevalence of chronic testicular pain following vasectomy (4). Davies reported 45 patients who were seen in consultation between May 1980 and April 1989 for chronic unilateral or bilateral “orchialgia” defined as intermittent or constant testicular pain three months or longer in duration that interferes with the daily activities. Ahmed and colleagues conducted a retrospective postal survey of 560 patients (mean age 36 years, range 25–55; mean time since vasectomy 19 months, range 8–39) who underwent vasectomy between July 1992 and December 1994, to determine the incidence of chronic

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testicular pain (CPT) (5). Of 396 replies, 108 (27.2%) patients complained of some testicular pain following their vasectomy operation. In 88 (82%) out of these 108 patients, the pain was brief and was not defined as CPTP, while 20 (19%) patients had pain for greater than three months and 33 (31%) patients required analgesics to control the pain. Only 17 patients required surgical intervention in the form of spermatic cord denervation. Other studies by McMahon et al. (6) showed a similar incidence of chronic testicular pain postvasectomy.

ANATOMY Classical anatomical studies reveal that the scrotum has a complex pattern of innervation. The main nerve supply of the scrotum arises from the perineal nerve, a branch of the femoral cutaneous nerve. A small contribution also arises from the inferior pudendal branch of the femoral cutaneous nerve. Finally the anterior and lateral aspects of the scrotum receive contributions mainly from the genital branch of the genitofemoral nerve and the anterior cutaneous branches of the iliohypogastric and ilioinguinal nerves (Table 1). This classic text description of the distribution and terminal course of the ilioinguinal and genitofemoral nerve was present in only 20% of cadaver dissection in a study performed by Yucel and Baskin. One of the main sensory nerves of the genital area, the genitofemoral nerve, has been reported to be missing in almost a third of the human cadavers. Also in the same study the sensory branch of the ilioinguinal nerve was absent in 40% of patients (7). The interscrotal septum has a pivotal role in scrotal sensation as it carries a high density of scrotal nerves. In many scrotal surgical techniques the interscrotal septum is violated. After scrotal surgery, de novo scrotal pain, and abnormalities of sensation are not uncommon. In light of these anatomical findings a probable explanation may be the disturbance of the nerves traveling in the septum. Scrotal nerves arising from the perineal branch of the pudendal nerve may be the neural pathway responsible in the mechanism of unexplained scrotal pain. The crucial point of the scrotal innervation is the penoscrotal junction. Some surgical approaches violate this junction. Avoiding the 5 and 7 o’clock position at the base of the penoscrotal junction is important to preserve the neural structures supplying the scrotum. The horizontal distribution of the scrotal nerves originates from the midline septum. The position of the surgical incisions in the scrotum should take into account this anatomical finding. Horizontal incisions on each hemiscrotum and preservation of the interscrotal septum are critical so as not to harm the neural structure of the scrotum.

TABLE 1 Referred Scrotal Pain Of urological origin Ureteric pathology Prostatitis Pelvic ureteric junction obstruction As a complication of Laparoscopic donor nephrectomy Of musculoskeletal origin Hip pain Intervertebral disc prolapse Tendonitis at the insertion of the inguinal ligament Entrapment neuropathies Gluteal fibrositis Other Aneurysm of the aorta/common iliac artery Diabetic neuropathy Antidepressive medications Hyperuricemia Self-palpation

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Sensory Innervation of the Testis and Epididymis Pain originating in the testis and epididymis is mediated by autonomic and somatic fibers that accompany the internal spermatic vessels. These fibers are then carried in the genital branch of the genitofemoral nerve and the ilioinguinal nerve. The autonomic supply from the testis is distributed to the presacral ganglia of the T10 to T12 segments, while from the epididymis the fibers are distinct and are distributed to the T10–L1 segments. The somatic fibers from the parietal and visceral layers of the tunica vaginalis and cremaster are carried by the genital branch of the genitofemoral nerve to L1,2. Other somatic nerve endings apparently are carried from the tunica vaginalis and scrotal skin by the posterior scrotal nerve S2,3 (8). The testis shares its innervation with the caput and corpus portion of the epididymis receiving its main innervation from the superior spermatic plexus via nerve fibers accompanying the internal spermatic vessels with contributions from the inferior spermatic plexus, superior hypogastric plexus, and other sympathetic chain ganglia. The parietal and visceral layers of the tunica vaginalis and the cremaster receive afferent innervation originating at L1–L2, carried by the genital branch of the genitofemoral nerve (9). Any organ that shares the same nerve pathway with the scrotal contents can present with pain in this region. DIAGNOSTICS Chronic scrotal pain syndromes occur at any age but the majority of the patients are in their mid to late thirties (9). The pain can be unilateral or bilateral, constant or intermittent, spontaneous or exacerbated by physical activities and pressure. It can remain localized in the scrotum or radiate to the groin, perineum, back, or legs. Furthermore a history of vasectomy, psychosomatic disorders, chronic prostatitis, neuromuscular disorders, or a history of inguinal surgery might be obtained from these patients. The complaint is of a squeezing deep ache in the testis like the day after you got kicked there, often bilateral or alternating from one side to the other, intermittent, and most commonly associated with low back pain. Sometimes it feels like the testicle is pinched in the crotch of the underwear but trouser readjustment does not help. There may also be pain in the inguinal area but no nausea or other symptoms. Back pain may be concurrent or absent and some patients have a long history of low back pain. Onset of pain is commonly related to activity that would stress the low back such as lifting heavy objects. Other stresses that might cause low back pain are imaginative coital positions, jogging, sitting hunched over a computer, long car driving, or other such positions of unsupported seating posture that flatten the normal lumbar lordosis curve (8). On clinical examination the testis may be tender but in the majority of patients is otherwise unremarkable. Additional laboratory and radiological investigations aim to exclude significant intratesticular pathology. In a postal questionnaire focusing on diagnostics and treatment practices for the management of chronic scrotal pain, among the members of the Swiss Society of Urology the most commonly used examinations are urinalysis in 96% and ultrasound in 93%. Additional assessments include blood sampling, duplex ultrasound, assessment for coexisting chronic prostatitis, and referral to an orthopedic surgeon, rheumatologist, or psychiatrist (10). In a prospective urology outpatient audit that was carried out in a representative sample of Canadian urologists, the most common investigations used to investigate chronic scrotal pain of possible epididymal origin were urinalysis, urine cultures, cystoscopy, ultrasound, and urodynamics (Table 2) (11). Scrotal ultrasound scanning is accepted today as a routine and possibly mandatory investigation of the patient presenting with scrotal symptoms. In a retrospective study of 160 patients appearing for scrotal ultrasound over a period of one year, Lau et al. concluded that all clinically significant abnormalities were identified on clinical examination (12). Clinically insignificant lesions identified by ultrasound alone did not affect the clinical management. The only real benefit of the scrotal ultrasound is to reassure the patient who is worried about cancer.

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TABLE 2 Definition and Classification of Chronic Epididymitis Inflammatory chronic epididymitis Obstructive chronic epididymitis Chronic epididymalgia Source: Adapted from Ref. 11.

Test cord block with saline as placebo, and local anesthetics are used in some occasions prior to offering surgical intervention, and has been advocated by all surgeons prior to embarking on microsurgical testicular denervation as a treatment modality in men with chronic testicular pain (13–15). There are no characteristic histopathological features reported. ETIOLOGY Referred Pain Any organ that shares the same nerve pathway with the scrotal contents can be present with pain in the region. Pain arising in the ureteran, hip, intervertebral disc prolapse, and entrapment neuropathies of the ilioinguinal or genitofemoral nerve, often due to inguinal hernias, or following their repair, are some of the secondary causes of chronic scrotal pain. Groin disruption as “Gilmore’s groin” can be confused with urological pain, most commonly with chronic prostatitis and chronic testicular pain (16). Tendonitis at the insertion of the inguinal ligament into the pubic tubercle may cause testis pain (4). Injection of the tubercle and ligament with lidocaine and steroids is usually helpful. Gluteal fibrositis, which causes a distinct tender nodule just lateral to the posterior superior iliac spine can produce pain. Pressure at this point will reproduce the pain and infiltration with local anesthetic will temporarily relieve it (17). A small indirect inguinal hernia may irritate the genital branch of the genitofemoral nerve. Pelvic-ureteric junction obstruction, with the intermittent hydronephrosis, caused referred testis pain, and the pain was relieved after pyeloplasty (18). Aneurysm of the common iliac artery or aorta has been reported to cause testis pain by involving the genital branch of the genitofemoral nerve (19). Chronic ipsilateral testicular pain has been reported as a complication of laparoscopic donor nephrectomy. The etiology remains unclear but may be injury to the sensory nerves of the testicle during dissection of the periureteral tissue or transection of the spermatic cord (20). Chronic testicular pain has been recognized as an underreported feature of diabetic neuropathy and even after withdrawal from imipramine used as antidepressant treatment (21,22). In patients with hyperuricemia and chronic testicular pain, the hypothesis of an intracanalicular deposit of uric acid crystals and/or resulting alteration in nerve endings has been suggested (23); a case report of testicular angina has been also reordered as well as pain due to “self-palpation” orchitis (24). It has also been suggested that wearing tight undergarments can be a cause of chronic testicular pain, too. Some patients attribute the start of their chronic testicular pain to some form of injury. This could be explained by the phenomenon of neural plasticity. In neural plasticity, disease, or injury may result in changes at all levels of the nervous system, so pain messages are amplified. Another explanation of post-injury/surgery chronic pain syndromes is the development of sprouting between axons. This can occur either at the level of the dorsal root ganglion or at the dorsal horn. This results in light touch stimuli being rerouted into pain pathways and felt as pain by the patient. There is a close clinical and diagnostic association of chronic epididymitis and chronic testicular pain. In a small case control study by Nickel et al. chronic epididymitis was defined as “symptoms of discomfort and/or pain at least three months in duration in the scrotum, testicle, or epididymis, localized to one or each epididymis on clinical examination.” The condition

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seems to impact significantly on patient quality of life. Patients with chronic epididymal pain appear to have many more general self-reported musculoskeletal, neurological, and infectious/ inflammatory medical problems. Depression seems to be a major problem in patients with chronic epididymitis. Nickel has proposed a classification system for chronic epididymitis according to its possible etiology. Chronic epididymitis can be classified in one out of three categories, namely inflammatory, obstructive, and chronic epididymal pain. The pain of inflammatory chronic epididymitis is associated with abnormal swelling or induration. Obstruction of the epididymis or vas deferens may result in pain/discomfort while there is no identifiable etiology in patients with chronic epididymal pain (11). There is more controversy in the relation of scrotal cystic lesion to the development of scrotal pain. Epididymal cyst is a common finding. In one of the recent series, epididymal cysts were a finding in 241 out of 1000 patients undergoing ultrasonography as a part of the testicular assessment. Large, clinically obvious cysts are usually painless, and surgical excision will not relieve the pain. However, in some men with testicular pain, careful examination will reveal a small cyst, compression of which reproduces symptoms. There have been anecdotal accounts of symptom relief following aspiration of such small, painful epididymal cysts, but no published series. Small epididymal cysts may be overlooked both on clinical examination and on ultrasound. In this series three of the smaller, but palpable cysts, were not recognized at ultrasound examination (unpublished data). Epididymal cysts and spermatoceles have a fibromuscular wall with cubical epithelium. Bacteriological studies suggest that the fluid within spermatoceles and epididymal cysts does not become infected under normal circumstances. In the symptomatic cyst it has been found that the level of interleukin 6, interleukin 8, and tumor necrosis factor alpha is high. These findings indicate that the local production of proinflammatory cytokines is involved in cyst formation (25). Thus, if any of the above cytokines are present in the epididymal cysts, fluid removal from cysts might be helpful. In the series of 1000 patients reported, following ultrasonographic assessment seven had intratesticular cysts. These cysts could be of infective or traumatic origin but the majority of them are of unknown etiology. There have been reports of chronic scrotal pain responding to enucleation of simple intratesticular cysts (26). Another rare cause of testicular pain is intratesticular varicosities, detected on scrotal ultrasonography, and duplex spectral analysis. Varicocele is a cause of pain in 2% to 14% of men suffering chronic scrotal pain (27). Urologists, who treat patients whose jobs require working in the standing position, or require heavy physical activity, often encounter patients with painful varicoceles.

The Role of Depression In a large series looking into satisfaction of patients who underwent vasectomy for contraception a 1% incidence of psychosexual problems, including depression, was reported (28). Although it is recognized that psychological symptoms co-occur with testicular pain, there is no investigation into the relative importance of psychological parameters in the development and maintenance of chronic testicular pain. Schover et al. in 1990 reported that a significant number of patients that suffer from testicular pain express signs of major depression and a number of these patients have chemical dependency (29). Studies on the psychological long-term effects of sterilization among 2000 cases in China showed that sterilization psychologically affected the depressive symptoms and anxiety under the neutral personality. Evidence exists to suggest that depression and chronic pain syndromes share common biologic pathways, namely, the serotogenic and noradrenergic systems. Chronic pain patients who are depressed require aggressive full dose treatment with antidepressants.

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Postvasectomy Chronic Pain Syndrome A number of authors report a small number of patients treated surgically for postvasectomy pain suggesting that vasovasostomy or vasoepididymostomy can give a successful outcome on an average of 60% to 70% of these patients. This, along with the evidence of pain during ejaculation as a presenting symptom in the postvasectomy pain group of patients, suggests that obstruction or congestion of the vas or in the epididymis may be the cause of the pain. Congestive epididymitis presents as pain and testicular tenderness on the affected side. Generally the occurrence of epididymitis is uncommon and is reported in 0.4% to 6.1% of vasectomies. Congestive epididymitis can occur sooner or later after vasectomy and linger. Typically it lasts weeks to months and it is extremely rare for it to last greater than one year. It is usually treated with analgesics and antibiotics. Congestive epididymitis has been attributed to pressure within the epididymis from sperm production in the presence of an occluded outlet. The term “epididymitis” might be a misnomer, because the condition is thought to result from mechanical pressure rather than from an inflammatory process. In one large series the frequency of congestive epididymitis with closed-ended vasectomy was reported to be higher than with open ended vasectomy (6% vs. 2%). Even in closed end vasectomy, the incidence varies according to the method of occlusion (30). Among the reported long-term complications of vasectomy is a syndrome of chronic noninfectious epididymal pain and induration, beginning months to years after vasectomy. This syndrome has been attributed to long standing obstruction with dilatation of the epididymal ducts, extravasation of sperm, and sperm granulomas with an inflammatory reaction. The syndrome appears to be quite rare and the attribution to vasectomy is based on case reports. Several investigators have discussed the probable effect of vasectomy on intratubular pressure in the testis and epididymis (31). It has been shown in rodents that in physiological conditions, intratubular hydrostatic pressure in seminiferous tubules is significantly lower than the pressure in the caput epididymis. Pressure in the caput is higher than the pressures in both small and large caudal tubules and the pressure in the epididymal vas. In the same animals two weeks after vasectomy, pressure in the caudal tubules, and epididymal vas were significantly higher. In man the intravasal pressure from the distal stump did not differ from normal prevasectomy values, but the pressure in the proximal segment showed a significant increase. It has been shown that the electric signals which propagate caudally along the vas deferens are interrupted by vasectomy and therefore may cause a functional obstruction pattern (32). Infiltration of the vas deferens with a local anesthetic such as bupivacaine prior to its division/ligation, may reduce both immediate, and long-term postvasectomy pain. In a small randomized study, it was found that the visual analogue scores of patients who had their vas infiltrated with 1 mL bupivacaine 0.5% prior to vas division and ligation, immediately and one year after vasectomy, were significantly lower than those of patients who had their vas infiltrated with local anesthetic after the vas had been divided and ligated. The formation of spermatic granuloma postvasectomy has been well documented but its protective or causative role in the postvasectomy testicular pain has been controversial (33). It has been suggested that the formation of a sperm granuloma at the vasectomy site allows decompression of the vas and epididymis without causing discomfort to the patient. On the contrary, during a 10-year postvasectomy follow-up of 505 patients the incidence of testicular pain was somewhat higher in patients who did not have a sperm granuloma at the vasectomy site. These findings suggest that an open ended vasectomy procedure could reduce the incidence of the postvasectomy pain but possibly at the price of a higher incidence of recanalization, hampering acceptance of the open-ended technique (34). A contradictory report suggested that the sperm granulomas at the vasectomy site were intensely painful in 40% of cases (35). It has recently been suggested that patients with suture granuloma, nerve proliferation, and fibrosis develop chronic scrotal pain which does not respond well in vasovasostomy, and patients with sperm granuloma but no nerve proliferation have a higher chance to remain pain free following vasovasostomy (36).

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The Role of Adrenergic Receptors Evidence for the importance of the adrenergic innervation of the vas deferens comes from studies of the human vas innervation and its vesicoelastic properties pre- and postvasectomy. It has been shown that the vas segment proximal and distal to the vasectomy site has increased rigidity but without reduction of the active force of contraction. A reduction has been also found in the cholinergic and possibly in the nonadrenergic–noncholinergic neurotransmitters of the postvasectomy vas stumps (37). Evidence for the importance of the post-junctional adrenergic receptors in the vas deferens comes from experimental work in the rat vas deferens, which has been used as a prototype for the study of the sympathetic nervous system path physiology. In an attempt to determine any changes in the sympathetic activity as a result of stress, rat vas deferens was used in a model of stress. A reduction in post-junctional a-adrenergic receptor sensitivity has been found. Data support the hypothesis that an activated sympathetic reflux is produced by the testis under stress. Stress causes a1-receptor mediated contraction of smooth muscle in the vas deferens and epididymis that results in pain. There is also very limited experimental evidence to suggest that the vas deferens of subjects who present with intractable chronic testicular pain, exhibits a reduction in the prejunctional auto inhibition mechanism in comparison to males who undergo vasectomy for family planning reasons (38,39). NONSURGICAL TREATMENT Surgery is to be avoided if possible. Even if infection has not been identified a small number of patients may respond to a combination of antibiotics and nonsteroidal anti-inflammatory drugs. The chronic scrotal pain can be helped by medications used to treat neuropathic pain syndromes. Therefore, the use of antidepressants (e.g., amitriptyline) and anticonvulsants (e.g., gabapentin) comes from their successful use in the neuropathic pain, not from their use in chronic pelvic/scrotal pain literature. It is important to use an adequate dose of the antidepressant or anticonvulsant therapy. Often the use of combination treatment is necessary. Those with intractable symptoms may benefit from a multidisciplinary team approach. Multidisciplinary health care necessitates tools that function across professional boundaries and that can handle differences in perspectives. The evidence of the efficacy of the multidisciplinary team’s approach is extrapolated from evidence of the same/similar approach in the treatment of chronic pelvic pain syndromes in female patients. Trigger point injections, transcutaneous electrical nerve stimulation analgesia and relaxation techniques, i.e., yoga, have been tried with good results (40). A spermatic cord blockade with a mixture of 1% lignocaine without adrenaline and 1 mL methylprednisolone can be performed on an outpatient basis and can be repeated if successful. Transrectal injections of local anesthetic (1% lidocaine) and 40 mg methylprednisolone into the region of the pelvic plexus, under the guidance of transrectal ultrasound, have been used and achieved partial pain relief. Other nonsurgical treatments with early promising results include pulsed radio frequency of the nerves innervating the area, biofeedback, and administration of a-adrenergic antagonists (41,42). SURGICAL TREATMENT For patients in whom all conservative treatments have failed and pain continues to impair their quality of life, surgical intervention may be considered. Levine et al. evaluated the results of microsurgical denervation of the spermatic cord in 27 patients with normal physical examination and negative scrotal ultrasound who had temporary relief after undergoing outpatients cord block. Complete pain relief was achieved in 76% and partial relief of their pain in 9.1%: the technique described involved division of the ilioinguinal nerve and its branches. The proximal end of the ilioinguinal nerve was buried under the external oblique fascia to reduce the likelihood of neuronal formation. Using the operative microscope, all fascia and cremaster fibers were divided. The proximal end of the vas

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was also divided even if the patient had previously undergone vasectomy, to eradicate sympathetic innervation which may contribute to a reflex sympathetic dystrophy (13). This procedure can be challenging in the presence of previous regional surgery. Heidenreich et al. also reported on microsurgical testicular denervation as a therapeutic option in patients with chronic testicular pain. After a median follow up of 20.6 months 11 out of 12 patients were pain free. No intra- or postoperative complications were reported (14). Cadedu et al. achieved a 71% mean reduction on the preoperative pain score in nine patients undergoing laparoscopic testicular denervation. The gonadal vessels were isolated circumferentially and divided cephalic to the vas deferens and its aviculture. No testicular atrophy was noted (15). The high success rate of these techniques could possibly be attributed to the selection of suitable patients. The recommended surgical treatment for chronic neuropathic pain after herniorrhaphy has been a two-stage operation including: (i) ilioinguinal and iliohypogastric neurectomies through an inguinal approach and (ii) genital nerve neurectomy through a flank approach. Amid reported a technique where simultaneous neurectomy of the ilioinguinal, iliohypogastric, and genital nerves without mobilization of the spermatic cord is performed with equally good results. It can be performed under local anesthesia and avoids testicular complications. Proximal end implantation of the nerves prevents adherence of the cut ends to the aponeurotic structures of the groin, which can result in recurrence of the pain (43). Epididymectomy There are contradictory reports of the response to epididymectomy. Padmore et al. reported that only 43% of patients who underwent epididymectomy for pain were satisfied with the results in comparison to 92% satisfaction of patients who underwent epididymectomy in the presence of epididymal cysts (44). The patient has to be counseled regarding the likelihood of poor outcome prior to undertaking the procedure. However, West et al. assessed the long-term outcome of 19 patients who underwent epididymectomies for chronic scrotal pain; only 14 patients had a good response. It was suggested that the presence of chronic inflammatory changes in the histological specimen is a predictor of poor outcome. Naglia et al., reported resolution of chronic postvasectomy pain in 69% of patients who underwent vasovasostomy. A small number of patients who fail to respond to medical or more invasive treatment will undergo orchiectomy. There is evidence in the literature that the inguinal approach gives superior results if compared to the scrotal approach and therefore inguinal orchiectomy is considered the procedure of choice (4). It is emphasized that orchiectomy should be the last resort and clearly compromises the situation if the patient should subsequently develop symptoms on the contralateral side. Finally the complex nature of the chronic scrotal pain is highlighted by the few patients who will continue to complain bitterly about scrotal pain even after they had undergone orchiectomy (phantom orchialgia). CONCLUSION Chronic scrotal pain syndromes remain a challenging entity. Further clinical and basic science research is required. It is, though, clear that patients with this spectrum of conditions are better served by a multidisciplinary approach. REFERENCES 1. Abrams P, Cardozo L, Fall M, et al. The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society. Am J Obstet Gynecol 2002; 187(1):116–26. 2. Fall M, Baranowski AP, Fowler CJ, et al. EAU guidelines on chronic pelvic pain. Eur Urol 2004; 46(6):681–9.

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3. Bowsher D. Neurogenic pain syndromes and their management. Br Med Bull 1991; 47(3):644–66. 4. Davis BE, Noble MJ, Weigel JW, Foret JD, Mebust WK. Analysis and management of chronic testicular pain. J Urol 1990; 143(5):936–9. 5. Ahmed I, Rasheed S, White C, Shaikh NA. The incidence of post-vasectomy chronic testicular pain and the role of nerve stripping (denervation) of the spermatic cord in its management. Br J Urol 1997; 79(2):269–70. 6. McMahon AJ, Buckley J, Taylor A, Lloyd SN, Deane RF, Kirk D. Chronic testicular pain following vasectomy. Br J Urol 1992; 69(2):188–91. 7. Yucel S, Baskin LS. The neuroanatomy of the human scrotum: surgical ramifications. BJU Int 2003; 91(4):393–7. 8. Holland JM, Feldman JL, Gilbert HC. Phantom orchialgia. J Urol 1994; 152(6 Pt 2):2291–3. 9. Wesselmann U, Burnett AL, Heinberg LJ. The urogenital and rectal pain syndromes. Pain 1997; 73(3):269–94. 10. Strebel RT, Leippold T, Luginbuehl T, Muentener M, Praz V, Hauri D. Chronic scrotal pain syndrome: management among urologists in Switzerland. Eur Urol 2005; 47(6):812–6. 11. Nickel JC, Siemens DR, Nickel KR, Downey J. The patient with chronic epididymitis: characterization of an enigmatic syndrome. J Urol 2002; 167(4):1701–4. 12. Lau MW, Taylor PM, Payne SR. The indications for scrotal ultrasound. Br J Radiol 1999; 72(861):833–7. 13. Levine LA, Matkov TG. Microsurgical denervation of the spermatic cord as primary surgical treatment of chronic orchialgia. J Urol 2001; 165(6 Pt 1):1927–9. 14. Heidenreich A, Zumbe J, Martinez F, Grozinger K, Engelmann UH. Microsurgical testicular denervation as therapy option in chronic testalgia. Urologe A 1997; 36(2):177–80. 15. Cadeddu JA, Bishoff JT, Chan DY, Moore RG, Kavoussi LR, Jarrett TW. Laparoscopic testicular denervation for chronic orchialgia. J Urol 1999; 162(3 Pt 1):733–5 (discussion 735–6). 16. Fon LJ, Spence RA. Sportsman’s hernia. Br J Surg 2000; 87(5):545–52. 17. Yeates WK. Pain in the scrotum. Br J Hosp Med 1985; 33(2):101–4. 18. Goldberg SD, Witchell SJ. Right testicular pain: unusual presentation of obstruction of the ureteropelvic junction. Can J Surg 1988; 31(4):246–7. 19. Ali MS. Testicular pain in a patient with aneurysm of the common iliac artery. Br J Urol 1983; 55(4):447–8. 20. Kim FJ, Pinto P, Su LM, et al. Ipsilateral orchialgia after laparoscopic donor nephrectomy. J Endourol 2003; 17(6):405–9. 21. Campbell IW, Ewing DJ, Clarke BF, Duncan LJ. Testicular pain sensation in diabetic autonomic neuropathy. Br Med J 1974; 2(920):638–9. 22. Perera M, Khan MA. Testicular pain and swelling on withdrawal of imipramine. Br J Psychiatry 1998; 173:268. 23. Lopez Laur JD, Chiapetta Menendez J. Chronic orchialgia. A diagnostic and therapeutic hypothesis. Actas Urol Esp 1997; 21(8):770–2. 24. Chauhan SP, Lodha SC, Solanki RL. Testicular angina. Br J Urol 1998; 82(4):601–2. 25. Kocak I, Dundar M, Yenisey C, Serter M, Gunaydin G. Pro-inflammatory cytokine response of the fluid contents of spermatoceles and epididymal cysts. Andrologia 2002; 34(2):112–5. 26. Hatsiopoulou O, Dawson C. Simple intratesticular cysts in adults: a diagnostic dilemma. BJU Int 2001; 88(3):248–50. 27. Karademir K, Senkul T, Baykal K, Ates F, Iseri C, Erden D. Evaluation of the role of varicocelectomy including external spermatic vein ligation in patients with scrotal pain. Int J Urol 2005; 12(5):484–8. 28. Orr D, Moore B. Vasectomy as a contraceptive method. Ir Med J 1989; 82(1):19–20. 29. Schover LR. Psychological factors in men with genital pain. Cleve Clin J Med 1990; 57(8):697–700. 30. Schwingl PJ, Guess HA. Safety and effectiveness of vasectomy. Fertil Steril 2000; 73(5):923–36. 31. Johnson AL, Howards SS. Intratubular hydrostatic pressure in testis and epididymis before and after vasectomy. Am J Physiol 1975; 228(2):556–64. 32. Shafik A. Electrovasogram in patients with obstructive azoospermia and absent vas deferens. World J Urol 1996; 14(6):393–6. 33. McDonald SW. Cellular responses to vasectomy. Int Rev Cytol 2000; 199:295–339. 34. Silber SJ. Vasectomy and vasectomy reversal. Fertil Steril 1978; 29(2):125–40. 35. Schmidt SS. Spermatic grauloma: an often painful lesion. Fertil Steril 1979; 31(2):178–81. 36. Nangia AK, Myles JL, Thomas AJ. Vasectomy reversal for the post-vasectomy pain syndrome: a clinical and histological evaluation. J Urol 2000; 164(6):1939–42. 37. Ghoniem GM, Shoukry MS, Fayed AA, Hellstrom WJ, Sakr MA. Human vasal changes after vasectomy: in vitro studies. Eur Urol 1997; 31(2):231–6. 38. Granitsioti P, Daly C, Kirk D, McGrath JC. Characterisation of post-junctional receptors along the length of the human vas deferens: differences from the rodents. BJU Int 2000; 83:365. 39. Granitsioti P, Daly C, Kirk D, McGrath JC. Physiology of the human vas deferens. BJU Int 2000; 85(5):43. 40. Macrae B. Pain—new thoughts on an old problem. Urol News 2000; 4(5):6–8.

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41. Cohen SP, Foster A. Pulsed radiofrequency as a treatment for groin pain and orchialgia. Urology 2003; 61(3):645. 42. Ye ZQ, Cai D, Lan RZ, et al. Biofeedback therapy for chronic pelvic pain syndrome. Asian J Androl 2003; 5(2):155–8. 43. Amid PK. Causes, prevention, and surgical treatment of postherniorrhaphy neuropathic inguinodynia: triple neurectomy with proximal end implantation. Hernia 2004; 8(4):343–9. 44. Padmore DE, Norman RW, Millard OH. Analyses of indications for and outcomes of epididymectomy. J Urol 1996; 156(1):95–6.

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Urethral Pain Syndrome and Pain Perceived as Related to the Penis Magnus Fall

Department of Urology, Sahlgrenska University Hospital, Gçteborg, Sweden

Andrew Paul Baranowski

The Centre for Urogenital Pain Medicine, Pain Management Centre, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, U.K.

URETHRAL PAIN SYNDROME Introduction Urethral pain syndrome, commonly misnamed as urethritis, is diagnosed in women presenting with dysuria with or without frequency, nocturia, and urgency in the absence of evidence of urinary infection. The pain is perceived in the urethra which may be tender to vaginal palpation. For the clinician, the female urethral pain syndrome is a well-known concept. Scientifically, though, this concept suffers tremendously from lack of systematic, epidemiologic, and pathophysiologic studies and an absence of consensus on definitions. Still, there are reasons to believe that this symptom complex is a commonplace affliction. In many ways the urethral pain syndrome may be similar to the prostate pain syndrome in males (often misnamed as “chronic prostatitis”). In fact, Galenos describes a female prostate, and by using wax casts of the female urethra Huffman (1) was able to demonstrate that from the urethral lumen there is a ramifying system of glands and crypts to be found spreading out towards the periphery (Fig. 1). One possible mechanism for the urethral pain syndrome is a “hidden infection.” It is easy to imagine that an infection arising from the lumen may result in obstruction of the ducts and a peripheral accumulation of purulent infection that may be difficult to eliminate by normal defense mechanisms or even by medical treatment. As a rule, it is thought that this localized infection does not demonstrate itself by a positive urine culture. In this context it should also be noted that routine methods used to identify urinary infection are very insensitive and some patients may have a genuine infection that is not recognized. Current automated laboratory methods will not detect colony counts below 104 colony forming units per ml of urine, when in the presence of symptoms an appropriate diagnostic threshold would rather be 102. Nearly one-third of acutely dysuric women with urinary infection caused by Escherichia coli, Staphylococcus saprophyticus, or Proteus have midstream urine colony counts in the range of 102 to 104 colony forming units/mL (2–4). Symptoms and Diagnosis Pain of varying degree is the most important symptom. Pain is most often experienced in the urethra and the vagina, combined with a feeling of dull pressure, sometimes radiating towards the groins and the sacral area. Pain and discomfort during intercourse is the rule rather than the exception. Very typically, pain and dysuria appear during and/or immediately following voiding but not before emptying of the bladder. Although not totally discriminant, this information is essential to elucidate since it distinguishes the typical urethral pain patient from the typical one with bladder pain syndrome (BPS). Another important sign of differentiation is distinct pain on palpation of the urethra in contrast to pain when palpating the bladder.

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Urethral meatus Paraurethral ducts Proximol urethra

ina Vag

l ca

nal

FIGURE 1 Extension of glands and ducts from the female urethra. Source: From Ref. 1.

Some of these women complain of an irritating, slight, continuous incontinence. That symptom can possibly be explained by impairment of inner urethral softness (5) due to inflammation of the mucous membrane that may result in a decrease of the “sealing” function of the mucosa. Cystoscopically, reddening and swelling of the urethral mucosa are characteristic findings if an inflammatory process is present. The mucosa is well vascularized and may bleed easily. In contrast, in longstanding chronic urethritis the mucosa may rather appear atropic, and areas of so-called squamous vaginal metaplasia often appear. In a true urethral pain syndrome, cystoscopy may be normal. Categories Urethral pain syndrome is an unexplored entity, and there are no established criteria or suggested classification such as for BPS or prostate pain syndrome. From a clinical point of view, at least four presentations can be distinguished using a similar classification to that currently recognized for the prostate (Table 1). Acute bacterial cystourethritis is a common condition as encountered in emergency clinics. The symptoms are a sudden onset of urgency, smarting pain when voiding, and sometimes hematuria. Chronic bacterial urethritis due to a defined focus occurs when a lesion like a diverticulum or urethral stone is the locus of chronic infection. Urethral concrements are rare findings. Diverticula are seen more frequently, although they are not common. Occasionally

TABLE 1 A Basic Classification of Urethral Pain Syndrome Acute bacterial cystourethritis Chronic bacterial urethritis due to a defined infectious focus Chronic urethral pain syndrome With inflammation Without inflammation Estrogen deficiency chronic urethral pain syndrome

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a diverticulum surrounds the urethra in a horseshoe manner and sometimes the lesion is multilocular. Pain associated with urethral diverticulum ranges from mild to extremely severe. Chronic urethral pain syndrome may be of inflammatory origin, for instance, due to an infection concealed in the peripheral glands and ducts or possibly an autoimmune phenomenon. However, other factors causing chronic pain symptoms might be in play, such as neuropathic pain mechanisms (possibly with neurogenic edema) or chronic pelvic floor dysfunction and urethral irritation. Estrogen has tropic properties both on the urethra and the nervous system. Estrogen deficiency often results in dysuria and urgency due to changes within the mucosa. Recurrent urinary tract infections, due to an atropic mucosa less resistant to bacterial invasion, may aggravate pain. Changes within nerve afferents, from the urethra, may result in aberrant neuromodulation and increased pain. Differential Diagnosis It is worth noting that the urethral pain syndrome is often associated with microscopic hematuria. However, malignancy has always to be borne in mind in chronic pain conditions. Although they are rare, the most prevalent malignancies in this area are squamous cell carcinoma, adenocarcinoma, mesonephric adenocarcinoma, and malignant melanoma and all have to be excluded. Carcinoma of the bladder may mimic urethral syndrome. The real differential diagnostic difficulties involve BPS and interstitial cystitis, particularly as there is no consensus on the dividing line between urethral pain syndrome and BPS. Moreover, the two entities may appear simultaneously. Misclassification would probably not be an exception. Distal ureteric stone or bladder stone should always be considered as diagnostic alternatives. Treatment Acute bacterial cystourethritis is a common problem in the emergency room and a short course of antibiotics normally cures this condition. Chronic bacterial urethritis due to a defined focus usually requires surgery. A stone in the urethra is an unusual finding and in most instances is easily corrected endoscopically. A urethral diverticulum can be a challenging surgical problem, since the lesion is often multilocular or may partially surround the urethra. Chronic urethral pain syndrome with no focal lesion having been identified forms the large and therapeutically problematic group, as the etiology and pathogenesis are obscure. Sporadic reports, mainly focused on treatment, appear in the literature. They include measures as varying as alpha-adrenergic blocking drugs, acupuncture, and Yag laser treatment. When first seeing the patient, a trial of antibiotics is routine and if the initial response is positive an extended course is given. Traditional but unfortunately scientifically less well documented treatments include urethral dilatation, massage, and the local application of cortisone and antibiotics cream. Problems owing to estrogen deficiency are managed by local or systemic estrogen. PAIN PERCEIVED IN THE PENIS Introduction The penis happens to be the conduit for the urethra and the comments above, relating the urethral pain syndrome, equally apply to both the male and female urethras. However, the penis is also a somato-neurovascular organ, the function of which is primarily reproduction. As well as being the organ of intermission and insemination, the penis has a major role in sexual satisfaction. The neurovascular construction is important for erection and potency, see Chapter 3. The nervous innervation and central processing is quite unique compared to other parts of the male body (but probably similar to the clitoris and vulva in the female). All somatosensory modalities (touch, warm, cold, etc.) are perceived from the penis (6). However, the thresholds are different from other parts of the body (7) and can vary depending upon the state of sexual arousal. The central sensitization process associated with sexual activity that

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produces genital hypersensitivity may be a physiological correlate of the pathological process that produces allodynia (pain associated with light touch) and hyperalgesia (increased sensitivity to painful stimuli) (see Chapter 6). Whether or not these central processing pathways are important for penile pain (and vulvar pain) is not known. Classification A basic classification for pain perceived in the penis is found in Table 2 and is based upon both the structure and function of the penis. Examples provided in the table and text are all based upon personal experience within the urogenital pain clinic of University College London Hospitals Foundation Trust. Very little has been published in this field. Local Conditions Producing Chronic Pain Within the Penis Recurrent infections and dermatological conditions rarely find their way to the chronic pain clinic. However, there is no doubt that the irritation, discomfort, and pain caused by such conditions can be very disabling and distressing for patients. Most such conditions are managed either by family doctors, dermatologists, or infectious disease doctors. As well as treating the local condition, consideration needs to be given to managing the symptoms with antipruritics, simple analgesics and neuromodulating drugs (Chapter 42). Repeated local trauma can be a cause of chronic pain, for instance patients with obsessional compulsive disorders performing multiple sexual activities or self-examinations. Peronie’s disease is rarely a cause of pain except where the plaques cause such deformity as to cause intercourse to be painful. Referred Pain The commonest site for referral to the penis is from the bladder outlet. In such circumstances, the referred sensation is usually associated with urinary symptoms. Having said that, urinary symptoms may be absent in certain painful bladder syndromes and it is also possible for severe penile pain to produce bladder symptoms. Whether or not isolated prostate pain refers to the penis is more difficult to say. In most acute cases of pain stemming from pathology of the prostate, the bladder and pelvic muscles are involved. Both of these structures may produce pain partly perceived in the penis. Referral from the musculoskeletal system is common and should be searched for in all cases. Usually the referral pattern is wider than the penis alone and it often involves the testes. TABLE 2 A Basic Classification of Pain Perceived in the Penis Nature of the pain Local conditions

Referred pain

Examples Infection Dermatitis Fibrous plaques Ischemia Visceral referral Somatic referral

Neuropathic

Central Peripheral

Psychiatric Penile pain syndrome

Site

Bladder Prostate Low back Tendons around pelvis Pelvic floor musculature Pubic symphysis Hips Cauda equina Neural axial (central sensitization) Sacral roots Sacral plexus Pudendal nerve Dorsal nerve of the penis

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Treatment of referred pain involves education of the patient and treatment of the primary pathology. Neuropathic Pain Nerve injury, both centrally and within the periphery, can result in neuropathic pain. There are several chapters within this book on pudendal nerve damage which, if the lesion affects neurons found within the terminal branch of the pudendal nerve (the dorsal nerve of the penis/clitoris), may result in penile pain. Diagnosing neuropathic pain is not as easy as most of us would like to believe (8). A good history and clinical examination may help. However, there remains a significant debate as to the meaning of certain findings within the history and examination. For instance, pain exacerbated by sitting and relieved immediately on standing is not pathomnemonic of pudendal neuralgia: such symptoms may arise from muscle hyperalgesia and central sensitization secondary to other pathologies. Careful quantitative sensory testing may have a role (9), but is time-consuming and results interpretation can be difficult. The skills are often only found in a limited number of centers. Nerve conduction studies and electro myographs may indicate that a nerve is damaged, but even proof of nerve damage is not proof that the damage is the cause of the pain that the patient suffers Nerve blocks can indicate a site of pain by using differential blockades at different sites along the nerves. The dorsal nerve of the penis innervates the glans, including the frenulum and corona as well as the dorsal and lateral aspects of the shaft. The frenulum is also innervated by a branch of the perineal nerve that supplies the ventral aspect of the shaft (10). Unfortunately, nerve blocks cannot distinguish between pain arising from the nerves themselves or the tissues from which they receive afferents. The tendency of nerves to converge centrally further confuses the picture. To a certain extent, the arguments for and against specific methods of identifying neuropathic pain are academic until better tools exist. In all suspected cases of neuropathic pain, the pain should be treated with neuromodulating drugs (11,12) and injection therapies, possibly including pulsed radiofrequency neuromodulation. Decompressive surgery should be considered when there is a suggestion of nerve compression (Chapter 38) and implant neuromodulation (Chapter 45) considered for those who have tried simpler options and where the patient has undergone an appropriate multidisciplinary assessment. It is that algorithm that is adopted at The National Hospital for Neurology and Neurosurgery in the Queen Square’s Pain Management Centre. Psychiatric Causes of Penile Pain This section on psychiatric causes of pain is not about the psychological distress that is often associated with urogenital pain; this is covered in several other chapters within this book. Psychiatric illness causing pain is a very controversial area and debates still abound as to whether a psychiatric condition can provide a “delusion of pain” in the same way that patients with psychotic conditions may hear voices. Certain central sensitization processes can produce pain symptoms which were previously not understood, and patients were in the past given a psychiatric label. An example here would be the patients diagnosed with psychiatric conditions because of allodynia and extreme hypersensitivity. Now that we understand those mechanisms better we can appreciate that a psychiatric label was incorrect. A good illustration is the lady who developed pudendal neuralgia 20 years ago while in a psychiatric hospital suffering with depression and sitting for extended periods of time. For the past 20 years she has sought an alternative diagnosis to the psychiatric one she was given for her pain. We were able to provide this by a combination of history, examination, and investigations. Other examples include several men who have been referred to us post circumcision as adults. The referral letters have contained comments suggesting that the patients have psychiatric disorders relating to the new appearance of the penis. Whereas it is well accepted that following circumcision patients may not be satisfied with the result (13), in all cases seen by us to date, there was significant allodynia suggesting a massive central sensitization response to the surgery. Interestingly, most of the patients improved with neuropathic treatments.

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On the other hand it must be accepted that psychiatric disorders may be associated with pain. A patient presented to the department with penile pain and an obsessive compulsive disorder (OCD) concerned that he may have penile cancer. His constant, repeated, self examination with local trauma produced pain which reinforced his concerns. Treating the OCD resolved the pain. The diagnosis of a psychiatric disorder causing pain is a very major diagnosis for the patient and should not be taken lightly. Penile Pain Syndrome This term was coined for the European Association for Urology (EAU) Guidelines on Chronic Pelvic Pain (14). Penile pain syndrome is the occurrence of pain within the penis that is not primarily in the urethra, with the absence of proven infection or other obvious pathology. It is a very useful term when the pain is perceived to be in the penis but no obvious cause can be found, physical or psychiatric. In the EAU Guidelines for chronic pelvic pain, the urogenital organs outside the anatomical pelvis were considered within the guidelines because of their close links, anatomically, physiologically, and pathologically with the structures within the pelvis. REFERENCES 1. Huffman JW. The detailed anatomy of the paraurethral ducts in the adult human female. Am J Obstet Gynecol 1948; 55:86–101. 2. Hooton TM, Scholes D, Stapleton AE, et al. A prospective study of asymptomatic bacteriuria in sexually active young women. N Engl J Med 2000; 343:992–7. 3. Hooton TM, Stamm WE. Diagnosis and treatment of uncomplicated urinary tract infection. Infect Dis Clin North Am 1997; 11:551–81. 4. Stamm WE, Hooton TM. Management of urinary tract infections in adults. N Engl J Med 1993; 329:1328–34. 5. Zinner NR, Sterling AM, Ritter RC. Role of inner urethral softness in urinary incontinence. Urology 1980; 16:115–7. 6. Bleustein CB, Arezzo JC, Eckholdt H, Melman A. The neuropathy of erectile dysfunction. Int J Impot Res 2002; 14(6):433–9. 7. Lefaucheur JP, Yiou R, Salomon L, Chopin DK, Abbou CC. Assessment of penile small nerve fibre damage after transurethral resection of the prostate by measurement of penile thermal sensation. J Urol 2000; 164(4):1416–9. 8. Rasmussen PV, Sindrup SH, Jensen TS, Bach FW. Symptoms and signs in patients with suspected neuropathic pain. Pain 2004; 110:461–9. 9. Pukall CF, Blinik YM, Khalife S, Amsel R, Abbott FV. Vestibular tactile and pain thresholds in women with vulvar vestibulitis syndrome. Pain 2002; 96(1-2):163–75. 10. Yang CC, Bradley WE. Innervation of the human glans penis. J Urol 1999; 161(1):97–102. 11. Rasmussen PV, Sindrup SH, Jensen TS, Bach FW. Therapeutic outcome in neuropathic pain: relationship to evidence of nervous system lesion. Eur J Neurol 2004; 11:545–53. 12. Hansson PT, Dickenson AH. Pharmacological treatment of peripheral neuropathic pain conditions based on shared commonalities despite multiple etiologies. Pain 2005; 113(3):251–4. 13. Masood S, Patel HR, Himppson RC, Palmer JH, Mufti GR, Sheriff MK. Penile sensitivity and sexual satisfaction after circumcision: are we informing correctly? Urol Int 2005; 75(1):62–6. 14. Fall M, Baranowski AP, Fowler CJ, et al. EAU guidelines on chronic pelvic pain. Eur Urol 2004; 46(6):681–9.

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Chronic Pelvic Pain in Women John F. Steege

Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, U.S.A.

INTRODUCTION The first step in understanding chronic pelvic pain (CPP) in women is to realize that it is a different entity entirely from acute pain, quite aside from its duration (CPP is generally defined as having been present for more than six months). The second is to recognize the referral patterns involved, the recruitment of surrounding organ systems, and the neurologic/ neuropathic components that are commonly part of pain that has been present for extended periods of time. These understandings have profound impact on the diagnostic and treatment processes brought to bear on this problem. While these ideas certainly apply to every organ system in the body, incorporation of this information into gynecologic practice has been hindered by two factors unique to the female reproductive tract: (i) it can be removed without severe threat to life or health (although the latter may be debated) and (ii) very often, removal of the reproductive tract in fact does resolve pain. Even when CPP and depression are present prior to hysterectomy, over 80% of women undergoing hysterectomy are pain free two years later (1). In addition, surgery itself may have a placebo effect lasting at least a year, in up to 50% to 100% of patients (2). Hence, in comparison with other specialties, in gynecology, surgery plays a more central role in treatment. The clinical tasks then are to (i) recognize when pain is multifactorial, (ii) determine what mix of medical and other therapies are appropriate, and (iii) appropriately integrate surgical intervention into an overall treatment plan. The following discussion will serve as a review of some known and some speculative factors in CPP, understanding of which should inform our treatments.

GENERAL PRINCIPLES IN UNDERSTANDING CPP Differences from Acute Pain In cases of acute pain (other than major trauma), nociceptive signals typically arise from a single organ system, or place within an organ system and the intensity of the signals generally reflects the intensity of tissue injury, e.g., pelvic or urinary tract infection, ovarian inflammation from torsion or hemorrhagic cyst. Physical history and examination findings, with imaging studies, together with a modicum of laboratory studies, generally narrow the differential diagnosis quickly. Treatments are amenable to scientific validation, and are for the most part often successful. When pain is chronic, none of the above is true. While history is often the key to understanding the illness, pain is usually not proportional to tissue pathology, multiple organ systems may contribute to the problem, physical examination findings are often not definitive, imaging studies have only modest value, and laboratory studies are very often uninformative. Pain referral patterns may defy neuroanatomic logic and successful treatment may require multiple therapeutic measures patiently applied for extended periods of time. The several aspects of chronic pain discussed below may help to explain these differences.

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Viscero-Somatic Convergence Somatic and visceral structures share innervation. Branches of thoracic nerves supplying the ovaries, for example, also supply the anterior abdominal wall in the lower quadrants. Ovarian pain may therefore be referred to the abdominal wall. If pain is present for long periods of time, the abdominal wall focus may continue sending nociceptive signals, i.e., become an autonomous source of pain after the ovarian cause has been treated or even after the ovary has been removed. Relationship to Organic Pathology In general, the more chronic the pain is, the less clear the relationship between organic tissue change and pain levels. This is certainly also true in gynecology, where we find that no gynecologic disease causes pain in everyone who has it and reported pain is often either much greater or much less than one might intuitively expect based on volume of disease. Endometriosis gives us a classic example. Older texts often stated that pain in this condition is often inversely related to disease volume. In fact, most series in which this question was specifically addressed simply find no clear relationship, neither direct nor inverse, between volume of disease and pain (3). As has long been appreciated by clinicians, as pain becomes chronic, affective changes such as anxiety and depression may worsen pain and psychosocial changes may increase the distress associated with the pain. Less well recognized is the phenomenon of recruitment of surrounding organ systems into the nociceptive chorus. Cross Talk Between or Among Organ Systems Clinicians are beginning to recognize and report overlaps among conditions in the pelvis: vulvar vestibulitis patients have a higher than expected frequency of bladder symptoms similar to those seen in interstitial cystitis (4), and endometriosis patients have a higher than expected frequency of irritable bowel syndrome (IBS) (5). Other examples are likely to emerge as these linkages are examined. Are these symptoms secondary to central affective changes, or are they the result of neurologic or neurohumoral communications on a much more local level? In clinical practice, one often sees that symptoms in surrounding organ systems resolve upon effective treatment of the primary condition (e.g., endometriosis) well before the central affective and the psychosocial changes have had sufficient time to improve. Systematic study of these observations is needed to shed further light on these interactions. Centralization The bane of the pain patient’s (and her physician’s) existence is the phenomenon of centralization: foci within the spinal cord and/or brain becoming the origin of pain signals, with peripheral tissues apparently playing a minimal or negligible role. Evidence from animal models of chronic pain suggests that actual remodeling of spinal cord neuronal connections may occur which link peripheral fibers, normally tasked to sense touch and pressure, to ascending fibers normally dedicated to nociception (6). Thus, with time, ordinarily non-painful stimuli may be centrally perceived as painful. Observation of this process at the human level is obviously going to be difficult, but this process might explain some clinical observations in pain patients. Current medical therapies are modestly effective at best only when this process is well established. The optimistic pain specialist believes that recovery is possible after prolonged periods of “rest” from the pain, at the behest of psychotropic, neuroleptic, and narcotic medications, but this is a difficult task indeed. Even when progress is made, relapses tend to occur, perhaps indirect evidence of durably altered central pathways. COMMON DISORDERS The above discussion will serve as a backdrop for the following paragraphs which will review the roles of common gynecologic disorders in CPP. The aforementioned will perhaps explain

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the clinical situations in which traditional treatments for these disorders are incompletely successful in relieving pain. Leiomyomata Uterine fibroids occur in 30% to 50% of reproductive age women, with frequency increasing with age, and higher frequency in certain ethnic groups, such as African-American women. Discomforts associated with their presence include generalized pressure sensations within the abdomen and specific discomforts related to pressure on the bladder, bowel, and sacrum. Pain may be referred to the low back and down the anterior thighs and is generally more severe in the premenstrual and menstrual phases. For reasons sometimes difficult to fathom, women with even very large uteri are often quite asymptomatic. Treatment for uterine fibroids is more often prompted by abnormal bleeding rather than pain. Indeed, uterine artery embolization (UAE) successfully treats about 90% of bleeding problems at two-year follow-up, and about 75% at five years (7). However, symptoms related to uterine size alone are less often successfully treated by this method. The decision about whether or not to undergo further therapy then usually hinges upon the severity of residual size-related symptoms and the degree to which they inhibit function. These understandings are important for the counseling process involved in choosing from among UAE, myomectomy, and hysterectomy for symptoms refractory to medical therapy. Endometriosis This disorder is no doubt the most common gynecologic disease associated with pelvic pain, with a prevalence of up to 25% of reproductive age women. It may be diagnosed by history and physical examination in slightly over 70% of cases (8), while laparoscopy remains the definitive diagnostic test. Contrary to common belief, the relief of pain by presumptive treatment with a gonadotropin-releasing hormone (GnRH) agonist does not confirm the diagnosis, as pain from other causes may be reduced by suppressing ovarian cycles (9). Pain from endometriosis typically starts with progressively severe dysmenorrhea, sometimes ultimately joined by deep dyspareunia and pelvic pain that is present for more and more of the menstrual month. Dyschezia (constipation due to long periods of voluntary suppression of urge to defecate), when present, may indicate the development of pelvic floor (levator) muscle spasm or direct invasion of the rectosigmoid colon by the infiltrative form of the disease. The mechanisms of pain production in endometriosis are far from clear. Traditionally, many gynecologic texts have held that pain is inversely proportional to volume of disease, i.e., those with early stage disease have more pain than those with anatomically more advanced disease. When surveyed, there does not seem to be any type of correlation between disease volume and pain, either direct or inverse, with the possible exception of deeply invasive fibrotic disease in the posterior cul-de-sac (10). Direct invasion of nerves (11), neural ingrowth into the peritoneum surrounding implants (12), prostaglandin production, inflammation, and bleeding from implants have all been offered as explanations, but none have “carried the day.” Particularly puzzling is the observation that up to 50% of women with endometriosis may have no pain at all. The presence of pain in endometriosis may therefore depend in part upon differences in central processing of nociceptive signals, differences in counter-inflammatory cytokine systems, or other systems as yet entirely unknown. Curiously, some preliminary work suggests that women with dysmenorrhea associated with endometriosis may have altered pain perception mechanisms in parts of the body quite remote from the pelvis (13). The clinician, therefore, having diagnosed the disease, must then make a clinical judgment about its role in a particular patient’s pain. There are multiple effective treatments for pain associated with endometriosis. First-line therapy should certainly include non-steroidal anti-inflammatory drugs (NSAIDs), oral contraceptives (either cyclic or continuous), and management of associated symptoms in surrounding organs (e.g., constipation, pelvic floor muscle pain). There is debate concerning the next step when these methods are insufficient. Continuous progestins, either oral (medroxyprogesterone, norethindrone) or intramuscular (medroxyprogesterone), may be employed at relatively

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modest expense and with an acceptable side-effect profile (14), although many clinicians feel that the diagnosis should be confirmed laparoscopically before the step is taken to suppress menstrual cycles completely. Presumptive treatment with a GnRH agonist does not confirm the diagnosis (as mentioned above), is quite expensive (at least in the United States) and has an adverse side-effect profile in terms of severe menopausal symptoms and bone calcium loss. Adding back estrogen and progestin hormones will reduce side effects, but has an uncertain impact on the volume of disease itself (15). If laparoscopy is performed, there is good evidence that treatment of the disease at the time improves pain (16). In terms of postoperative therapy, the bulk of research evidence supports the notion that oral contraceptives and continuous progestins are as effective as GnRH agonists for pain relief (17). Pelvic Adhesions The role (or lack thereof) of adhesions in pelvic pain has been a subject of hot debate for decades. A perhaps cynical view is that prior to the advent of operative laparoscopy, when there really was no good surgical solution to adhesions, many clinicians and academicians denied that they played any role in pain. When it became clear that laparoscopic treatment could reduce the amount of adhesive disease, then claims were made that this procedure reduced pain. Current clinical consensus would hold, again without solid research evidence, that moderate adhesions may be worth treating, while mild adhesions are probably not very important, and severe adhesions are very likely to re-form during the healing process, no matter how skilled and careful the surgeon might be. Although multiple adhesion prevention substances have been developed, it is safe to say that their impact is modest at best and usually limited to very specific surgical situations (18). As in the case of endometriosis, every experienced clinician recognizes that adhesions do not always cause pain. The decision about whether or not to surgically intervene must therefore be a carefully considered clinical judgment, fortified by a complete review of all other possible contributing causes. When surgery either fails to relieve pain or does so for only a brief period, attention should be directed to other treatment modalities rather than a return to the operating room. Complicating this picture, and always a source of humility for the surgeon, is that the placebo effect of surgery may range as high as 55% to 100%, and may last for a year or more! (2) Altered Pelvic Support Clinical complaints associated with pelvic relaxation are often more subtle than those attributed to the other gynecologic problems discussed so far. The words used by women with pelvic relaxation to describe their discomforts are often subtle: “pressure,” “heaviness,” and “aching” being among them, as opposed to “sharp” and “cramping,” often used when describing pain from endometriosis. Complaints of dyspareunia are also often more subtle as well. Treatment of this problem often falls in the province of the general gynecologist or urogynecologist, as opposed to the gynecologic pain specialist. Diagnostic assessment of pelvic relaxation has been well described and made more reproducible by the introduction of the pelvic organ prolapse quantification (POPQ) examination technique (19). The literature so far lacks careful descriptions of clinical symptoms correlated with POPQ measurements, except for the complaint of stress incontinence. It is therefore left to the physician’s clinical judgment to integrate historical and pelvic examination data to assess the importance of pelvic relaxation itself in the patient’s symptoms, as opposed to perhaps concomitant contributions by vaginal dryness, levator pain, and bowel symptoms. In many women, careful attention to the chronology of the development of the pain will tell the story: prolapse was tolerated well initially, but over time, increasing discomforts with defecation and intercourse may have been added due to levator dysfunction, etc. Rectal symptoms deserve more focused discussion. There are certainly many asymptomatic rectoceles in the world and most providers are accustomed to asking about constipation as a symptom of this disorder. However, there are many women who will assist the defecation

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process by placing one or two fingers in the vagina and “milking” a reluctant stool out. Unless directly asked about it, many will be too embarrassed about this to mention it spontaneously. Whether or not this represents a clinical problem necessitating surgical repair is an individual judgment the patient and physician need to make, taking into account the particular surgical risks and likely benefits in that particular patient. Although the problem has not been systematically reported in the gynecologic literature, clinicians focusing on gynecologic pain disorders are aware of a small, but important incidence of vaginal pain and dyspareunia that may develop following posterior colporrhaphy. The possibility of developing this problem needs to be included in preoperative counseling. Neuropathic Pain Pain often occurs in the absence of definable structural abnormality. One common example of this is the phenomenon of neuropathic pain, which is loosely defined in the pain literature as pain in the absence of structural change. After hysterectomy, for example, the suture line at the vaginal cuff may become intrinsically sensitive, resulting in dyspareunia. Pain from the vaginal incisions of anterior and posterior repairs are another good example. Finally, vulvar vestibulitis is an inflammatory condition of the vaginal vestibule that is quite common, and has both inflammatory and neuropathic components, as topical agents targeting each of these factors seem to have therapeutic value. Musculoskeletal Dysfunction Perhaps the most important addition to the general understanding of pelvic pain in the past 20 years has been the growing appreciation of musculoskeletal disorders as part of many pelvic pain disorders. One might break this category down into the following categories: (i) primary musculoskeletal problems causing pain that is erroneously attributed to gynecologic causes; (ii) musculoskeletal problems that occur following pain caused by gynecologic disorders; and (iii) transient musculoskeletal problems that occur following gynecologic surgery. Comfort in the lower back, hips, and pelvic floor seems to depend upon adequate tone, flexibility, and balanced strength within and across these systems. While a comprehensive review is beyond the scope of this discussion, a number of most common disorders deserve mention. Primary Musculoskeletal Disorders

Lower Back Pain

Chronic low back pain is arguably the most common chronic pain problem of all, and is certainly very high on the list of problems responsible for lost time from work and disability claims. From a gynecologic perspective, there are certain forms of this problem that cause pain sometimes mistakenly labeled as gynecologic in origin, or that result from deteriorations in posture and conditioning that may result from pelvic pain arising from other sources. These disorders are often present without the patient having been labeled as having chronic low back pain, and include sacroiliac disorders and facet syndromes. Sacroiliac Pain

The articulation between the sacrum and the ileum is a large joint with a synovial lining and buttressed by a strong joint capsule. The joint may be stressed by weakness and imbalances of surrounding musculature, is relaxed and loosened by pregnancy, and is innervated by branches of the L4–S3 nerves. Inflammation in the joint is common, resulting in tenderness when palpated, and at times referring pain to the anterior lower quadrants (20). When a patient with this referral pattern is evaluated by a gynecologist, tenderness elicited during pelvic examination may then be erroneously attributed to the adnexal structures, bowel, or appendix, resulting in fruitless pursuit of a visceral etiology. Evaluation and treatment by a physical therapist is the most productive next step. Screening tests for various arthritides may be done, but are rarely positive in the absence of other clinical signs pointing to these disorders. Treatment with NSAIDs is useful, but long-term relief is more often achieved by correction of muscular weakness and imbalances (core muscle groups).

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Facet Syndromes

Adjacent transverse processes of the thoracic and lumbar vertebrae have a synovial interface which is vulnerable to inflammation. When a nearby segmental body wall nerve is irritated by this inflammation, referred pain radiating around to the anterior abdominal wall may result (21). The pain may be reproduced by direct palpation of the involved transverse process(es). The diagnosis is confirmed when local anesthetic injection eliminates the pain, and long-term treatment options include repeated local anesthetic injections (possibly with steroids added), physical therapy, and chiropractic approaches. Hip Muscle Pain

The piriformis and obturator muscles may be weakened from deconditioning, and may become painful in the presence of abnormal shortening or lengthening. Again, changes in posture and other alterations of body mechanics may contribute to the problem. For example, pelvic floor spasm may alter how a person sits (avoiding pressure on the pelvic floor by lifting up one buttock, crossing the legs, slumping forward in the chair, etc.), leading to compensatory shortening or lengthening of the nearby piriformis and/or obturator muscles. Pain in these muscle groups may again be mistaken for adnexal pain from the reproductive tract. An examiner can detect pain from these muscle groups during pelvic examination by palpating the muscles directly via the vagina, ideally using a single vaginal examining finger. The discomfort is accentuated if the patient is also asked to externally rotate the thigh against resistance, which causes these muscles to flex. In approximately 25% of cases, the sciatic nerve traverses the belly of the piriformis, hence spasm of the muscle may cause neuralgic symptoms radiating down the leg in sciatic distribution, a condition labeled “pseudo-sciatica.” Disorders of the hip muscles, like the sacroiliac joint, are commonly seen in physical therapy practice and are best treated by them, using a variety of strengthening, stretching, and core muscle development exercises. Pelvic Floor Pain

A host of names has been used to describe this disorder: levator ani syndrome, proctalgia fugax, pelvic floor dyssynergia, and levator spasm, among others. A close relative is introital muscle spasm (bulbocavernosus), labeled vaginismus in most cases. Vaginismus and pelvic floor muscle dysfunction may coexist in the same patient, but are quite distinctly separate disorders (22). The label used depends on the vantage point of the clinical assessor: gastroenterologists call it a defecatory disorder (pelvic floor dyssynergia), while gynecologists may call it by one of the other names listed. This disorder may appear as its own independent syndrome, or it may develop as a response to symptoms from other forms of pelvic pathology, endometriosis in particular. It may also begin in response to the discomforts of gynecologic surgery. When it presents as a new, postoperative problem, it may resolve spontaneously, but comfort can be improved by prescribing the appropriate exercises. Diagnosis of this problem is readily made by history and confirmed by pelvic examination. The woman who describes a sense of pelvic heaviness or pressure, “like everything is going to fall out,” will suffer (when pelvic relaxation is, in fact, not present) from levator pain until proven otherwise. Confirmation during single-digit transvaginal pelvic examination is a relatively simple matter, accomplished by pressing on each levator in turn and asking if the resulting discomfort is part of the symptom complex. Following this with a request for voluntary contraction and relaxation will then assess the patient’s control over these muscles. Treatment may start with self-directed contraction/relaxation cycles, emphasizing short periods of contraction, in contrast to the usual Kegel pelvic floor strengthening instructions. The problem in levator spasm more often is not weakness but inability to relax. If these exercises are either not possible for the patient to do or provide insufficient relief, then again physical therapy will often be useful. This approach often requires work by a physical therapist comfortable with performing transvaginal massage of the levator floor. Pelvic floor biofeedback may be additive, but is not often necessary. Muscle relaxant medications, while intuitively appealing, are very minimally helpful and often accompanied by intolerable side effects of constipation and sedation.

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The above disorders may all occur either alone or in any combination, challenging the clinician’s diagnostic acumen. To add further complexity, recent observations suggest that visceral structures in different organ systems may communicate with each other, most likely by neurotransmitter or neurohumoral mechanisms, to contribute to the symptom complex. MULTI-ORGAN SYNDROMES Reproductive Tract–Gastrointestinal Tract Women with pelvic symptoms have more irritable bowel syndrome (IBS) symptoms than the general female population (approximately 35% vs. 12%) (23). Some early literature noted that, compared to women with gynecologic pathology, IBS was more common in women undergoing hysterectomy in whom no gynecologic pathology was found (24). This was interpreted to suggest that the real cause of pain was the IBS, a diagnosis that had been overlooked. More recent literature suggests that pelvic pain is relieved following hysterectomy in over 90% of cases (25). Both of these observations may be true. The presence of gynecologically based symptoms may activate symptoms from the intestinal tract. The initial studies cited would have added more to the literature if they had followed the women with IBS to see if it resolved following hysterectomy. The association of gastrointestinal symptoms with vulvar symptoms is another overlap that does not seem logical at first glance. However, the shared innervation of the lower bowel and the vulva via the pudendal nerves and their rectal branches (S4) allow these interactions at least some intuitive logic, although as clinicians we are not accustomed to thinking about them in this manner. We have observed these associations on a relatively frequent basis in the context of a clinic dealing specifically with CPP problems. The degree to which this also occurs in the general population awaits further epidemiologic research. Reproductive Tract–Urinary Tract Much recent literature has focused on the bladder as a cause of pelvic pain. Painful bladder syndromes including interstitial cystitis, until recently, have probably been underdiagnosed. The cardinal symptoms are frequency, urgency, dysuria, and nocturia, all in the absence of bacteriuria. The NIDDK research diagnostic criteria include bladder petechial hemorrhage following cystoscopy with hydrodistention (26), while many clinicians feel that pain experienced following instillation of potassium chloride (KCl) into the bladder is sufficient confirmatory evidence. In its more severe forms, the stereotypic patient has discomforts that are very difficult to treat and tend to recur even after apparently successful treatment (27). In other patients, more subtle versions of bladder discomfort may occur, often accompanying other disorders, such as vulvar vestibulitis. The bladder, urethra, and vaginal vestibule develop from the same embryologic anlage, suggesting that they may be similarly prone to developing chronic inflammation or pain. In these milder forms, the therapeutic outlook is not nearly as bleak. GENERAL PRINCIPLES OF MANAGEMENT OF CPP Peripheral-Tissue Symptom Reduction Most clinicians are familiar with this approach: treating the known disease to the degree appropriate for the level of symptoms and the stage of the organic disease. In the case of endometriosis, an extensive literature attests to the efficacy of both medical (listed above) and surgical therapies. When pain either persists without response to these treatments or recurs following some period (months to years) of initial response, the clinical task is more complex. Does this mean the disease has either recurred or is more extensive than first appreciated? Or does it mean that the implants themselves are less important, and other complicating factors, such as those listed above, have come to play more important roles? It appears that much clinical disservice has been perpetrated in the relentless pursuit of the implant, while ignoring

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TABLE 1 Therapies for Bladder Symptoms Oral medications Pentosan polysulfate sodium 100 mg tid 6 months or longer Antibiotics Analgesics Tricyclic antidepressants (low dose) Antihistamines Antiepileptics Diet/behavioral changes Bladder diet (low-acid foods, avoid caffeine, etc.) Bladder drill: scheduled voids, with gradually increased intervals Bladder instillations Heparin, lidocaine Dimethyl sulfoxide Chlorpactin Silver nitrate

other elements of the pain problem. (Analagous statements might be made, perhaps, concerning pelvic adhesions and uterine fibroids.) Surrounding Organ Symptom Reduction Treatment of bladder (Table 1) and bowel (Table 2) symptoms are, of course, often part of the clinical task. The patient is perhaps best served when one physician assumes the burden of dealing with all of these voices in the nociceptive choir, rather than referring the patient out to a range of specialists, each one focusing on a particular organ system. The sequencing (arranging, if you will, to continue the musical metaphor) of the treatments is largely still an art form, requiring careful attention to potential drug interactions and overall cost. Analgesics That the use of non-narcotic medications is appropriate for treating pain goes almost without saying, taking into account the well-known toxicities of high-dose, long-term use of agents such as acetaminophen (hepatotoxicity) and the NSAIDs (gastritis, increased cardiovascular risk). However, nothing stirs up controversy faster than a discussion of narcotic treatment of chronic pain. Fortunately, many forms of gynecologic pain retain at least some semblance of cyclicity, allowing rest periods in between treatments, thus mitigating against habituation or addiction. For those for whom pain is a constant companion, regular narcotic use may serve to provide an acceptable level of relief, and thus improve function. The traditional cautions about narcotic prescription apply. They should not be used in those with prior or current alcohol addiction or in poly-substance users; they should be used with great caution in the presence of depression, unless that illness is being adequately addressed; and they should be prescribed on a contract basis. This means that the patient TABLE 2 Therapies for Bowel Symptoms Symptom

Drug

Daily dose

Diarrhea

Loperamide Diphenoxylate HCl Hyoscyamine sulfate Dicyclomine HCl Trimipramine maleate Fiber Lacutlose Sorbitol Cisapride

Titrate: 4 mg average 20 mg 1.5 mg 80 160 mg 50 mg O30 g 10 30 g 10 30 g 40 80 mg

Constipation

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signs an agreement stating that she will obtain controlled drugs from only one prescriber and one pharmacy, at a schedule set by the prescriber. Early refills are not permitted, and proposed changes in dose schedule must be discussed with the prescriber. Although such an agreement has no legal standing, it serves to convey the serious manner in which such drugs are handled. Treatment of Neuropathic Pain Medications directed at abnormal nociceptive signals eminating from either normal tissue or tissue that is already being maximally medically or surgically treated include the antidepressants (Table 3a), antiepileptics (Table 3b), and local anesthetics (Table 3c). In general, we prefer to start with the local anesthetics and follow with the antidepressants, as these drugs have better therapeutic indices than do the antiepileptics. Centralization This is one of the more difficult areas of pain management. Pain specialists dealing with chronic headache and back pain are generally more familiar than pelvic pain specialists with treatment measures aimed at this part of the problem. The rationales for treatment all have to do with our understanding of nociceptive signal modulation at the spinal cord level. Most commonly used are magnesium and dextromethorphan supplementation. Thorough clinical documentation of the value of these approaches is lacking, as they are seldom employed as single agents. The Rehabilitation Model Once a pain problem is recognized as a chronic pain problem, the patient education process begins. Patient and physician alike must often surrender the hope for identification and eradication of a single factor, and must rather sign up for a longer, but ultimately more rewarding, task of evaluating and treating multiple factors simultaneously. For example, hormonal measures may be used to control the endometriosis, while dietary measures are suggested to quiet the bladder, and physical therapy employed to reduce musculoskeletal components. At the start of this process, the patient must understand that improvement often comes in small increments. Timetables are difficult to calculate, but as a first-order approximation, problems of more than a year or two duration often take 6 to 12 months to substantially improve or resolve. As is true in any rehabilitation process, it is essential for the patient to have a strong will to improve and a commitment to not just comply with treatments, but actively devote her energies to maximizing the positive elements, both physical and emotional, in her life. THE DOCTOR-PATIENT RELATIONSHIP The process of evaluating and treating pain, as well as guiding the patient and her family during the rehabilitative process, is a delicate dance. The clinician is challenged to offer clear support, a sense of caring, and a level of availability greater than that required in many areas of medicine. At the same time, the clinician must maintain an appropriate emotional distance, avoid fostering too much dependence in the relationship, and always demonstrate to the patient that her improvement depends as much on her efforts as it does on the clinician’s. TABLE 3 Medications for Neuropathic Pain Tricyclic antidepressants Nortriptyline, amitriptyline 25 75 mg qhs Antiepileptics Gabapentin 300 3600 mg qd in divided doses Lamotrigene 100 400 mg qd in divided doses Tegretol 200 1200 mg qd in divided doses Local anesthetics Topical 5% lidocaine ointment Lidocaine 1% patch

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CONCLUSIONS Chronic pain in general is one of the most challenging problems in clinical medicine, and urogenital pain is no exception. Our understanding of the pathophysiology of chronic pain is most limited, although it seems that most have at least (and at last) given up the mind-body split as a conceptual framework. As more research examines these problems, more treatments will be developed, giving hope for the sufferer. New concepts that include interactions among organ systems, and new understandings of spinal cord control mechanisms, will pave the way for novel therapeutic approaches (28). A constant in this ever changing field will remain the need for the thoughtful, empathetic clinician whose skills include the ability to perform a thorough clinical evaluation and help the patient make the best use of her own inner resources for recovery. REFERENCES 1. Hartmann KE, Ma C, Lamvu GM, Langenberg PW, Steege JF, Kjerulff KH. Quality of life and sexual function after hysterectomy in women with preoperative pain and depression. Obstet Gynecol 2004; 104(4):701–9. 2. Turner JA, Deyo RA, Loeser JD, et al. The importance of placebo effects in pain treatment and research. J Am Med Assoc 1994; 271:1609–14. 3. Vercellini P, Trespidi L, Colombo A, Vendola N, Marchini M, Crosignani PG. A gonadotropinreleasing hormone agonist versus a low-dose oral contraceptive for pelvic pain with endometriosis. Fertil Steril 1993; 60:75–9. 4. Fitzpatrick CC, DeLancey JO, Elkins TE, McGuire EJ. Vulvar vestibulitis and interstitial cystitis: a disorder of urogenital sinus-derived epithelium? Obstet Gynecol 1993; 81:860–2. 5. Moore J, Barlow D, Jewell D, Kenedy S. Do gastrointestinal symptoms vary with the menstrual cycle? Br J Obstet Gynaecol 1999; 106(12):1322–5. 6. Baron R. Peripheral neuropathic pain: from mechanisms to symptoms. Clin J Pain 2000; 16(Suppl. 2):S12–20. 7. Spies JF, Bruno J, Czeyda-Pommersheim F, Magee ST, Ascher SA, Jha RC. Long-term outcome of uterine artery embolization of leiomyomata. Obstet Gynecol 2005; 106:933–9. 8. Ling FW, Pelvic Pain Study Group. Randomized controlled trial of depot leuprolide in patients with chronic pelvic pain and clinically suspected endometriosis. Obstet Gynecol 1999; 93:220. 9. Riley JL, Robinson ME, Wise EA, Myers CD, Fillingim RB. Sex differences in the perception of noxious experimental stimuli: a meta-analysis. Pain 1998; 74:181–7. 10. Fidele I, Parazzini F, Bianchi S, et al. Stage and localization of pelvic endometriosis and pain. Fertil Steril 1990; 53:155. 11. Anaf V, Simon P, El Nakadi L, et al. Relationship between endometriotic foci and nerves in rectovaginal endometriotic nodules. Hum Reprod 2000; 15:1744–50. 12. Berkley K, Dmitrieva N, Curtis KS, Papka RE. Innervation of ectopic endometrium in a rat model of endometriosis. Proc Natl Acad Sci USA 2004; 101:11094–8. 13. Bajaj B, Bajaj P, Madsen H, Arendt-Nielsen L. Endometriosis is associated with central sensitization: a psychophysical controlled study. J Pain 2003; 4:372–80. 14. Prentice A, Deary AJ, Bland E. Progestins and anti-progestagens for pain associated with endometriosis (Cochrane Review). The Cochrane Library, Issue 2. Oxford: Update Software, 2001. 15. Prentice A, Deary AJ, Goldbeck-Wood S, Farquhar C, Smith SK. Gonadotropin-releasing hormone analogues for pain associated with endometriosis (Cochrane Review). The Cochrane Library, Issue 2. Oxford: Update Software, 2001. 16. Sutton CJ, Pooley AS, Ewen SP, et al. Follow-up report on a randomized, controlled trial of laser laparoscopy in the treatment of pelvic pain associated with minimal to moderate endometriosis. Fertil Steril 1997; 68:1070. 17. Vercellini, op cit.a. 18. Farquhar C, Vandekerckhove P, Watson A, Vail A, Wiseman D. Barrier agents for preventing adhesions after surgery for subfertility (Cochrane Review). The Cochrane Library, Cochrane Database of Systematic Previews 1999, Issue 2. Art. No. CD000475. 19. Bump RC, Mattiasson A, Bo K, et al. The standardization of terminology of female pelvic organ prolapse and pelvic floor dysfunction. Am J Obstet Gynecol 1996; 175:10–7. 20. King-Baker P. Musculoskeletal origins of chronic pelvic pain. Obstet Gynecol Clin North Am 1993; 20:719. 21. Marks R. Distribution of pain provoked from lumbar facet joints and related structures during diagnostic spinal infiltration. Pain 1989; 39:37–40. 22. Sinake M, Merritt JL, Stillwell GK. Tension myalgia of the pelvic floor. Mayo Clin Proc 1977; 52:717.

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23. Williams RE, Hartmann KE, Sandler RS, Miller WC, Steege JF. Prevalence and characteristics of irritable bowel syndrome among women with chronic pelvic pain. Obstet Gynecol 2004; 104(3):452–8. 24. Prior A, Whorwel PJ. Gynaecological consultation in patients with the irritable bowel syndrome. Gut 1989; 30:996. 25. Kjerulff KH, Langenberg PW, Rhodes JC, et al. Effectiveness of hysterectomy. Obstet Gynecol 2000; 95:319. 26. National Kidney and Urologic Disease Information Clearinghouse. Interstitial Cystitis. (Accessed June 2, 2006 at http://www.niddk.nih.gov/health/urolog/pubs/cystitis/cystitis/htm) 27. Parsons CL. Prostatitis, interstitial cystitis, chronic pelvic pain, and urethral syndrome share a common pathophysiology: lower urinary dysfunctional epithelium and potassium recycling. Urology 2003; 62:976–82. 28. Melzack R. From the gate to the neuromatrix. Pain 1999; 82(Suppl. 6):121.

27

Dysmenorrhea Ian Milsom

Department of Obstetrics and Gynecology, Sahlgrenska Academy at Gçteborg University, Sahlgrenska University Hospital, Gçteborg, Sweden

INTRODUCTION The word dysmenorrhea is derived from the greek word meaning “difficult monthly bleeding.” Women with dysmenorrhea experience periodic cramps with or without associated vegetative symptoms during or immediately before the start of menstruation (Table 1). Dysmenorrhea is the most common form of menstrual complaint in young women. Prevalence has been reported to be as high as 90% (1–9). About 15% of adolescents and young women describe their dysmenorrhea as severe. In young women dysmenorrhea is responsible for a substantial proportion of repeated short-term absenteeism from school and work (1–9). Recent reports from the U.S.A. have stated that dysmenorrhea accounted for 600 million lost hours and two billion dollars in lost productivity annually (8,9). The pain characteristic of dysmenorrhea is similar in character to delivery pains with milder episodes between periods of more intensive pain. The symptoms start often before menstruation and are seldom experienced for more than 24 hours. The pain affects working ability and is a considerable handicap for sufferers. PRIMARY DYSMENORRHEA Normally, primary dysmenorrhea starts after the menarche when ovulatory cycles have been established. There is no organic explanation behind the occurrence of primary dysmenorrhea and it has therefore also been named “essential dysmenorrhea.” SECONDARY DYSMENORRHEA In contrast to primary dysmenorrhea there is always an organic explanation behind the occurrence of secondary dysmenorrhea (Table 2). Membranous dysmenorrhea is an extremely uncommon form of secondary dysmenorrhea that is characterized by the expulsion of the endometrium intact as a cast of the uterine cavity. When the cast is expelled during menstruation the woman experiences severe pain. The exact etiology has not been established but a genetic disposition is suspected. PREVALENCE The reported prevalence of dysmenorrhea varies considerably in different studies from only a few percent to more than 90% of young women. This large variation may partly be explained by the fact that the diagnosis has normally been based on a subjective assessment. Another possible explanation is the varying composition of the different populations studied. However it is generally accepted that dysmenorrhea is a common condition among young women and it is the commonest form of menstrual complaint (1–9). Sweden has unique prerequisites for the performance of epidemiological studies because of its continually updated register over the entire population which permits the selection of a representative group from the total population. A longitudinal study of the prevalence of

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TABLE 1 Characteristic Dysmenorrhea Symptoms Pain Localized to the lower abdomen Commences often before menstruation Seldom experienced for more than 24 hours Referred pain In the groins Along the inside of the thighs In the lower back Vegetative symptoms Nausea Vomiting Headache Irritability Gastrointestinal symptoms Diarrhea Constipation

dysmenorrhea among young women born in 1962 and resident in the city of Go¨teborg was started in 1981 (4,6). In 1981, a one in four sample of girls (nZ2621) born in 1962 and resident in the city of Go¨teborg was obtained at random from the population register. By means of systematic randomization, 656 girls were chosen from the total population. Ninety one percent (nZ596) of the contacted girls answered and returned the postal questionnaire on dysmenorrhea. There were no indications that the nonresponders differed from the responders indicating that the studied population was representative of 19-year-old women from Gothenburg. The severity of dysmenorrhea was assessed by a verbal multidimensional scoring system which grades the severity of pain and also takes into account the effect on daily activity and analgesic requirements (Fig. 1, Grade 0–III). During 1986 and 1991 the same women who answered the questionnaire in 1981 were contacted again. They were requested to answer the same questions now aged 24 and 29 years of age respectively. A reduction in dysmenorrhea, mainly moderate-severe dysmenorrhea was recorded between 19 and 29 years of age. Severe dysmenorrhea was reported by 7% of 29-yearolds compared to 15% of 19-year-olds. Absence from work or school because of dysmenorrhea was reduced from 51% at 19 years of age to 35% at 24 years of age. The prevalence of dysmenorrhea has also been studied in a Norwegian study performed at a factory in Bergen (3). Half of the women reported that they suffered from dysmenorrhea. Thirty percent had been absent from work due to menstrual pain the last six months before the interview. Dysmenorrhea was less common in women O30 years of age. The prevalence of dysmenorrhea in a Finnish study (2) of 331 school girls between 13 and 20 years of age was found to be approximately 50%. The majority had symptoms for one to two days. The pain was so severe in 25% of the girls that their school work was affected. The results of these Scandinavian studies have more recently been confirmed by a study from New Zealand. More than 50% of young women from the city of Wellington reported that they were troubled by menstrual pain. Twenty-eight percent suffered from moderate to severe menstrual pain that influenced their way of life. TABLE 2 Organic Changes That Cause Secondary Dysmenorrhea Endometriosis Cervical strictures Pelvic adhesions following salpingitis Fibroids Endometrial polyp Intrauterine device

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%

Grade 0 = Menstruation is not painful and daily activities are unaffected

100

Grade I = Menstruation is painful but seldom inhibits normal activities; analgesics are seldom required. Mild pain

75 50

Grade II = Daily activity affected. Analgesics required and give pain relief so that absence from work or school is unusual. Moderate pain

25 0

19 yrs

24 yrs

Grade III = Activity clearly inhibited. Poor effect of analgesics. Vegetative symptoms. Severe pain.

29 yrs

FIGURE 1 Dysmenorrhea ranked in order of prevalence and severity in the same women at 19, 24, and 29 years of age (nZ456). The severity of dysmenorrhea was assessed by the verbal multidimensional scoring system described in (5). Grade 0 menstruation is not painful and daily activities are unaffected; Grade I menstruation is painful but seldom inhibits normal activities, analgesics are seldom required, mild pain; Grade II daily activity is affected, and analgesics are required for pain relief so that absence from work or school is unusual, moderate pain; Grade III activity is clearly inhibited, poor effect of analgesics, vegetative symptoms, and severe pain.

HANDICAP Dysmenorrhea is an important periodic handicap for many young women and is one of the most common causes of repeated short-term absenteeism among young women. The extent of lost working time or school days as a result of dysmenorrhea has important consequences for the afflicted individual and society. The importance of dymenorrhea is also apparent from an economic point of view. The national economic consequences of dysmenorrhea are extremely apparent. According to official statistics from the Swedish Department of National Insurance, dysmenorrhea causes more than 230,000 lost working days in Sweden where the total female population is approximately four million. This figure is probably low as many young women are known to provide other diagnoses than dysmenorrhea when reporting sick as a result of menstrual pain. In the Gothenburg study 8% of 19-year-old women reported that they were absent from school or work every menstruation (Table 3). Six percent were absent every other menstruation. In total, 51% had been absent from school or work at some time due to dysmenorrhea. The duration of absenteeism was generally half to one day, but in 10% the absenteeism exceeded two days. Recent reports from the U.S.A. have stated that dysmenorrhea accounted for 600 million lost hours and two billion dollars in lost productivity annually (8,9). Dysmenorrhea influences not only intellectual or working ability but also the level of achievement in many other areas. In sports, it is not unusual that doctors assist sportswomen in

TABLE 3 Absenteeism Due to Dysmenorrhea Among 19-Year-Olds from Gothenburg Absenteeism from school or work Every menstruation Every other menstruation Sometimes Never Duration of absenteeism 1/2 1 day O2 days

Frequency (%) 8 6 37 49 90 10

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TABLE 4 Factors Associated with the Prevalence and Severity of Dysmenorrhea The longer the duration of menstruation, the greater the prevalence and severity of dysmenorrhea The heavier the menstruation, the greater the prevalence and severity of dysmenorrhea Early menarche, then more often dysmenorrhea Mother or sister with dysmenorrhea, then more often dysmenorrhea Oral contraceptive pill use, then less dysmenorrhea Parity, more children then less dysmenorrhea

avoiding menstruation at the time of important competitions such as National, European and World championships as well as the Olympic Games. FACTORS OF IMPORTANCE FOR THE PREVALENCE AND SEVERITY OF DYSMENORRHEA There are several factors that influence the prevalence and severity of dysmenorrhea (Table 4). For example, there is a significant association between the duration of menstruation and the severity of dysmenorrhea. The same applies to the amount of menstrual bleeding: the greater the menstrual blood loss, the more severe the dysmenorrhea. Women with an early menarcheal age more often have dysmenorrhea. There are also some negative associations. Women who use the oral contraceptive pill have less dysmenorrhea than other women. Women who have given birth to a child have less dysmenorrhea than women who have never been pregnant or who have had a miscarriage. There is also evidence for associations within the same family. ETIOLOGY The etiology of dysmenorrhea has been the topic of interest for many years and many theories have been proposed (Table 5). There are several older theories of historic interest. Some of these theories are based on a possible association between dysmenorrhea and uterine position or anomalies. More modern theories relate to an increased myometrial activity during periods of dysmenorrhea. Hippocrates Hippocrates, the father of medical science, postulated that women with dysmenorrhea were poisoned during menstruation. Today we know that this hypothesis was not entirely incorrect. Prostaglandins appear to be the “poison” described more than 2000 years ago. Cervical Stenosis The poisoning theory presented by Hippocrates has later been connected with the hypothesis that the uterine cervix is extremely narrow in women with dysmenorrhea, hindering the TABLE 5 Theories and Attempts at an Explanation of Dysmenorrhea Poisoning (Hippocrates) Cervical stenosis Uterine position Uterine size Uterine innervation Psychological factors Uterine contractility Uterine blood flow Prostaglandins Vasopressin

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outflow of menstruation. The narrowing of the cervical canal could be real or functional. The connection is twofold; the entrapped menstrual blood may cause increased pressure in the uterine cavity, with resultant pain, or substances within the entrapped menstrual blood may be reabsorbed and induce an increased muscle activity. The old theory that dysmenorrhea was caused by functional cervical stenosis led to attempts to treat dysmenorrhea by instrumental dilatation of the cervical canal. Under anesthesia the cervix was dilated with Hegar stifts. Experience has taught us that many women became symptom-free after dilation, but only for a short time. On the other hand, it has not been possible to find any difference in the presence of cervical stenosis between women with dysmenorrhea and women with painless menstruation (10,11). Uterine Position It has also been postulated that the cervical canal could be closed, causing a functional stenosis if the uterus is strongly anteflexed or retroflexed. The functional stenosis gives rise to pain, inducing an increase in intrauterine pressure or enhancing the reabsorbtion of “poisonous” products from menstrual blood as described in the section on cervical stenosis. However it has not been possible to find any difference in uterine position, in particular the occurrence of anteflexion or retroflexion, between women with dysmenorrhea and women with painless menstruation. Uterine Size On examination of young women with dysmenorrhea one often finds a small hypoplastic uterus. Uterus hypoplasia is often mentioned as a possible cause of dysmenorrhea. However there is no direct evidence to suggest that a small uterus per se is a cause of dysmenorrhea. Dysmenorrhea is however more common in nulliparous women who have a smaller uterus. Uterine Nerves Clinical experience strongly indicates that dysmenorrhea is reduced or eliminated after the birth of a child. Part of the explanation of the disappearance of dysmenorrhea following the birth of a child is the influence of a full-term pregnancy on uterine innervation. In animal experiments the short adrenergic neurones in the myometrium have been shown to degenerate during a full-term pregnancy (12,13). They return only partially after delivery. Psychological Factors It has been postulated that women with dysmenorrhea have a low pain threshold and emotional difficulties in identifying themselves as sexually mature women. However, the results of scientific studies comparing the psychological status of women with and without dysmenorrhea have not been able to identify any significant differences (14). Uterine Contractility As early as 1932, physiologists demonstrated an increased uterine contractility in the mammalian uterus during estrus (15). With similar techniques of uterine pressure measurement it was possible to demonstrate an increased uterine activity in the uterus of women with dysmenorrhea in the 1940s. Women with dysmenorrhea had & & &

more frequent uterine contractions; contractions of a higher amplitude; a higher basal uterine tonus.

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A 200 150 100 50 0

0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

FIGURE 2 An intrauterine pressure recording.

compared to women with painless menstruation. The explanation of the increased uterine activity was still, however, unknown. The intrauterine pressure recording above (Fig. 2) shows approximately 22 contractions per hour with an amplitude of up to 200 mmHg and a basal uterine tonus of approximately 50 mmHg. The total intrauterine pressure recording was registered for four hours. Registration shows a clear hyperactivity, with a three to four times higher frequency of contractions and an amplitude approximately four times higher than normal. Even basal uterine tonus was four to five times higher than what is normally recorded in women with pain-free menstruation. Prostaglandins During recent years more and more evidence has been presented to substantiate the primary role of prostaglandins in the etiology of primary dysmenorrhea. Women with dysmenorrhea have significantly higher concentrations of prostaglandin in the endometrium during menstruation than women without dysmenorrhea (16). The use of the oral contraceptive pill has been shown to reduce the concentration of Prostaglandin F2alpha (PGF2a) in the endometrium during the bleeding period. The reduction in prostaglandin concentrations was associated with a reduction in pain during the bleeding period. Uterine Blood Flow There is considerable evidence to substantiate the fact that uterine blood flow is negatively influenced in women with dysmenorrhea. The inhibition of uterine circulation leads to ischemia and endometrial necrosis. The changes in blood flow may be caused by the muscle contractions but may also be caused directly as a result of increased vasopressin activity. During blood flow measurements women have reported that maximum pain experienced coincided with periods of reduced blood flow (17,18). Vasopressin Vasopressin has been shown to have a possible etiological roll in the pathophysiology of dysmenorrhea (19,20). After the observation that reduced blood flow in the uterus was associated with pain, analyses of vasopressin concentrations were performed. An increased vasopressin concentration was found in women with primary dysmenorrhea. The etiological roll of vasopressin has also been confirmed in a study where a competitive inhibitor to vasopressin was used. This resulted in a significant reduction in uterine activity and a concomitant relief of dysmenorrhea. Vasopressin is produced in the posterior lobe of the pituitary. PATHOPHYSIOLOGY OF DYSMENORRHEA The pathophysiological process that involves the ever increasing liberation of prostaglandins is part of a vicious circle resulting in pain (21). This process is described in Figure 3. Lysosomes are intracellular organelles which contain lytic enzymes such as phospholipases and acid phosphatases. These enzymes are retained within the lysosome by the

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Trauma

Lysosome Cellmembrane

Phospholipids acid phosphatases

Hormones

Continued PG-synthesis Liberation of phospholipids Endometrial necrosis

Dysmenorrhea "The vicious circle” Arachadonic acid

PG-synthetase

Menstruation

PG synthetaseinhibition

PGF2α

Contraction of the spiral arteries and myometrial contractions,

FIGURE 3 Schematic diagram representing the pathophysiology of dysmenorrhea.

lysosome membrane. At the end of the menstrual cycle labilization of the lysosome membrane occurs, releasing these lytic enzymes into the cell cytoplasm. It is thought to be the changed hormonal balance at the end of the menstrual cycle which initiates the labilization. When the lytic enzymes are released into the cell, they break down the cell membrane which is composed of two protein chains and phospholipids. Phospholipids are important components of prostaglandins. Arachidonic acid is formed from the phospholipids under the influence of an enzyme phospholipase Aw 2 . Arachidonic acid is converted via endoperoxides to PGF2a. This stage in prostaglandin synthesis is under the influence of the enzyme cyclooxygenase, which can be inhibited by nonsteroidal anti-inflammatory (NSAID) drugs.

DIAGNOSIS OF PRIMARY DYSMENORRHEA The diagnosis primary dysmenorrhea is based on the medical history. Dysmenorrhea is primary (or essential) if the painful menstrual periods have been present since the menarche. Gynecological examination in women with primary dysmenorrhea is normal: there is no organic explanation behind the occurrence of menstrual pain.

DIAGNOSIS OF SECONDARY DYSMENORRHEA Dysmenorrhea is secondary if the painful menstrual periods start some time following the menarche and previously the individual has experienced periods without dysmenorrhea. There is always an organic explanation behind secondary dysmenorrhea. It is necessary to perform an investigation in these women to diagnose the exact cause of the menstrual pain. The investigations often involve ultrasound examination or possibly X ray. Endoscopic examinations are often necessary.

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Endometriosis Peritoneal endometriosis consists of brown-black deposits of endometrial tissue in the peritoneum. Endometriosis localized to the ovary is called an endometrioma. The bleeding which occurs at the time of menstruation fills the cyst with blood products. Subsequent decomposition of these blood products colors the contents and the surface of the cyst brown-black. Post Salpingitis Tubal Damage, and Adhesions Tubovarian damage with adhesions between the fallopian tubes and ovaries and the body of the uterus are a common occurrence following salpingitis and may give rise to dysmenorrhea. Adhesions in the pelvis between the fallopian tubes and the pelvic wall are also commonly encountered following salpingitis. The most extreme form is called “frozen pelvis.” Fibroids Fibroids are a benign form of uterine tumor. Their localization varies and they may be subserous, intramural, or submucous. Uterus Duplex, Uterus Bicornis, and Uterine Septum Congenital malformations such as uterus duplex, uterus bicornis, and uterus septus are uncommon causes of secondary dysmenorrhea. Vaginal or cervical atresia with ensuing hematocolpos and/or hematometra is an uncommon cause of secondary dysmenorrhea in young girls. Secondary dysmenorrhea generally starts later in life, but when anatomical changes are the cause the debut of symptoms will be earlier and is often confused with primary dysmenorrhea. Uterus duplex occurs when the Mu¨llerian ducts develop side by side without joining. The duplication can even involve the vagina, but in the majority of cases is restricted to a double uterus with a double or single cervix and a normal vagina. Uterus bicornis develops when the Mu¨llerian ducts have merged partially so that the the body of the uterus is doubled but the cervix and vagina are normal. Various different malformations as a result of defective merging of the Mu¨llerian ducts may be seen. The uterus may appear to be normal (at vaginal examination and during laparoscopy) but defective merging may have resulted in a septum dividing the uterine cavity in two. Imperforate Hymen and Hematocolpos The hymen is the residual surface where the vagina subsequently becomes separated from the urogenital sinus. If this transition is not completed then an imperforate hymen remains and a lumen will not develop. It is unusual to diagnose this malformation before the menarche. After the menarche menstrual products will be prevented from leaving the vagina resulting in a protrusion of these entrapped blood products behind the hymen in the vulva. If the hymen remains intact then the menstrual products will be retained within the vagina forming a hematocolpos. The vagina fills slowly and successively so that pain is not that severe. Even the uterus (hematometra) and fallopian tubes (hematosalpinx) can subsequently become dilated before a diagnosis is made. Psychosomatic Factors Synonymous with other pain conditions, dysmenorrhea may have psychosomatic repercussions. This means that it may be difficult to differentiate between psychological and somatic components in some women suffering from dysmenorrhea.

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TREATMENT It is essential that women with dysmenorrhea receive effective treatment. It is therefore important to ask women if they have painful periods when taking a gynecological history. Many women are still not aware that effective treatment is available. Prostaglandin Synthetase Inhibitors The NSAIDs are the method of choice in the treatment of primary dysmenorrhea (21–29). Moderate to severe dysmenorrhea can be treated with prostaglandin synthetase inhibitors (PGSIs). Salicylic acid blocks the synthesis of prostaglandins but the effect is only weak, and its use in dysmenorrhea is limited. Treatment with NSAIDs should be started as soon as the first symptoms of dysmenorrhea are felt. The NSAIDs provide effective pain relief for 70% to 80% of women with primary dysmenorrhea. Contraindications are asthma, anticoagulant treatment, heart failure, kidney diseases, peptic ulcer and allergy for salicylates. The Importance of Over-the-Counter Availability When considering treatment for dysmenorrhea, it is important to consider the availability of treatment (30). Many women are unaware of the exact time when menstruation and concomitant dysmenorrhea will develop, and for the majority of women the most intensive pain is experienced during the first 12 to 24 hours of menstruation. Therefore, it is imperative that analgesic medication is available at the commencement of menstruation. The NSAID preparations became routine treatment for dysmenorrhea during the 1980s, and there are now several well-established drugs for use in dysmenorrhea at prescription dose. However, because they were available only on prescription their availability was restricted. In many countries (e.g., Sweden, U.S.A., and U.K.), a variety of NSAIDs have now become available in pharmacies as over-the-counter drugs. This has made treatment more readily available for women suffering from dysmenorrhea. Oral Contraceptives Women with dysmenorrhea who also require contraception can be recommended the combined oral contraceptive pill OC. OCs provide effective pain relief for 70% to 80% of women with primary dysmenorrhea (31–35). Low dose pills are to be recommended as there is no evidence that older high-dose pills are more effective. There are some indications that progestogen-dominated pills have a better effect. If the pill or PGSI alone are ineffective then the two can be combined and together will often give adequate pain relief. In those cases where neither the pill, PGSI, nor a combination of the two are effective, the patient should be investigated by a gynecologist regarding the possibility of secondary dysmenorrhea. Investigation often starts with a laparoscopy. Other Analgesics Potent analgesics with a central action were commonly used in the treatment of dysmenorrhea before OCs and modern PGSI became available. The effects of this widespread use of potent analgesics was not always only positive. Many women were negatively affected by the use of potent analgesics as side effects such as tiredness, sleepiness, and reduced mental ability were common. In some cases the effects and consequences of treatment were more negative than the dysmenorrhea itself. Today there is no reason why centrally acting analgesics should be used in women with dysmenorrhea when PGSI and OCs are now available. Alternative Forms of Pharmacological Treatment Administration of a b2 adrenergic—receptor stimulagonist, e.g., terbutaline (Bricanylw) has been shown to eliminate or reduce premature contractions that threaten to induce preterm birth. Terbutaline has a poorer effect on the nonpregnant uterus. High doses are required to reduce

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the uterine hyperactivity associated with primary dysmenorrhea. When such high doses are required, side effects such as tachycardia, tremor, and nausea are all too troublesome. Synthetic retro-progesterone (Duphastonew) given daily for a greater part of the menstrual cycle is registered under the indication “primary dysmenorrhea.” This treatment has, however, not been shown to be as effective as PGSI or OCs and is used very little. Possible Future Drugs Continued research, is being performed aimed at producing new forms of treatment for dysmenorrhea (36,37). The calcium antagonist nifedipine inhibits uterine activity and reduces dysmenorrheic pain. However calcium antagonists have as yet not been introduced into the clinical arsenal of drugs for the treatment of dysmenorrhea as they are still too unselective. The relationship between vasopressin and menstrual pain has been studied. There is an increase in vasopressin release in women with primary dysmenorrhea. Attempts have therefore been made to treat dysmenorrhea with a competitive inhibitor to vasopressin. Non-pharmacological Treatment Transcutaneous electrical nerve stimulation has been shown to be an effective method for the treatment of primary dysmenorrhea (38,39). Possible mechanisms are a reduction in uterine ischemia and/or inhibition of impulse transmission in the pain pathways on a spinal or supraspinal level. Continuous low-level topical heat has also been shown to be effective (40). EVALUATION OF DYSMENORRHEA THERAPY The evaluation of drugs used in the treatment of dysmenorrhea should not purely be based on a subjective assessment (27). The pain associated with dysmenorrhea is difficult to assess and other negative symptoms such as nausea, vomiting, headache, and irritability may influence the woman’s ability to assess experienced pain. REGISTRATION OF INTRAUTERINE PRESSURE The development of a technique for measuring intrauterine pressure has permitted a more objective evaluation of dysmenorrhea treatment. With microelectronic components it has been possible to construct a pressure sensitive receptor so small that it can be incorporated in the tip of a catheter only 2.5 mm in diameter (Fig. 4). The catheter is introduced into the uterine cavity via the cervix and positioned with its tip in the fundus of the uterus. Pressure changes in the uterine cavity are transferred via the pressure sensitive tip to a writer and can thus be documented.

FIGURE 4 The small microtransducer catheter which can be inserted into the uterine cavity to measure intrauterine pressure (on the right). The catheter is positioned adjacent to a copper intrauterine device (on the left) in order to demonstrate the size of the catheter.

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Intrauterine pressure, (mmHg) 200 Contractions

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FIGURE 5 A 30-minute section of an intrauterine pressure registration demonstrating measurement parameters, such as basal tonus, contraction amplitude, frequency of contractions, and the area under the curve.

The figure above (Fig. 5) illustrates a 30-minute tracing of intrauterine pressure in a woman with severe dysmenorrhea. The basal tonus is approximately 50 mmHg. The frequency of contractions is approximately 10 per 30-minute period. The amplitude of the contractions reaches a maximum of 200 mmHg. By measuring the area under the curve it is possible to simultaneously take into account basal tonus and amplitude and frequency of the contractions. Figure 6 illustrates intrauterine pressure measurements in two women with severe primary dysmenorrhea. One woman was given 500 mg paracetamol (Alvedonw) 30 minutes after the registration was started (Fig. 6A). As can be seen in the picture there was little or no effect of the medication on uterine contractility. The second woman was given 500 mg naproxen (Naprosynw) 30 minutes after the registration was started (Fig. 6B). As can be seen in the picture there was an obvious reduction in the amplitude and frequency of the contractions and in the basal tonus after approximately 1.5 hours. The woman experienced symptomatic pain relief concomitant with the reduction in uterine activity. CONCLUSION Dysmenorrhea is an important periodic handicap for many young women and is one of the most common causes of repeated short-term absenteeism among young women. The extent of lost working time or school days as a result of dysmenorrhea has important consequences for 500 mg paracetamol Intrauterine pressure, mm Hg (A)

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FIGURE 6 Two intrauterine pressure registrations before and after medication. (A) In the woman who received 500 mg paracetamol, there was little or no effect on uterine contractility. (B) There was an obvious reduction in amplitude and frequency of contractions and in the basal tonus in the woman who received 500 mg naproxen.

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the afflicted individual and society. Substantial evidence has been presented to support the primary role of prostaglandins in the etiology of primary dysmenorrhea, and there are also studies indicating a reduced uterine blood flow in women with dysmenorrhea. Dysmenorrhea is primary (or essential) if the painful menstrual periods have been present since the menarche. Gynecological examination in women with primary dysmenorrhea is normal, and there is no organic explanation for occurrence of the menstrual pain. Dysmenorrhea is secondary if the debut of painful menstrual periods starts after a longer time following the menarche. There is always an organic explanation (e.g., endometriosis, pelvic adhesions, fibroids, endometrial polyp, etc.) behind secondary dysmenorrhea. It is necessary to perform an investigation (ultrasound, possibly X ray, or endoscopic examination) in these women to diagnose the exact cause of the menstrual pain. The NSAIDs or OCs are the method of choice in the treatment of primary dysmenorrhea. If the oral contraceptive pill or NSAIDs alone are ineffective then the two can be combined and together will often give adequate pain relief. In those cases where neither the pill, NSAIDs, nor a combination of the two are effective, the patient should be investigated by a gynecologist regarding the possibility of secondary dysmenorrhea. REFERENCES 1. Svennerud S. Dysmenorrhea and absenteeism. Some gynaecological and medicosocial aspects. Acta Obstet Gynecol Scand 1959; 38:1. 2. Widholm O, Kantero R-L. Correlations of menstrual traits between adolescent girls and their mothers. Acta Obstet Gynecol Scand 1971; 50:30. 3. Bergsjo¨ P, Jenssen H, Vellar OD. Dysmenorrhea in industrial workers. Acta Obstet Gynecol Scand 1975; 54:255. 4. Carey HM. Dysmenorrhea. Med J Aust 1975; 2:349. 5. Andersch B, Milsom I. An epidemiologic study of young women with dysmenorrhea. Am J Obstet Gynecol 1982; 144:655. 6. Pullon S, Reinken J, Sparrow M. Prevalence of dysmenorrhoea in Wellington women. N Z Med J 1988; 101:52. 7. Sundell G, Milsom I, Andersch B. Factors influencing the prevalence and severity of dysmenorrhea in young women. Br J Obstet Gynaecol 1990; 97:588. 8. Coco AS. Primary dysmenorrhea. Am Fam Physician 1999; 60:489–98. 9. Davis AR, Westhoff CL. Primary dysmenorrhea in adolescent girls and treatment with oral contraceptives. J Pediatr Adolesc Gynecol 2001; 14:1–2. 10. Asplund J. The uterine cervix and isthmus under normal and pathological conditions. Acta Radiol 1952; 91:1. 11. Ylikorkala O, Dawood MY. New concepts in dysmenorrhea. Am J Obstet Gynecol 1978; 130:833. 12. Thorbert G. Regional changes in structure and function of adrenergic nerves in guinea pig uterus during pregnancy. Acta Obstet Gynecol Scand 1978; 79(Suppl.):1. 13. Sjo¨berg NO. Dysmenorrhea and uterine neurotransmitters. Acta Obstet Gynecol Scand 1979; 87(Suppl.):57. 14. Cullberg J. Mood changes and menstrual symptoms with different gentagen oestrogen combinations. Acta Psychiatr Scand 1972; 236(Suppl.):1. 15. Novac E, Reynolds SRM. The cause of primary dysmenorrhea with special reference to hormonal factors. J Am Med Assoc 1932; 99:1466. 16. Lundstro¨m V, Gre´en K. Endogenous levels of prostaglandin F2a and its metabolites in plasma and endometrium of normal and dysmenorrheic women. Am J Obstet Gynecol 1978; 130:640. ˚ kerlund M, Bengtsson LP, Ulmsten U. Recording of myometrial activity in the non-pregnant human 17. A uterus by a micro-transducer catheter. Acta Obstet Gynecol Scand 1978; 57:429. ˚ kerlund M, Bengtsson LP, Carter AM. A technique for monitoring endometrial or decidual blood 18. A flow with an intrauterine thermister probe. Acta Obstet Gynecol Scand 1975; 54:469. ˚ kerlund M. Pathophysiology of dysmenorrhea. Acta Obstet Gynecol Scand 1979; 87(Suppl.):27. 19. A ˚ kerlund M, Melin P. Uterine blood flow and myometrial activity at menstruation and 20. Hauksson A, A the action of vasopressin and a synthetic antagonist. Br J Obstet Gynaecol 1988; 95:898. 21. Henzl MR, Izu A. Naproxen and naproxen sodium in dysmenorrhea: development from in vitro inhibition of prostaglandin synthesis to suppression of uterine contractions in women and demonstration of clinical efficacy. Acta Obstet Gynecol Scand 1979; 87(Suppl.):105–17. 22. Lundstro¨m V, Gre´en K, Svanborg K. Endogenous prostaglandins in dysmenorrhea and the effect of prostaglandin synthetas inhibitors (PGSI) on uterine contractility. Acta Obstet Gynecol Scand 1979; 87(Supp.):51–6.

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23. Pulkinnen MO. Suppression of uterine activity by prostaglandin synthetas inhibitors. Acta Obstet Gynecol Scand 1979; 87(Suppl.):39–43. 24. Henzl MR. A new perspective on Dysmenorrhea. The role of prostaglandins and prostaglandin inhibitors. J Reprod Med 1980; 25(4 Suppl.):191–242. 25. Chan WY, Fuchs F, Powell AM. Effects of naproxen sodium on menstrual prostaglandins and primary dysmenorrhea. Obstet Gynecol 1983; 61:285–91. 26. Chan WY. Prostaglandins and nonsteroidal antiinflammatory drugs in dysmenorrhea. Annu Rev Pharmacol Toxicol 1983; 23:131–49. 27. Milsom I, Andersch B. Effect of ibuprofen, naproxen sodium and paracetamol on intrauterine pressure and menstrual pain in dysmenorrhea. Br J Obstet Gynaecol 1984; 91:1129. 28. Milsom I, Andersch B. Ibuprofen and naproxen sodium in the treatment of primary dysmenorrhea: a double blind cross-over study. Int J Gynaecol Obstet 1985; 23:305–10. 29. Fraser I. Prostaglandins, prostaglandin inhibitors and their roles in gynecological disorders. Clin Obstet Gynecol 1992; 6:829–57. 30. Milsom I, Minic M, Dawood MY, et al. Comparison of efficacy and safety of non-prescription dose of naproxen and naproxen sodium with ibuprofen, acetaminophen and placebo in the treatment of primary dysmenorrhea (pooled-analysis of five studies). Clin Ther 2002; 24:1384–400. 31. Lalos O, Joelsson I. Effect of an oral contraceptive on uterine tonicity in women with primary dysmenorrhea. Acta Obstet Gynecol Scand 1981; 60:229. 32. Milsom I, Andersch B. Effect of various oral contraceptive combinations in dysmenorrhea. Gynecol Obstet Invest 1984; 17:284. ˚ kerlund M. Influence of a combined oral 33. Hauksson A, Ekstro¨m P, Juchnicha E, Laudanski T, A contraceptive on uterine activity and reactivity to agonists in primary dysmenorrhea. Acta Obstet Gynecol Scand 1989; 68:31. 34. Milsom I, Sundell G, Andersch B. The influence of different combined oral contraceptives on the prevalence and severity of dysmenorrhea. Contraception 1990; 42:497–506. 35. Nabrink M, Solum T, Birgersson L, Colling-Saltin A-S. Modern oral contraceptives and dysmenorrhea. Contraception 1990; 42:275. 36. Andersson K-E, Ulmsten U. Effects of nifedipine on myometrial activity and lower abdominal pain in women with primary dysmenorrhoea. Br J Obstet Gynaecol 1978; 85:142. ˚ kerlund M, Stro¨mberg P, Forsling ML. Primary dysmenorrhea and vasopressin. Br J Obstet 37. A Gynaecol 1979; 86:484. 38. Lundeberg T, Bondesson L, Lundstro¨m V. Relief of primary dysmenorrhea by transcutaneous nerve stimulation. Acta Obstet Gynecol Scand 1985; 64:491. 39. Milsom I, Hedner N, Mannheimer C. A comparative study of the effect of high intensity transcutaneous nerve stimulation and oral naproxen on intrauterine pressure and menstrual pain in patients with primary dysmenorrhea. Am J Obstet Gynecol 1994; 170:123–9. 40. Akin MD, Weingand KW, Hengehold DA, Goodale MB, Hinkle RT, Smith RP. Continuous low-level topical heat in the treatment of dysmenorrhea. Obstet Gynecol 2001; 97:343–9.

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Pelvic Pain in Gynecological Practice Endometriosis-Related Urogenital Pain Lennart Hahn

Department of Obstetrics & Gynecology, Sahlgren’s University Hospital, Gothenburg, Sweden

INTRODUCTION Endometriosis is an enigmatic disease, defined as the presence of endometrial-like tissues outside the endometrial lining of the uterus. It is an estrogen-dependent disease, but the fundamental cause is still unknown. It is associated with abdominal and pelvic pain as well as with infertility. In this chapter only the aspects of pain will be discussed. EPIDEMIOLOGY AND PATHOGENESIS Endometriosis is a common disease and is probably underdiagnosed. The incidence in women of reproductive age is estimated up to 10% (1) but in women with pelvic pain the incidence increases up to 25% (2). The most widely accepted theory is based on the presence of retrograde menstruation, where endometrial cells pass through the fallopian tubes into the peritoneal cavity where they implant (3). However, as 90% of women sometimes have retrograde menstruation (4), more factor(s) are needed for the disease to develop. They include genetic (5), immunological (6), or other hitherto unknown factors. DIAGNOSIS AND CLINICAL PICTURE The diagnosis of endometriosis, mainly based on the findings at laparoscopy, can be very easy and also very difficult. In fact, biopsies from normal appearing peritoneum have shown endometriosis in 6% of the cases (7). Generally the disease starts with an increased vascularization at the place of the implant, then progresses from small uncolored vesicles that later develop into different colors, red from bleeding, then dark black and finally white when they are considered as inactive and not causing any pain. The final stage is usually one of fibrosis with adhesions. Endometriosis can also affect the ovaries, where the secretion of the implants leads to the development of cysts, so called endometriomas. The relation between the extent of peritoneal endometriosis according to a scoring system, rAFS (Revised American Fertility Society) (8) and the pain is poor. Other clinical manifestations of endometriosis, by some researchers considered to distinctly differ from peritoneal implants and from ovarian cysts (9), are hard nodular aggregates containing smooth muscle as well as endometrial glands and stroma. These lesions invade deep pelvic structures such as the rectovaginal septum. They may easily be overlooked during laparoscopy but can be diagnosed through a careful clinical examination, preferably during anesthesia. The correlation between the extent of these lesions and pelvic pain is better than with the peritoneal lesions. The fibrotic nature of the lesions together with different hormone receptor patterns (9) leads to a diminished response to medical treatment as well as to technical difficulties at operations. The most common locations of peritoneal endometriosis are the uterosacral ligaments, the ovaries, the ovarian fossae, and the vesicouterine fold. Less common locations are the pouch of Douglas, broad ligaments, and the uterine serosa. The cardinal symptoms are dysmenorrhea and dyspareunia, and oral contraceptives and non-steroid anti-inflammatory drugs (NSAIDs)

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are usually not effective to reduce the pain. As this chronic disease progresses the pelvic pain progresses from a cyclical pain to a more continuous one. There are also extragenital locations of endometriosis, estimated to consist of up to 15% of all endometriosis. Lesions in the gut are the most common, making up a third of the reported extragenital lesions. It is most common in those segments that are close to the uterus. The lesions may grow in a circular way to stricture the gut and mimic colonic cancer. Other locations, supporting the hypothesis of implantation, are cicatricial, in the abdomen as well as in the vagina. Finally, the urinary tract lesions that are engaged in 2% to 4% of all and 20% of all extragenital endometriosis are mostly in the bladder and the ureter (49% each) and very seldom in the kidney and urethra (9). They are often considered as the result of a more aggressive form of endometriosis with more fibrosis and tissue damage. In the bladder, the trigone area, the rear wall, and the ureteral ostium are the preferred sites of endometriosis. The growth of the implants is always from the peritoneal cavity. At cystoscopy the lesion may look like an irregular blue-brown lesion surrounded by a mucosa that can be edematous and which bleeds easily. In later stages, the lesions may look like the peritoneal lesions in different colors. The symptom of bladder endometriosis is pain when the bladder is distended. This may lead to sensations of urgency. The symptoms may initially be cyclical, e.g., more pronounced at menstruation, but later in the disease more continuous. Hematuria is reported to be not very common. When the ureter is engaged, it is almost always the distal part below the pelvic rim that is affected. Because of the slow progression of the disease it does not necessarily give rise to pain. The end result may well be a silent kidney. Sometimes a hydronephrosis can occur leading to intermittent pains. It is a rare finding that urogenital endometriosis exists without concomitant gynecological disease. The risk of urological involvement increases with the extent of endometriosis that can be clinically evaluated. Preoperative imaging of the urinary system (intravenous pyelography, ultrasound ormagnetic resonance) is highly recommended before a major operation when hysterectomy and/or salpingo-oophorectomy is considered. TREATMENT Because of the fibrotic nature of endometriosis engaging the urinary system, the common medical treatments (Gonadotropin Releasing Hormones, gestagens a.o.) often fail to relieve symptoms of pain. The lesions are therefore usually removed surgically. There is no good evidence for the use of medical treatment postoperatively in endometriosis in the urinary system. The results of postoperative treatment in other forms of endometriosis are conflicting, and a gynecologist should be consulted about recent advances in medical treatment. REFERENCES 1. Wheeler JM. Epidemiology of endometriosis-associated infertility. J Reprod Med 1989; 34:41–6. 2. Eskenazi B, Warner ML. Epidemiology of endometriosis. Obstet Gynecol Clin North Am 1997; 24:235–58. 3. Sampson JA. Peritoneal endometriosis due to the menstrual dissemination of endometrial tissue into the peritoneal cavity. Am J Obstet Gynecol 1927; 14:422–69. 4. Halme J, Becker S, Winf R. Accentuated cyclic activation of peritoneal macrophages in patients with endometriosis. Am J Obstet Gynecol 1984; 148:85–90. 5. Moen MH, Magnus P. The familial risk of endometriosis. Acta Obstet Gynecol Scand 1993; 72:560–4. 6. Lebovic DI, Mueller MD, Taylor RN. Immunobiology of endometriosis. Fertil Steril 2001; 75:1–10. 7. Nisolle M, Paindaveine B, Bourdon A, et al. Histologic study of peritoneal endometriosis in infertile women. Fertil Steril 1990; 53:984–8. 8. The American Fertility Society. Revised American Fertility Society classification of endometriosis. Fertil Steril 1985; 43:351–2. 9. Donnez J, Nisolle M, Gillerot S, et al. Rectovaginal septum adenomyotic nodules: a series of 500 cases. Br J Obstet Gynaecol 1997; 104:1014–8.

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Vulvar Pain Syndrome Etiology, Epidemiology, and Research David C. Foster

University of Rochester School of Medicine and Dentistry, Rochester, New York, U.S.A.

Historically, vulvar pain syndrome cannot be separated from the earlier description of painful intercourse (dyspareunia). The problem of dyspareunia was first described in the Egyptian papyri scrolls over 2000 years ago. The earliest description of vulvar pain syndrome per se can be traced to T. Galliard Thomas’ (circa 1896) description of “hyperesthesia vulvae” (1). In 1928 Howard Kelly described vulvar vestibulitis as focal spots of erythema that were “a fruitful source of dyspareunia” (2), and in 1959, Robert O’Donnell described a classical surgical procedure for entry dyspareunia, later known as the perineoplasty (3). In contrast to the contemporary, decade-long expansion of pain research into conditions such as post-herpetic neuralgia (PHN) and diabetic neuropathy, research into the causes and treatments of vulvar pain syndrome per se have only begun in the last several years. EMBRYOLOGY DEFINES ANATOMY In no other anatomic region, in either gender, do epithelia derived from each of the trilaminar embryonic cell lines (ectoderm, endoderm, and mesoderm) juxtapose more closely than in the vulvovaginal region (Fig. 1). The genital tubercle, urethral fold, and genital swelling make up the gland clitoris, labia minora, and labia majora, respectively, and are of ectodermal origin (4). Because of this fact, the histologic characteristics of the external vulva are those of skin including keratinized stratified squamous epithelium, well-developed rete pegs, and skin appendages including hair follicles, sebaceous glands, and sweat glands (Fig. 1A). The visible margin of keratinization is known as Hart’s line and approximates the junction of ectoderm and endoderm. Consistent with its origin, the stratified squamous epithelium of the vestibule commonly lacks both keratinization and a granular zone. The glands of the vestibule differ from the vulva outside of Hart’s line. They consist of acini lined by mucinous epithelium and ducts lined by transitional epithelium, identifying the urogenital sinus origin (Fig. 1B). The vulvar vestibule, structurally and functionally, bears a closer resemblance to the lower urinary tract than to the external vulva or vagina (5,6). The junction of Wolffian duct-derived (lower) vagina and vulvar vestibule is the hymeneal membrane. The vagina is a fibromuscular tube lined by a stratified squamous mucous membrane derived from two mesodermal derivatives: Muellerian duct and the Wolffian duct. Glandular elements are normally not found in the vagina (Fig. 1C). With respect to immune response in general and inflammatory pain specifically, a close molecular communication has been recognized between the overlying epithelium and the immunologically responsive cells in the connective tissue. This close, bidirectional communication has been likened to an epithelial– immune cell “internet” (7). Thus, given the embryologically defined transition in surface epithelia one might seek to find an embryologically defined transition in immune responsiveness and inflammation within the underlying connective tissue. VULVAR PAIN SYNDROME EPIDEMIOLOGY The National Health and Social Life Survey (NHSLS) (8) was the first population-based assessment of sexual dysfunction since the seminal work of Kinsey reported in 1948 (9). The NHSLS found that 15.6% (230 of 1479) of women reported sexual dysfunction secondary to

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FIGURE 1 (See color insert. ) The lower female genital tract demonstrates a close juxtaposition of three embryologic derivatives: (A) external vulva (ectoderm), (B) vestibulu (endoderm), and (C) vagina (mesoderm).

“pain during sex” (8). Of the women with dyspareunia in the NHSLS, the proportion suffering from vulvar pain syndrome cannot be determined based upon the absence of a standard classification at the time of the study. Meana et al. (10) used structured interviews, standardized pain measures, psychometric tests, and gynecologic exams, to characterize dyspareunia into defined disease entities. Four diagnostic subtypes of dyspareunia were identified: no dyspareunia-related physical findings (24%), vulvar vestibulitis (46%), vulvovaginal atrophy (13%), and mixed—other conditions (17%). The two subtypes contributing to two-thirds of cases, “vulvar vestibulitis” and “no physical findings,” appeared to have unique psychosocial profiles. The “no physical findings” subtype was characterized by higher measures of psychologic and relationship maladjustment coexisting with similar measures to controls for sexual response (desire, arousal, intercourse frequency, and frequency of orgasm). In contrast, the “vulvar vestibulitis” subtype was characterized by similar measures to controls for psychological symptoms but reported significant impairment of sexual function and negative attitudes toward sexuality. Of all subtypes of dyspareunia, women with vulvar vestibulitis reported the highest prevalence of pain to vulvar touch and pain with gynecologic exam. Harlow and Stewart used Massachusetts Town Census directories to identify 4915 women aged 18 to 64. According to a self-administered questionnaire, 3358 of women returning the questionnaire noted a 16% report of chronic burning, knife-like, sharp pain, or pain with contact that lasted more than three months (11). Of note, this percentage is nearly identical to the earlier findings from the NHSLS. The problem of dyspareunia decreased with increasing age with the highest incidence under 25 years old. Hispanic women were at greatest risk of chronic vulvar pain, whereas Caucasian and African-American women had a similar risk. A follow-up study by Harlow et al. reported on a more select sample of presumptive vulvar pain syndrome cases (NZ125) and age-matched controls from the same population (12). Presumptive vulvar pain syndrome cases reported less overall family support in childhood and more frequently feeling danger in their home, neighborhood, or school. The follow-up study by Harlow et al. found African Americans significantly underrepresented in vulvar pain syndrome cases in contrast to their first report. Several widely divergent estimates have been posed for the lifetime cumulative incidence of vulvar pain syndrome ranging between 200,000 and 14 million (11). DEVELOPMENT OF A CLASSIFICATION OF VULVAR PAIN SYNDROME A useful classification of disease should provide at least one of several goals: & & &

Reflect the understanding of pathophysiology of the condition Provide insight into the choice of therapy Predict prognosis of defined disease subsets

A useful classification of chronic vulvar pain has remained elusive for several reasons. First, the pathophysiology of vulvar pain syndrome remains obscure, second, therapeutic options

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have not been well studied for efficacy and prognosis, and finally, a diverse group of providers, including gynecologists, dermatologists, neurologists, psychiatrists, and physical therapists manage chronic vulvar pain, contributing differences in disease understanding and treatment focus. Chronic vulvar pain excludes vulvar pain of less than three months’ duration and can be subdivided into vulvar pain syndrome, per se, and chronic vulvar pain secondary to other chronic/recurrent vulvar conditions. Vulvar pain syndrome commonly arises from preexisting pathologic conditions such as infection, trauma, other inflammation, or possibly spontaneously but the presence of the preexisting condition is no longer necessary for maintenance of the chronic pain state. Secondary pain, in contrast, requires a chronic condition such as lichen sclerosus, erosive vulvovaginitis, chronic/recurrent candidiasis, or persistent vaginal fissures to coexist with the chronic vulvar pain state. We anticipate that the list of “secondary” pain conditions may expand as further understanding of chronic vulvar pain develops. This chapter focuses on the primary type of vulvar pain syndrome. The reader is referred to other reviews of chronic vulvar conditions producing secondary vulvar pain (13). Primary Type of Chronic Vulvovaginal Pain—Vulvar Pain Syndrome Recognizing the need for an updated vulvar pain syndrome classification, the 1999 World Congress of the International Society for the Study of Vulvovaginal Disease (ISSVD) convened a discussion group to update classification of chronic vulvar pain. The discussion group was charged with defining the major category and subdivisions of chronic vulvar pain without visible dermatosis. The group proposed the term “vulvar dysesthesia (vulvar pain syndrome)” for the broad category and subdivided vulvar dysesthesia into dimensions of “generalized” versus “localized” and “provoked” versus “unprovoked” pain (14). “Localized vulvar dysesthesia” was synonymous with vulvar vestibulitis syndrome (VVS) and included less commonly used descriptors: vestibulodynia and clitorodynia. The pain of VVS could present as either a “provoked” or “unprovoked” type. The ISSVD group concluded that the older term “vulvar vestibulitis” implied inflammation and was misleading because of poor correlation between vestibular pain and classical inflammatory infiltrate. Instead, the group recommended a change from the term “vestibulitis” to “vestibulodynia.” General acceptance of the proposed classification and terminology has met with slow approval and many clinicians in the field continue to use the term “vulvar vestibulitis” or VVS. In this chapter we will use the recognized acronym “VVS” to refer to localized vulvar pain syndrome or vestibulodynia. Localized Vulvar Pain Syndrome (Vulvar Vestibulitis) In the premenopausal woman, the most common cause of long-standing dyspareunia is VVS (10,15). An estimated 10% to 15% of women will meet the VVS diagnostic criteria at some time in their lives. VVS-afflicted women commonly suffer significant psychosocial problems including sexual dysfunction, anxiety, infertility, and divorce (16–18). VVS is characterized by dyspareunia and pain to light touch associated with one or more painful foci of the vulvar vestibule and no identifiable source of pain such as herpes, candida, or pemphigoid. An early vulvar pain syndrome paper by Peckham et al. (19) reported on 67 women with VVS, which they termed “focal vulvitis.” They noted that vestibular inflammation was “rarely seen with the naked eye,” whereas vestibular hypersensitivity and allodynia on physical exam were “essential” diagnostic criteria. Exquisite sensitivity to touch was found to be characteristically focal, reproduced with remarkable precision by independent observers, and separated from nontender areas of the vulva and vagina by a matter of millimeters (19). In 81% of patients all painful foci were located on the mucosa of the lower (posterior) half of the vestibule, between 3:00 and 9:00 inclusive, and limited by the line of keratinization (Hart’s line) and the hymeneal ring. Friedrich’s criteria (20) remain the accepted standard for diagnosis and include: (i) severe pain on vestibular touch or attempted vaginal entry, (ii) tenderness localized within the vestibule, and (iii) physical findings of erythema of various degrees. In contrast to other types of vulvar pain syndrome, the highly localized regions of pain in vulvar vestibulitis show distinct differences in mechanical, thermal, and deep pressure pain threshold (21). Distinct differences in pain response to light touch permit a clear definition of disease with

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high interrater reliability (22). VVS has been further subdivided by some into “primary” and “secondary” types. “Primary” type VVS arises from first contact by tampon or sexual intercourse whereas “secondary” type VVS arises following a period of time of pain-free tampon insertion or intercourse (23). Analysis of the difference between VVS types found primary VVS cases reported higher pain levels by Visual Analog Scale and were found to have lower systolic blood pressures (23). Generalized Vulvar Pain Syndrome (Dysesthetic Vulvar Pain Syndrome ) and Neuralgia of the Pelvic Floor In contrast to VVS, generalized vulvar pain syndrome encompasses a more diverse and less well-defined group of conditions. The disease category includes chronic vulvovaginal pain (vulvar pain syndrome) that lacks a focal region of hyperesthesia and/or allodynia. Generalized vulvar pain syndrome can present with “provoked” or “unprovoked” pain. Similar to localized vulvar pain syndrome, the etiology of generalized vulvar pain syndrome remains uncertain and may be even more enigmatic. A substantial number of these cases may be ultimately categorized as neuralgia. Injury, infection, surgical entrapment, or compression of the pudendal, ilioinguinal, genitofemoral nerves, and sacral nerve roots may be the basis of a subset of vulvar pain cases included within the category of generalized vulvar pain syndrome, categorized as neuralgia. Pelvic pain secondary to neuralgia may actually result from damage or injury to the neuraxis at a variety of locations including cerebral cortex, spinal cord, sacral plexus, and peripheral nerve. Are Generalized and Localized Vulvar Pain Syndromes Distinct Conditions? Several studies have attempted to use psychometric measures to distinguish between localized and generalized vulvar pain syndrome with mixed success (24,25). Reed et al. (26). performed an extensive and methodical exam of the vulva measuring allodynia and hyperalgesia by Q tip at multiple lower genital sites. A retrospective review of medical records found significantly higher levels of pain with sitting and washing in localized vulvar pain syndrome compared to the generalized variety. There was also a higher reported rate of Candida albicans infection with localized vulvar pain syndrome. Comparing responses to an extensive 27-page questionnaire covering demographics, medical history, family history, sexual history, and attitudes, it was found that generalized and localized vulvar pain syndrome are essentially indistinguishable. The authors concluded that generalized and localized vulvar pain syndrome represented two presentations on a continuum of severity of the same condition. Similar observations by others led to the conclusion that location (generalized vs. localized) and pain stimulus characteristic (provoked vs. unprovoked) do not distinguish distinct disease entities (25,27). PROPOSED ETIOLOGIES FOR VULVAR PAIN SYNDROME Viral Infection as a Possible Pain Etiology: Human Papilloma Virus, Herpes Zoster, and Herpes Simplex Virus Earlier studies associated human papilloma virus (HPV) with vulvar and vestibular inflammation and pain (28–30). The studies were based upon several lines of indirect evidence including the clinical observation of papillomatous projections found in the vestibule, visually consistent with HPV. More recently, several authors have demonstrated via molecular techniques that the labial micropapillomatosis was not commonly associated with HPV (31,32) and that micropapillomatosis was actually a normal variant seen in up to 50% of premenopausal women (33). Histologic criteria for the diagnosis of HPV have been quite variable and are likely to have been overdiagnosed, particularly with respect to vulvar vestibulitis. Indirect evidence for an HPV causation was based on the observation that various formulations of interferon were successful in clearing both HPV-associated warts and vulvar pain (34). The HPV–VVS relationship was questioned by Marinoff et al. (35) who reported that a significant pain improvement from alpha-interferon administration occurred independent of histologically demonstrated HPV change. Presently, there is a general agreement that an HPV

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pathogenesis for VVS is unlikely. On the other hand, many experts agree that the treatment for HPV-associated infection including application of trichloroacetic acid (36), podophyllin, and laser ablation may be clinically suspected as iatrogenic causes of genital injury. Other viruses of the neurotropic herpes family have also been implicated in the development of vulvar pain syndrome. Reactivation of herpes zoster is the etiopathogenesis behind the development of PHN that can involve the pudendal nerve. In contrast, herpes simplex virus (HSV) has not been associated with long-standing neuralgia and vulvar pain syndrome. HSV has been indirectly implicated based upon a limited number of vulvar pain syndrome patients who symptomatically improved following antiviral treatment with acyclovir (37). To date, no controlled retrospective or prospective studies have indicated herpes infection to be a risk for vulvar vestibulitis. Infection: Vulvovaginal Candidiasis Vaginal candidiasis is the most commonly recognized precursor to VVS, although a significant number of “yeast infections” are found to be only self-reported, without the aid of laboratory confirmation (18,38). The pathogenesis of vulvovaginal candidiasis is complex due to variables in resistance in both host and characteristics of the invading organism (39). Using standard patch testing, VVS patients report a heightened cutaneous sensitivity to low doses of crude yeast extract (40). The inflammatory mechanism may be based on several factors including direct epithelial cell damage, hypersensitivity, or allergic reaction. Metabolic Disturbances and VVS: The Oxalate Story Excessive urinary excretion of oxalate was proposed to cause VVS following the observation that a small number of VVS cases reported relief of pain following a low oxalate diet and calcium citrate supplementation (41). Attempts to replicate the finding of elevated urinary oxalates and clinical response to the low oxalate diet have not been successful (42,43). Most view the initial report of high urinary oxalate causing VVS as unsubstantiated. Genetics, Inflammation, and Vulvar Pain The presence of allele 2 ðC=CÞ of the interleukin receptor antagonist gene (IL-1RN) has been associated with several chronic inflammatory conditions of mucocutaneous origin including ulcerative colitis, psoriasis, and Sjo¨gren’s disease (44–46). Jeremias et al. (47) were the first to report an association between allele 2 ðC=CÞ IL-1RN and VVS. In cases of VVS, Jeremias found 53% to be allele 2 ðC=CÞ IL-1RN compared to 8.5% of a sample of asymptomatic women. The increased risk of VVS-afflicted women carrying allele 2 ðC=CÞ IL-1RN has been supported by an additional study from the same group and our group. Mechanistically, allele 2 ðC=CÞ IL-1RN has been associated with a relative imbalance of IL-1b and interleukin receptor antagonist, favoring IL-1b-mediated inflammation. A recent study found that VVS cases produce more IL-1b following immunologic perturbation of peripheral leukocytes (48). Further research will be needed to clarify the relationship of allele 2 ðC=CÞ IL-1RN and chronic inflammatory states. A genetically defined association of skin pigmentation and VVS pain may also exist. Several reports, including our own, found a significant association between VVS and the Caucasian race (18,49,50). The assertion of a genetically defined racial difference in VVS is controversial, and others have suggested that socioeconomic and cultural differences confound the effect of race. Extensive in vivo studies of neuroinflammatory pain have demonstrated that alpha-melanocyte-stimulating hormone (a-MSH), a central mediator of skin darkening, also acts to reduce tissue concentrations of proinflammatory cytokines and nullifies chronic pain induced by cytokines such as IL-1b (51–53). The melanocortin receptor (MC1R) combined with its ligand—a-MSH—may act as part of a physiologic “braking system” during a normal inflammatory response. Six single nucleotide polymorphisms (SNPs) of the MC1R gene, Val60Leu, Val92Met, Arg142His, Arg151Cys, Arg160Trp, and Asp294His, have been shown to be associated with either reduced cAMP activity or reduced a-MSH affinity for the receptor (54,55). The variant MC1R SNPs reduce a-MSH-mediated anti-inflammatory activity and thereby hinder the normal melanocortin-mediated modulation of inflammation and

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pain. A genetically determined, nonfunctional MC1R could therefore be the basis of “autocrine brake failure.” The combined effects that identified genetic variants at both IL-1RN and MC1R loci could therefore lead to an additive effect of unmodulated neuroinflammatory pain (56). Nerve Trauma and Vulvar Pain Syndrome Surgical entrapment, or compression of the pudendal, ilioinguinal, genitofemoral nerves and sacral nerve roots, may be the basis of a subset of vulvar pain cases categorized as neuralgia. Pudendal nerve injury may follow obstetric or mechanical trauma, excessive straining following use of narrow bicycle saddles, or surgical correction of prolapse by the vaginal approach (57–60). Ilioinguinal nerve injury has been associated with needle suspensions for urinary incontinence and other surgical procedures in proximity to the external inguinal ring (61,62). Neuralgia pain is characterized by episodic, lancinating, needle-like pain found in the distribution of the specific nerve or dermatome. For example, ilioinguinal neuropathy presents as a lateralized burning or lancinating-type pain which radiates to the ipsilateral labia majora and inner thigh. Ilioinguinal neuropathy is commonly associated with a decreased sensation to touch of the region of innervation and pain is relieved by local injection of anesthetics in the vicinity of the ilioinguinal nerve. Clinically, the diagnosis of neuralgia is commonly based upon a temporal relationship to a traumatic event and classical symptoms and signs. Pudendal nerve terminal motor latency via St Mark’s electrode has been used as a diagnostic marker of pudendal neuropathy and neuralgia (63,64). As is evident in other forms of neuralgia, the evidence of damage through nerve conduction defects may be minimal or impossible to document (65). In addition, pudendal nerve motor latency abnormalities do not appear to predict response to surgical unentrapment of the pudendal nerve (66). Several reports advocate the use of computed tomography (CT) guidance to assist injection of local anesthetics to aid in confirming the diagnosis and provide temporary relief of pudendal neuralgia (67,68). In a small number of patients with perineal pain of “obscure origin,” sacral meningeal (Tarlov’s) cysts have been identified by magnetic resonance imaging (MRI) (69). In patients with diffuse vulvar pain of obscure origin, MRI is recommended. Circumvaginal Motor Spasm (Vaginismus, Proctalgia Fugax, Unstable Urethra) Neuromuscular dysfunction may also contribute to chronic vulvar pain. Glazer et al. have compared the electromyographic (EMG) behavior of the pelvic floor in cases of “dysesthetic vulvar pain syndrome” to asymptomatic women. Cases were found to have reduced ability to contract the pelvic floor, reduced ability to relax the pelvic floor, and increased muscular instability at rest, compared to asymptomatic controls (70). We reported that VVS cases demonstrate abnormally high urethral pressure variability compared to normal controls and controls with extragenital chronic pelvic pain (56). This finding supported Glazer’s observation of increased pelvic floor motor instability. Although variation in muscular tone of the urethral sphincter was felt to be the probable source of this variability, the external urethral sphincter comprises a portion of the pelvic diaphragm and commonly functions in concert with the levator muscles. Two additional conditions of the anal canal, proctalgia fugax and anal fissures, are attributable to motor problems of the pelvic floor. Anal canal pressure variability has been demonstrated in proctalgia fugax, a chronic pain condition of the rectum. Proctalgia fugax cases differ from sex- and age-matched controls by the development of an increase in baseline and amplitude of anal canal pressure variability during an acute episode of pain (71). The frequency and amplitude of anal canal pressure variability appears very similar to frequency and amplitude of urethral instability reported in our study discussed above (56). Three clinical trials for treatment of anal fissures have provided additional insight into the phenomenon of chronic pain of pelvic muscle origin (72–74). The reported clinical responses to botulinum toxin and topical glyceryl trinitrate therapy suggest that the pathogenic basis for development of an anal fissure is sphincter spasm (74,75). With respect to internal (smooth muscle) versus external (striated muscle) sphincter, fissure healing was most closely associated with reduced tone of the external sphincter (73). Whether excessive urethral and anal canal pressure variability is present in all chronic vulvar pain patients or only found in a subset remains unknown.

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EVIDENCE FOR PERIPHERAL SENSITIZATION OF NOCICEPTORS Cytokine Alterations and VVS Peripheral sensitization may result from changes in the type or density of ion channels near the site of injury or inflammation (76,77). Responsiveness of sensory neurons, especially pain fibers, may be upregulated by intradermal or subcutaneous proinflammatory factors such as IL-1b, TNF-a, IL-6, IL-8, and prostaglandin E2 (78–80). VVS-afflicted women show higher tissue concentrations for IL-1b localized to the vulvar vestibule (81). Characteristically in VVS, the “pain to light touch” known as allodynia declines markedly within millimeters of the vestibule. Median tissue levels of IL-1 and TNF-a were 2.3- and 1.8-fold elevated, respectively, in women with vulvar vestibulitis compared to pain-free women. When analyzed by selected anatomic site in patients with vulvar vestibulitis, highest median levels of IL-1b were found at the hymen, corresponding to the region of greatest allodynia. VVS and Increased Nerve Density Several studies have found an increase in nerve fiber density in vulvar vestibulitis correlating with the vestibular region of heightened allodynia and hyperalgesia. Westrom et al. reported that stromal nerve fiber density per square unit was significantly correlated with the level of inflammation (82). However, nerve fiber density was not significantly correlated with the presence or absence of pain. The authors used S-100 immunostain and rated inflammation and nerve fiber density on a subjective scale of none, mild, moderate, severe, and extensive. Of the immunocytochemical antisera available for identification of peripheral nerves, protein gene product 9.5 (PGP 9.5) has been demonstrated to give reliable results with particularly good staining of epidermal fibers. Bohm-Starke et al. used PGP 9.5 to study biopsies in the vicinity of the Bartholin’s gland (83). The authors used a semiquantitative measure and reported a significantly higher number of intraepithelial nerve fibers in vulvar vestibulitis cases than in asymptomatic controls. Tympanidis et al. used PGP 9.5 staining in 12 cases and 8 controls, and analyzed random sections using quantitative analysis software. They reported a significant increase in density of PGP 9.5 immunoreactive fibers in the 12 cases. The density difference was seen at the dermal epidermal border (84). This study also qualitatively analyzed calcitonin gene-related peptide immunostaining in proximity to peripheral nerves of the vulvar vestibule and found no significant difference between cases and controls. In a subsequent article the same group has reported a quantitatively increased density of vanilloid receptors (VR-1) but scant evidence of voltage-gated sodium channel NA(v) 1.8 (PN3) immunoreactivity in vulvar pain syndrome cases (85). EVIDENCE FOR CENTRAL SENSITIZATION IN VULVAR PAIN SYNDROME Central sensitization is characterized by allodynia and receptive field expansion theoretically based upon enhanced neural responsiveness within the dorsal horn (76,86). The phenomenon of central sensitization in VVS has undergone only limited study. Using standard pain stimuli, VVS cases report pain localized to the vulvar vestibule as well as enhanced pain sensitivity at other anatomic locations such as the deltoid muscle (87,88), thumb, and shin (88). Concurrent with the condition of VVS, embryologically related, adjacent regions of the lower urogenital tract, such as the bladder, may also be chronically painful. This enigmatic mixture of chronically painful sites has been coined the “urogenital sinus syndrome” (6). Inflammatory substances, such as capsaicin, have been used experimentally to measure clinical pain dimensions of hyperalgesia, allodynia, and receptive field expansion that characterize central sensitization (89–96). Within a period of seconds to minutes following topical or intradermal application enhanced cutaneous sensitivity (punctate hyperalgesia and dynamic allodynia) develops beyond the region of initial pain. A dose-dependent response in both area and duration of punctate hyperalgesia follows the application of topical capsaicin (97). Using an intradermal capsaicin challenge, VVS cases demonstrated (i) an expanded receptive field to painful stimuli involving both the upper and lower extremities, and (ii) an enhanced pain sensitivity to varied stimuli including spontaneous pain secondary to capsaicin, punctate

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hyperalgesia to von Frey stimulus, and dynamic allodynia to a stroked spring wire stimulus (98). The observed receptive field expansion conforms to recent VVS studies using stimuli other than capsaicin (87,88) and is consistent with widespread hypersensitivity to painful stimuli reported in other conditions such as fibromyalgia (94) and irritable bowel syndrome (IBS) (99). Evidence of Autonomic Dysregulation in VVS In the resting state, VVS cases have been found to have elevated heart rates and lower systolic blood pressures compared to pain-free controls (98). The pattern of increased heart rate and lower blood pressure has been reported in patients with a number of chronic pain syndromes including IBS, fibromyalgia, and temporomandibular joint syndrome (100–102). Pain thresholds have also been shown to increase (greater pain tolerance) with increasing blood pressure in pain-free humans (103) and animal experiments (104). The precise “pain—low blood pressure” mechanism remains to be clarified but has been proposed to be mediated by opioid and non-opioid mechanisms. As previously noted, “primary” type VVS may include a significantly higher proportion of cases with low systolic blood pressure compared to “secondary” VVS (23). Brain Functional MRI in Vulvar Pain Syndrome Pukall et al. performed functional MRI on 14 VVS cases and 14 age-matched controls (105). Differences in brain activity following non-painful stimuli were found in the bilateral Brodmann’s area 6 (BA6), right cerebellum, inferior parietal lobule, and left S2. The noxious stimulus rating was significantly higher in the VVS cases with activation in bilateral S2, bilateral mid-posterior insular cortex (IC), left basal ganglia, inferior parietal lobule, bilateral BA6, bilateral anterior IC, right BA43/42, bilateral anterior IC, and left BA40. In the control group significant activation occurred in left S2 and left mid-posterior IC. Between-group comparison demonstrated significant differences in bilateral mid-posterior IC, bilateral BA6, left BA40, and left anterior IC. Although the significance of such differences in brain activity remains to be uncovered, the fact that they can be measured will certainly spur further research. DEVELOPMENT OF QUANTITATIVE SENSORY TESTING MEASURES OF VULVAR PAIN SYNDROME The Cotton Swab Test The cotton swab test (CST) has become a widely used instrument for the clinical confirmation of VVS. Clinicians commonly use a CST technique modified by the report of Bergeron et al. (22). who refined the technique and performed reliability testing. A moistened cotton swab is applied in a perpendicular fashion to defined points of the labia majora, minora, and lower vagina. Responses range on a numeric scale from “0” (no pain) to “10” (worst pain ever). For painful regions of the vestibule the CST stimulus evoked responses above 6/10 on a pain intensity scale. The authors found that although interrater reliability was good, there appeared to be consistent variation between examiners suggesting that technique made a difference. Quantitative Sensory Testing: Vulvar Algesiometers Several researchers have designed instruments capable of producing calibrated mechanical stimuli to the vulva. These instruments, known as algesiometers, are particularly valuable in tracking pain thresholds over multiple office visits permitting a measure of response to therapy. The vulvar algesiometer, developed by Curnow et al. (106), provides eight force settings (“0”–“7”) corresponding to a calibrated pulse force range between 178 and 1868 mN. Numerically higher algesiometer scores indicate better tolerance to increasing mechanical stimulus and therefore an improved condition. A pilot study of 25 vulvar vestibulitis cases was tested before and after therapy at four sites of the vulvar vestibule (107). “Clinical response” was defined as full pain relief during penetrative intercourse. “Clinical responders” reported a pretreatment median score of 21/32 and a posttreatment median score of 32/32

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(Mann Whitney, pZ0.0001). In contrast, “Clinical non-responders” cases reported a median of 18/32 posttreatment. Another quantitative sensory testing (QST) algesiometer named the vulvalgesiometer was introduced by Pukall et al. (108) The system consists of a series of spring-driven cotton swab pistons held in place by a modified syringe. The advantage to this QST instrument is the mechanical simplicity and low production expense. The authors reported initial good results with the system compared to the standard CST. CONTEMPORARY THERAPY: MEDICAL, SURGICAL, PHYSICAL THERAPY, AND COGNITIVE BEHAVIORAL THERAPY Suggested empiric therapies of vulvar vestibulitis have included tricyclic antidepressants (TCAs) such as amitriptyline and desipramine, topical lidocaine, intralesional interferon, systemic acyclovir, sympathectomy, acupuncture, low oxalate diet, capsaicin, botulinum toxin, corticosteroids, fluconazole, topical cromolyn, psychotherapy, hypnotherapy, biofeedback, spinal cord stimulation, and surgery (34,35,37,41,109–117). Unfortunately, treatment efficacy has often been limited by medication side effects and the hesitancy to undergo surgery, and randomized clinical trials are very limited to date. Medical Options: Topical Therapy Given the highly localized, mucocutaneous pain in vulvar vestibulitis, topical therapy to the vestibule is intuitively attractive. Topical agents including lidocaine, estrogen, and capsaicin have not been subjected to clinical trials. A pharmacologically distinct local effector, lidocaine (class 1B antiarrhythmic), has been reported to relieve neuropathic pain and suppress inflammation in conditions such as interstitial cystitis, post herpetic neuralgia (PHN), ulcerative colitis, and experimental colitis, following repeated topical applications (79–84). The lidocaine patch has been specifically approved by the Food and Drug Administration (FDA) for treatment of PHN, a “model” neuropathic pain syndrome where a majority of patients have allodynia (85). The neuroinflammatory state found in vulvar vestibulitis may be analogous to the “irritable nociceptor (pain fiber)” found in PHN (86). In terms of mechanism, lidocaine may act “locally” to block the neuroinflammatory process through a number of mechanisms including a reduced release of IL-1b (84) Topical lidocaine has been found to be well tolerated at the squamomucosal junction of the lower genital tract. The predominant side effect is transient burning upon application, resulting in a 1% to 2% cessation of use (87). An overnight treatment with topical 5% lidocaine was reported to improve the ability to have sexual intercourse over fourfold (16% pretreatment vs. 76% posttreatment) (115). The immediate analgesic effect of topical lidocaine, although different from the long-term anti-inflammatory effect described above, may additionally improve adherence to treatment. Another proposed topical therapy, cromolyn cream failed to improve pain greater than placebo in VVS (117). Medical Options: TCAs Although the mechanism of analgesic action of TCAs remains unknown, prospective randomized trials find that TCAs reduce chronic pain in diabetic neuropathy, PHN, and post-stroke central pain (118–120). Higher blood levels and a duration of two weeks of tricyclic therapy were associated with reduced pain (120). McKay reported upon a retrospective study of women with “essential” vulvar pain syndrome who responded to low-dose amitriptyline (20–100 mg) (111). Amitriptyline was less effective in vulvar pain syndrome patients under the age of 40, unless they also had symptoms of fibromyalgia or urethral syndrome. Pagano reported upon a retrospective study of amitriptyline in 230 women with vulvar vestibulitis (38). The dose of amitriptyline ranged from 10 to 75 mg and 58% “responded well” to treatment with 20% “cured” at six months. Medical Options: Gabapentin and Others An alternative oral agent, gabapentin, is a structural analogue of g-aminobutyric acid whose mechanism of action is not fully understood. Gabapentin has been demonstrated in clinical

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trials to be effective for PHN and diabetic neuropathy (121). An unrandomized pilot study of 17 VVS patients was treated with gabapentin doses ranging from 300 to 1200 mg and 14 of 17 (82%) reported partial or complete relief of pain (122). Medical Options: Combined (Peripheral and Systemic) Therapy Treatment of chronic pain conditions, such as vulvar vestibulitis, through a combined “central” and “peripheral” approach is intuitively attractive. In an open-label study in 53 vestibulitis patients, we found that 71% became fully asymptomatic or sexually functional with minimal pain with combined desipramine and topical lidocaine therapy compared to 50% response to desipramine alone (123). The median effective dose of desipramine was 150 mg daily. Reported side effects included constipation, dry mouth, nervousness, dizziness, and somnolence in decreasing order of frequency with a treatment drop-out rate of 25%. The most common side effect, which resulted in discontinuation, was the complaint of “nervousness.” After cessation of desipramine, two-thirds of cases continued to report pain relief for at least six months. Presently, a National Institutes of Health-sponsored randomized clinical trial is underway to evaluate the therapeutic efficacy of combined oral desipramine–topical lidocaine therapy. Botulinum Toxin Therapy for Levator Syndrome (Circumvaginal Muscle Spasm) Botulinum toxin (Botoxw, Allergan, Inc. Irvine, California, U.S.A.) has also been shown to permit spontaneous healing of chronic anal fissures in a dose–response fashion, particularly when injection is directed toward the external anal sphincter (73,74). Long-term follow-up, however, finds a significant recurrence rate of chronic anal fissures associated with recovery of sphincter tonus. Combined therapy with botulinum toxin and surgery was reported effective in a refractory case of vulvar pain syndrome (114). Because the levator muscles are situated deep to the perineal surface, botulinum toxin injection may be facilitated by electromyographic guidance of injection. Physical Therapy and Cognitive Behavioral Therapy As mentioned earlier, neuromuscular dysfunction may contribute to the pathophysiology of chronic vulvar pain. EMG biofeedback has been found to be effective in facilitating a resumption of sexual activity in 22 of 28 (79%) of women with vulvar vestibulitis undergoing therapy (70). The authors noted that in contrast to surgery, biofeedback provided a low morbidity and cost-effective alternative. Surgery: Perineoplasty A recent review of 23 publications reporting perineoplasty results for VVS found a majority with “successful” outcome (complete responseCpartial response) ranging from 56% to greater than 90% with an overall fully asymtomatic and significantly better postoperative response of 80% (113). Our case series reflected similar findings to the report of collected studies (124). Long-term (mean postoperative 63 months) outcome was reported for 93 vulvar vestibulitis cases that underwent perineoplasty. Eighty-eight percent reported that pain had not returned or that they were “minimally symptomatic.” Postoperative complication rate was low with 1 of 93 reporting anal sphincter weakness. Differences in surgical success across subgroups for age, parity, duration of symptoms, type of pathology, degree of partner support, psychiatric history, sexual abuse history, and the patient’s opinion of the postoperative appearance did not achieve statistical significance. The surgical procedure can be summarized in the following steps (Fig. 2). The incision begins at the lower margin of the labium minus and proceeds across the perineal body, running above the palpable upper edge of the external anal sphincter (1–1.5 cm from the anal orifice), and ending at the opposite lower margin of the labium minus (Fig. 2 step 1). A mucosal flap is developed by undermining the posterior vestibule, residual hymenal tissue, and lower one-third to one-half of the posterior vagina (Fig. 2 step 2). Excision of painful and commonly scarred posterior vestibule is carried up to include only the hymenal ring, leaving the entire posterior

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Step 2

Step 3

FIGURE 2 Stepwise illustration of vestibulectomy with vaginal advancement performed for treatment of localized vulvar pain syndrome (vulvar vestibulitis).

vaginal flap for final mobilization. After adequate hemostasis is achieved, the vagina flap is advanced down to the perineal body surgical margin. The advanced flap and skin of the perineal body are approximated with an underlying series of absorbable monofilament sutures and the edges approximated with a second layer of interrupted absorbable sutures (Fig. 2 step 3). Bergeron et al. (125) reported on a randomized clinical trial comparing three treatments for vulvar vestibulitis: cognitive behavioral therapy, surface EMG biofeedback, and vestibulectomy (perineoplasty). All treatment groups reported significant reductions in pain measures at posttreatment and six-month follow-up. The perineoplasty group reported significantly better outcome measures of pain reduction and improved sexual functioning than the other two treatment groups. Although perineoplasty approaches 90% effectiveness in relief of dyspareunia, the actual basis for efficacy is unknown. Surgery: Pudendal Nerve Release A randomized clinical trial of the effectiveness of the transgluteal pudendal nerve release found 50% pain relief at three months and 71% at 12 months in the surgical treatment arm compared to 6.2% at three months and 13.3% at 12 months in the non-surgical treatment arm (126,127). Other published data on technique and therapeutic outcome of various decompressive operations for pudendal, ilioinguinal, and sacral nerve root compression are limited to collections of case reports (66,128). Small series on surgical management of sacromeningeal (Tarlov’s) cyst have also been published (69,129). For pudendal neuralgia, CT-guided infiltration with anesthetic–cortisone combinations have been reported to be effective in selected cases (67,68). Although local phenol injection and radioablation of pudendal nerve have been clinically performed, published outcomes are not available. Particularly with injection of caustic agents such as phenol, concern must be raised with uncontrolled spread of caustic effect into the region of the sacral plexus. Surgery: Implantable Nerve Stimulation (Interstimw) Subchronic, implantable sacral nerve root stimulation (Interstimw, Medtronic, Inc., Minneapolis, Minnesota, U.S.A.) has been FDA approved for the management of severe urgency/frequency disorders of the bladder. Following release, sacral nerve root stimulation has been reported to reduce narcotic requirements in severe interstitial cystitis (130). As a result, interest has

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developed in the utility of the Interstim device for difficult neuropathies such as pudendal neuralgia. The technique of S1 to S4 transforaminal stimulation requires patience and a significant time for precise positioning. Early experience using the technique has been favorable in terms of pain relief. Problematically, the transforaminal leads tend to migrate away from the point of effective stimulation with body movement. FUTURE THERAPY: TOWARD A MECHANISTICALLY BASED TREATMENT RATIONALE The long-term goal in treatment of lower genital tract pain will be the development of a mechanistic-based classification of disease and treatment decision based upon the most effective treatment against the identified mechanism. Development of in vitro cell culture bioassays or the refinement of an animal model may provide the impetus for the development of such mechanistically based treatments. Before industry-funded research is likely to proceed, researchers will need to clearly answer the questions of prevalence, proportions of subsets, and long-term morbidity of chronic vulvar pain. REFERENCES 1. Thomas TG. Hyperesthesia of the Vulva. The Diseases of Women. Philadelphia, PA: Lea Brothers, 1891:150–1. 2. Kelly HA. Gynecology. New York: D. Appelton & Co., 1928:236. 3. O’Donnell R. Relative hypospadius potentiated by inadequate rupture of the hymen: a cause of chronic inflammation of the lower part of the female urinary tract. J Int Coll Surg 1959; 32:374. 4. WoodruffT JD, Parmley TH. The Vulva. Atlas of Gynecologic Pathology. New York: J.B. Lippincott Co., 1988:1.2–1.6. 5. Robboy SJ, Ross JS, Prat J, Keh PC, Welch WR. Urogenital sinus origin of mucinous and ciliated cysts of the vulva. Obstet Gynecol 1978; 51:347–51. 6. McCormack WM. Two urogenital sinus syndromes. Interstitial cystitis and focal vulvitis. J Reprod Med 1990; 35:873–6. 7. Fujihashi K. A mucosal internet: epithelial cell–immune cell interactions. Mucosal Immunology. San Diego: Academic Press, 1999:619–30. 8. Laumann EO, Paik A, Rosen RC. Sexual dysfunction in the United States: prevalence and predictors. J Am Med Assoc 1999; 281:537–44 (see comments; erratum appears in J Am Med Assoc 1999; 281(13):1174). 9. Kinsey AC, Pomeroy WB, Martin CE. Sexual Behavior in the Human Female. Philadelphia, PA: WB Saunders Co., 2006. 10. Meana M, Binik YM, Khalife S, Cohen DR. Biopsychosocial profile of women with dyspareunia. Obstet Gynecol 1997; 90:583–9. 11. Harlow BL, Stewart EG. A population-based assessment of chronic unexplained vulvar pain: have we underestimated the prevalence of vulvodynia? J Am Med Womens Assoc 2003; 58:82–8. 12. Harlow BL, Stewart EG. Adult-onset vulvodynia in relation to childhood violence victimization. Am J Epidemiol 2001; 161:871–80. 13. Foster DC. Vulvar disease. Obstet Gynecol 2002; 100:145–63 (Review; 80 refs.). 14. Moyal-Barracco M, Lynch PJ. 2003 ISSVD terminology and classification of vulvodynia: a historical perspective. J Reprod Med 2004; 49:772–7. 15. Goetsch MF. Vulvar vestibulitis: prevalence and historic features in a general gynecologic practice population. Am J Obstet Gynecol 1991; 164:1609–14 (discussion). 16. Nunns D, Mandal D. Psychological and psychosexual aspects of vulvar vestibulitis. Genitourin Med 1997; 73:541–4. 17. Stewart DE, Reicher AE, Gerulath AH, Boydell KM. Vulvodynia and psychological distress. Obstet Gynecol 1994; 84:587–90. 18. Foster DC, Woodruff JD. Case control study of vulvar vestibulitis syndrome. J Womens Health 1995; 4:677–80. 19. Peckham BM, Maki DG, Patterson JJ, Hafez GR. Focal vulvitis: a characteristic syndrome and cause of dyspareunia. Features, natural history, and management. Am J Obstet Gynecol 1986; 154:855–64. 20. Friedrich EG. Vulvar vestibulitis syndrome. J Reprod Med 1987; 32:110–4. 21. Bohm-Starke N, Hilliges M, Brodda-Jansen G, Rylander E, Torebjork E. Psychophysical evidence of nociceptor sensitization in vulvar vestibulitis syndrome. Pain 2001; 94:177–83. 22. Bergeron S, Binik YM, Khalife S, Pagidas K, Glazer HI. Vulvar vestibulitis syndrome: reliability of diagnosis and evaluation of current diagnostic criteria. Obstet Gynecol 2001; 98:45–51.

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