Diagnosis and Treatment of Breakthrough Pain: Oxford American Pain Library

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O A P L OXFORD AMERICAN PAIN LIBRARY

The Diagnosis and Treatment of Breakthrough Pain

This material is not intended to be, and should not be considered, a substitute for medical or other professional advice. Treatment for the conditions described in this material is highly dependent on the individual circumstances. While this material is designed to offer accurate information with respect to the subject matter covered and to be current as of the time it was written, research and knowledge about medical and health issues is constantly evolving, and dose schedules for medications are being revised continually, with new side effects recognized and accounted for regularly. Readers must therefore always check the product information and clinical procedures with the most up-to-date published product information and data sheets provided by the manufacturers and the most recent codes of conduct and safety regulation. Oxford University Press and the authors make no representations or warranties to readers, express or implied, as to the accuracy or completeness of this material, including without limitation that they make no representations or warranties as to the accuracy or efﬁcacy of the drug dosages mentioned in the material. The authors and the publishers do not accept, and expressly disclaim, any responsibility for any liability, loss, or risk that may be claimed or incurred as a consequence of the use and/or application of any of the contents of this material.

O A P L OXFORD AMERICAN PAIN LIBRARY

The Diagnosis and Treatment of Breakthrough Pain Perry G. Fine, MD Professor of Anesthesiology Pain Research Center University of Utah School of Medicine Salt Lake City, UT With contributions by

Andrew N. Davies, FRCP Consultant in Palliative Medicine Royal Marsden Hospital, Surrey Sutton, UK

Scott M. Fishman, MD Chief, Division of Pain Medicine University of California Davis, CA Executive Series Editor

Russell K. Portenoy, MD Chairman of Pain Medicine & Palliative Care Beth Israel Medical Center New York, NY

1 2008

1 Oxford University Press, Inc., publishes works that further Oxford University’s objective of excellence in research, scholarship, and education. Oxford New York Auckland Cape Town Dar es Salaam Hong Kong Karachi Kuala Lumpur Madrid Melbourne Mexico City Nairobi New Delhi Shanghai Taipei Toronto With ofﬁces in Argentina Austria Brazil Chile Czech Republic France Greece Guatemala Hungary Italy Japan Poland Portugal Singapore South Korea Switzerland Thailand Turkey Ukraine Vietnam

Copyright © 2008 by Oxford University Press, Inc. Published by Oxford University Press, Inc. 198 Madison Avenue, New York, New York 10016 www.oup.com

Oxford is a registered trademark of Oxford University Press All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior permission of Oxford University Press. Library of Congress Cataloging-in-Publication Data Fine, P. G. (Perry G.) The diagnosis and treatment of breakthrough pain / Perry G. Fine with Andrew N. Davies. p. ; cm.—(Oxford American pain library) Includes bibliographical references. ISBN 978-0-19-536903-8 (alk. paper) 1. Pain–Diagnosis. 2. Pain–Treatment. I. Davies, Andrew, 1963– II. Title. III. Series. [DNLM: 1. Pain–therapy–Handbooks. 2. Analgesics, Opioid–therapeutic use–Handbooks. 3. Pain–diagnosis–Handbooks. WL 39 F495d 2008] RB127.F564 2008 616'.0472–dc22 2007040530 9 8 7 6 5 4 3 2 1 Printed in the United States of America on acid-free paper

Acknowledgments

v

The authors extend their gratitude to Janet Marietta of the Pain Research Center, University of Utah, for her very helpful administrative support, ensuring the timely completion of this handbook

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Contents 1 2 3 4 5 6 7 8 9 10

Incidence, prevalence, and characteristics Clinical features Assessment Principles of management Oral opioid analgesics Oral transmucosal opioid analgesics Opioid analgesics via other routes Nonopioid pharmacotherapy Nonpharmacologic interventions Risk assessment and management in long-term opioid therapy Index

1 13 25 35 47 55 75 85 97 111 125

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Chapter 1

The term “breakthrough pain” began appearing in the medical literature in the 1980s on the heels of the increased attention, brought about by the World Health Organization, to the global problem of undertreated cancer pain. During that time, it became apparent that cancer patients commonly experience intermittent exacerbations of severe pain against a background of continuous, or baseline, pain. Episodic pains that would “break through” during the treatment of background pain that was otherwise well controlled through the use of around-the-clock opioid therapy were categorized by Portenoy and Hagen (1990) in a seminal work titled “Breakthrough pain: Deﬁnition, prevalence and characteristics.” The deﬁnition of breakthrough pain proffered in that article took root and has been used in pain management parlance ever since (Box 1.1). As opioid therapy has become more commonly used in the treatment of chronic noncancer pain over the past decade, it has become equally apparent that a similar pattern of supervening severe pain episodes can confound otherwise well-managed chronic pain (Zeppetella et al., 2001). Recognizing the similarities of symptoms, independent of underlying pathophysiology, a group of pain management experts came together in 2006 to create a unifying deﬁnition, based on a review of all the literature on the subject in all populations studied to date. The more generalized deﬁnition incorporates the additional observation that breakthrough pain seriously disrupts the quality of patients’ lives (Fig. 1.1). Therefore, the term breakthrough pain is now categorically determined to deﬁne the particular clinical circumstance wherein patients who have controlled baseline pain experience severe episodes of pain that breaks through the medical therapy (usually opioids) that has relieved the baseline pain.

Box 1.1 Deﬁnitions of breakthrough pain • A transitory exacerbation of pain that occurs on a background of otherwise stable pain in a patient receiving chronic opioid therapy (Portenoy and Hagen, 1990). • In patients with chronic baseline pain undergoing analgesic drug therapy on most days, breakthrough pain is a transitory pain that lasts from seconds to hours, is more severe than the background pain, and has a negative effect on function or quality of life (Fine and Portenoy, 2007).

1

Incidence, prevalence, and characteristics

Incidence, prevalence, characteristics CHAPTER 1

2

Although the term breakthrough pain is widely used among pain management specialists, other terms are also used in the medical literature to describe the same phenomenon, including “episodic pain,” “exacerbation of pain,” “pain ﬂare,” “transient pain,” and “transitory pain” (Colleau, 1999). Nevertheless, it is important to use terms precisely and unambiguously so that clinical syndromes can be properly identiﬁed and distinguished, both to advance clinical science through research and to treat patients most appropriately.

Classiﬁcation Breakthrough pain can be classiﬁed according to its relationship to speciﬁc events or to analgesic dosing (Portenoy and Hagen, 1990; Davies, 2005; Portenoy et al., 2006): • Spontaneous pain (also known as “idiopathic pain”): this type of pain occurs unexpectedly and is unrelated to other known provoking causes. • Incident pain (also known as “precipitated pain” or, when appropriate, “movement-related pain”): this type of pain is related to speciﬁc events and can be subclassiﬁed into three categories: 1. volitional—pain is precipitated by a voluntary act (e.g., walking); 2. nonvolitional—pain is precipitated by an involuntary act (e.g., coughing); and 3. procedural—pain is related to a therapeutic intervention (e.g., dressing change). • End-of-dose failure—This type of pain is related to analgesic dosing (i.e., declining analgesic blood levels). As discussed earlier, the diagnosis of breakthrough pain relies on the coexistence of “adequately controlled background pain” (Portenoy et al., 2004). Some authors regard end-of-dose failure as an artifact of actual (rather than ideal) medication duration of action rather than a subtype of breakthrough pain per se, and this is remedied by increasing the usual analgesic dose or increasing the number of dosages per day (e.g., from every 12 hours to every 8 hours for a continuous-release formulation) (Simmonds, 1999). Nevertheless, convention developed over the past 15 years categorizes end-of-dose failure as a subtype of breakthrough pain. Table 1.1 shows the prevalence of breakthrough pain subtypes in English-language studies applying standard criteria for breakthrough pain (Portenoy and Hagen, 1990; Fine and Busch, 1998; Portenoy et al., 1999; Zeppetella et al., 2000; Gomez-Batiste et al., 2002; Hwang et al., 2003).

Epidemiology Cancer-related pain Pain is a common problem in patients with cancer. Indeed, the prevalence of pain has been reported to be 30% to 40% among patients with early disease (receiving

Table 1.1 Prevalence of breakthrough pain subtypes in studies using standard criteria for breakthrough pain Study Portenoy and Hagen, 1990

Spontaneous pain 27%

Breakthrough pain subtypes Incident pain End-of-dose failure 43% 18%

No data 38%

⬇50% 49%

No data 13%

Zeppetella et al., 2000 Gomez-Batiste et al., 2002

59% 32%

24% 52%

17% 15%

Hwang et al., 2003

17%

64%

19%

Portenoy et al., 2006

31%

69%

19%

Fine and Busch, 1998 Portenoy et al., 1999

Updated with permission from Davies, 2006.

Comments 12% of pain types were “mixed” in nature (incident and end-of-dose failure). Incident pain precipitants: movement 22%; coughing 12%; sitting 4%; touch 2%. No further details in paper. Incident pain precipitants: movement 27.8%; defecation 5.7%; urination 3.8%; coughing 3.7%; sitting 3.7%; breathing 1.9%; eating/drinking 1.9%. No further details in paper. Incident pain precipitants: movement 38%; eating/drinking 3%; defecation 2%; coughing 2%. Data based on initial assessment of patient. Incident precipitants: movement 44%; coughing 4%; eating/drinking 4%; defecation 2%; sitting 2%. Incident pain precipitants: sitting, standing, driving, cold weather, stress, eating.

Incidence, prevalence, characteristics CHAPTER 1

4

anticancer therapy) and 70% to 90% among patients with advanced disease (Foley, 2004). Similarly, breakthrough pain is a common problem in patients with cancer. The prevalence of breakthrough pain has been reported to be 19% to 95% among various groups of patients (Zeppetella and Ribeiro, 2003). This disparity reﬂects a number of factors, including differences in the deﬁnition used, in the methods used, and in populations studied (Mercadante et al., 2002). Furthermore, the reporting of breakthrough pain across populations in international studies is affected by certain language and geographical variables. Many authors have adopted the diagnostic criteria for breakthrough pain used by Portenoy and Hagen (1990). These criteria are (1) the presence of stable analgesia in the previous 48 hours, (2) the presence of controlled background pain in the previous 24 hours (i.e., average pain intensity of none, mild, or moderate for over half of the previous 24 hours), and (3) the presence of “temporary ﬂares of severe or excruciating pain” in the previous 24 hours. Table 1.2 shows the prevalence of breakthrough pain in English-language studies applying standard criteria for breakthrough pain (Portenoy and Hagen, 1990; Fine and Busch, 1998; Portenoy et al., 1999; Zeppetella et al., 2000; Gomez-Batiste et al., 2002; Fortner et al., 2002, 2003; Hwang et al., 2003). It should be noted that these ﬁgures represent the prevalence of breakthrough pain in selected populations of cancer patients rather than the prevalence of breakthrough pain in the general population of cancer patients. Interestingly, the International Association for the Study of Pain (IASP) survey of cancer pain characteristics and syndromes found that pain specialists from English-speaking (United States, Canada, Australia) and northern/western European countries reported more breakthrough pain than pain specialists from South American, Asian, and southern/eastern European countries (Caraceni and Portenoy, 1999; Caraceni et al., 2004). Breakthrough pain appears to be more common in patients with advanced disease (Colleau, 2004), in patients with poor performance status (Caraceni et al., 2004), in patients with pain originating from the vertebral column (and, to a lesser extent, other weight-bearing bones/joints) (Caraceni et al., 2004), and in patients with pain originating from the nerve plexuses (and, to a lesser extent, nerve roots) (Caraceni et al., 2004).

Noncancer chronic pain Although breakthrough pain is commonly spoken about, there are few studies that explicate breakthrough pain, using similar criteria as in cancer pain studies, in noncancer populations with chronic pain syndromes. The most detailed report (Portenoy et al., 2006) characterized breakthrough pain in patients from several pain programs around the United States. Of 228 patients recruited, 168 (74%) met criteria for breakthrough pain (using an assessment algorithm originally designed for cancer patients). The most common pain syndrome was low back pain (52%), with other patients carrying diagnoses of abdominal or pelvic

Table 1.2 Prevalence of breakthrough pain in studies applying standard criteria for breakthrough pain Study

Type of population

Portenoy and Hagen, 1990

Hospital inpatients (pain team referrals) United States n = 90 Palliative care patients (home setting)—United States n = 22 Hospital inpatients—United States n = 178

Fine and Busch, 1998

Portenoy et al., 1999

Zeppetella et al., 2000

Fortner et al., 2002

Gomez-Batiste et al., 2002

Fortner et al., 2003

Hospice inpatients—United Kingdom n = 414 Cancer patients (home setting) —United States n = 1000 Palliative care patients (various settings)—Spain n = 407 Cancer patients (outpatient setting)—United States n = 373

Prevalence of breakthrough pain (see comments) 63%

86% 51%

89%

63%

41%

23%

Comments

Criteria for BTP outlined in this study. 90 patients assessed; 63 patients reported controlled background pain; 41 patients reported BTP. Only patients with pain eligible. 22 patients assessed; 22 patients reported background pain; 19 patients reported BTP. Only patients on regular opioid analgesics eligible. 178 patients assessed; 164 patients reported controlled background pain; 84 patients reported BTP. 381 patients assessed (33 patients not assessable); 245 patients reported background pain; 218 patients reported BTP. Telephone survey of cancer patients. 1000 patients assessed; 256 patients reported regular analgesic usage; 160 patients reported BTP. 397 patients assessed (10 patients not assessable); 163 patients reported BTP. Nonspeciﬁc data relating to the patients’ pain scores and pain medications were used to diagnose presence of BTP. 373 patients assessed; 144 patients reported background pain; 33 patients were deemed to have BTP. (continued)

Table 1.2 (Continued) Study

Type of population

Hwang et al., 2003

VA hospital patients (inpatient/outpatient setting) —United States n = 74

Portenoy et al., 2006

Chronic (noncancer) pain patients patients (outpatient setting, 9 pain programs) —United States n = 228

BTP: breakthrough pain; VA: Veterans Affairs. Updated with permission from Davies, 2006.

Prevalence of breakthrough pain (see comments) 70%

74%

Comments

Only patients with pain eligible. 74 patients assessed, 74 patients reported background pain; 52 patients reported BTP. After a week of treatment, BTP prevalence decreased from 70% to 36%. Telephone survey employing assessment tool designed for cancer patients. Inclusion criteria: patients with well-controlled baseline pain using stable opioid dose; episodic pains had to be in “severe” or “excruciating” range to qualify as BTP.

Clinical features Breakthrough pain is not a single entity but rather a spectrum of very different entities. The clinical features vary from individual to individual, and may vary within an individual over time (Portenoy, 1997). However, the clinical features of the breakthrough pain are often related to the clinical features of the background pain (Portenoy et al., 1999). There appears to be an association between the presence of breakthrough pain and the intensity/frequency of the background pain; that is, patients with breakthrough pain often have more severe or more frequent background pain (Portenoy et al., 1999; Caraceni et al., 2004). Indeed, breakthrough pain is associated with poor overall pain control (Mercadante et al., 1992; Bruera et al., 1995) and, not surprisingly, decreased satisfaction with overall pain control (Zeppetella et al., 2000). In patients with cancer, breakthrough pain is also a marker of poor prognosis (Bruera et al., 1995), and its prevalence appears to increase with progressive, far-advanced disease (Fine and Busch, 1998). Breakthrough pain may result in a number of other physical, psychological, and social problems (see Chapter 2). Indeed, the presence of breakthrough pain

Incidence, prevalence, characteristics

The etiology of the breakthrough pain is often the same as that of the background pain (Portenoy and Hagen, 1990; Portenoy et al., 1999; Portenoy et al., 2006). Thus, breakthrough pain may be due to (a) a direct effect of the underlying disease, (b) an indirect effect of the underlying disease (i.e., secondary to disability or deconditioning), (c) a direct or an indirect effect of the treatment, or (d) an effect of a concomitant illness (Zeppetella and Ribeiro, 2003). Indeed, breakthrough pain may be experienced by patients with all stages of cancer (at diagnosis, during active treatment, during remission, during relapse/progression, following cure) (Portenoy and Hagen, 1990; Portenoy et al., 1999) and by patients with chronic pain syndromes of varying duration (Portenoy et al., 2006). Table 1.3 shows the etiology of breakthrough pain in relevant published studies (Portenoy and Hagen, 1990; Portenoy et al., 1999; Zeppetella et al., 2000; Portenoy et al., 2006). Not surprisingly, the pathophysiology of the breakthrough pain is also often the same as that of the background pain. Thus, breakthrough pain may be (a) nociceptive, (b) neuropathic, or (c) mixed (nociceptive and neuropathic). Occasionally, the cause may be undetermined, in which case the condition would best be described as breakthrough pain of indeterminate pathophysiology. Table 1.3 shows the pathophysiology of breakthrough pain in relevant published studies (Portenoy and Hagen, 1990; Portenoy et al., 1999; Zeppetella et al., 2000; Portenoy et al, 2006).

CHAPTER 1

Etiology

7

pain, arthritis, neck pain, complex regional pain syndrome, ﬁbromyalgia, headache, and various neuropathies.

Table 1.3 Etiology/pathophysiology of breakthrough pain Study Primarily caused by malignancy

Portenoy and Hagen, 1990* Portenoy et al., 1999* Zeppetella et al., 2000* Portenoy et al., 2006†

76% 65% 71%

* Cancer patients. †

Noncancer patients.

Updated with permission from Davies, 2006.

Etiology of breakthrough pain Caused by cancer treatment (chemotherapy or radiation therapy; surgery) 20% 35% 11%

Caused by another disease

4% 0% 19%

Pathophysiology of breakthrough pain Mixed pain Nociceptive Neuropathic pain pain

53% 38% 74% 42%

27% 10% 9% 18%

20% 52% 16% 40%

Poorly controlled pain has serious consequences on peoples’ lives and is a major public health problem. Breakthrough pain is a common occurrence in patients with chronic pain syndromes of various etiologies and must be evaluated and treated concomitantly in order to mitigate against the myriad ill consequences of inadequate pain management. The following quotes from patient interviews capture the powerful impact of pain and its relief: You can’t ﬁnd it [inner peace] in that darkness of pain . . . I can’t emphasize that the pain blinds you to all of that, blinds you to all that’s positive. I mean the real bad pain . . . it just closes you down. You just can’t get through it . . . it’s an iron door and it’s one thing you don’t wanna go through . . . you just wanna, wanna stop. Once the pain was relieved it was the most beautiful experience of my life, to be able to participate and control the pain. (Coyle, 2004) Later chapters will address issues of the assessment, the general principles of management, and speciﬁc options for the management of breakthrough pain.

References Bruera E, Schoeller T, Wenk R, et al. A prospective multicenter assessment of the Edmonton Staging System for cancer pain. Journal of Pain and Symptom Management. 1995; 10:348–355. Caraceni A, Martini C, Zecca E, et al. Breakthrough pain characteristics and syndromes in patients with cancer pain. An international survey. Palliative Medicine. 2004; 18:177–183. Caraceni A, Portenoy RK. An international survey of cancer pain characteristics and syndromes. IASP Task Force on Cancer Pain. International Association for the Study of Pain. Pain. 1999;82:263–274.

Incidence, prevalence, characteristics CHAPTER 1

Conclusion

9

can have a signiﬁcant negative impact on quality of life (Portenoy et al., 1999; Hwang et al., 2003; Taylor et al., 2007). The degree of interference seems to be related to the characteristics of the breakthrough pain: patients with spontaneous pain (Portenoy et al., 1999) and patients with severe pain (Swanwick et al., 2001) may experience particular problems. Not surprisingly, breakthrough pain is associated with the increased use of health-care services (i.e., increased outpatient visits, increased inpatient admissions) (Fortner et al., 2002). The result of the increased use of health-care services is an increase in direct costs (e.g., physician time and expense, prescription costs) and in indirect costs (e.g., transportation costs, time away from work) for all components of the health-care system (public and commercial insurance), the patient, and caregivers (Fortner et al., 2003).

Incidence, prevalence, characteristics CHAPTER 1

Fine PG, Portenoy RK. A Clinical Guide to Opioid Analgesia (2nd ed.). New York: Vendome (in press).

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Colleau SM. The signiﬁcance of breakthrough pain in cancer. Cancer Pain Release. 1999;12:1–4. Colleau SM. Breakthrough (episodic) vs. baseline (persistent) pain in cancer. Cancer Pain Release. 2004;17:1–3. Coyle N. In their own words: Seven advanced cancer patients describe their experience with pain and the use of opioid drugs. Journal of Pain and Symptom Management. 2004;27:300–309. Davies A. Current thinking in cancer breakthrough pain management. European Journal of Palliative Care. 2005;12(Suppl):4–6. Davies A. Cancer-Related Breakthrough Pain. Oxford, UK: Oxford University Press, 2006. Fine PG, Busch MA. Characterization of breakthrough pain by hospice patients and their caregivers. Journal of Pain and Symptom Management. 1998;16:179–183.

Foley KM. Acute and chronic cancer pain syndromes. In Doyle D, Hanks G, Cherny N, et al. (eds.), Oxford Textbook of Palliative Medicine (3rd ed., pp. 298–316). Oxford, UK: Oxford University Press, 2004. Fortner BV, Demarco G, Irving G, et al. Description and predictors of direct and indirect costs of pain reported by cancer patients. Journal of Pain and Symptom Management. 2003;25:9–18. Fortner BV, Okon TA, Portenoy RK. A survey of pain-related hospitalizations, emergency department visits, and physician ofﬁce visits reported by cancer patients with and without history of breakthrough pain. Journal of Pain. 2002;3:38–44. Gómez-Batiste X, Madrid F, Moreno F, et al. Breakthrough cancer pain: Prevalence and characteristics in patients in Catalonia, Spain. Journal of Pain and Symptom Management. 2002;24:45–52. Hwang SS, Chang VT, Kasimis B. Cancer breakthrough pain characteristics and responses to treatment at a VA medical center. Pain. 2003;101:55–64. Mercadante S, Maddaloni S, Roccella S, et al. Predictive factors in advanced cancer pain treated only by analgesics. Pain. 1992;50:151–155. Mercadante S, Radbruch L, Caraceni A, et al. Episodic (breakthrough) pain: Consensus conference of an expert working group of the European Association for Palliative Care. Cancer. 2002;94(3):832–839. Portenoy RK. Treatment of temporal variations in chronic cancer pain. Seminars in Oncology. 1997;5(S16):7–12. Portenoy RK, Bennett DS, Rauck R, et al. Prevalence and characteristics of breakthrough pain in opioid-treated patients with chronic noncancer pain. Journal of Pain. 2006;7(8):583–591. Portenoy RK, Forbes K, Lussier D, et al. Difﬁcult pain problems: An integrated approach. In Doyle D, Hanks G, Cherny N, et al. (eds.), Oxford Textbook of Palliative Medicine (3rd ed., pp. 438–458). Oxford, UK: Oxford University Press, 2004. Portenoy RK, Hagen NA. Breakthrough pain: Deﬁnition, prevalence and characteristics. Pain. 1990;41:273–281. Portenoy RK, Payne D, Jacobsen P. Breakthrough pain: Characteristics and impact in patients with cancer pain. Pain. 1999;81:129–134.

Zeppetella G, O’Doherty CA, Collins S. Prevalence and characteristics of breakthrough pain in cancer patients admitted to a hospice. Journal of Pain and Symptom Management. 2000;20:87–92. Zeppetella G, O’Doherty CA, Collins S. Prevalence and characteristics of breakthrough pain in patients with non-malignant terminal disease admitted to a hospice. Palliative Medicine. 2001;15:243–246. Zeppetella G, Ribeiro MD. Pharmacotherapy of cancer-related episodic pain. Expert Opinion on Pharmacotherapy. 2003;4:493–502.

Incidence, prevalence, characteristics

Taylor DR, Webster LR, Chun SY, et al. Impact of breakthrough pain on quality of life in patients with chronic, noncancer pain: Patient perceptions and effect of treatment with oral transmucosal fentanyl citrate (OTFC, ACTIQ). Pain Medicine. 2007;8(3):281–288.

CHAPTER 1

Swanwick M, Haworth M, Lennard RF. The prevalence of episodic pain in cancer: A survey of hospice patients on admission. Palliative Medicine. 2001;15:9–18.

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Simmonds MA. Management of breakthrough pain due to cancer. Oncology (Huntington). 1999;13:1103–1108.

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Chapter 2

Clinical features Breakthrough pain can have multiple causes with multiple pathophysiologies, and it can present with numerous clinical features and complications. In most patients, due to its severity (by deﬁnition) and impact on quality-of-life indicators, breakthrough pain is a cause of signiﬁcant morbidity. From a practical standpoint, breakthrough pain is recognized, and most readily differentiated, by its temporal pattern. This is best described visually (Fig. 2.1).

As discussed in Chapter 1, breakthrough pain can be classiﬁed according to its relationship to speciﬁc events or to analgesic dosing (Davies, 2005): • Spontaneous pain (also known as idiopathic pain): this type of pain occurs unexpectedly and seems to be most commonly caused by underlying neurological pain-inducing disorders. • Incident pain (also known as precipitated pain or, when appropriate, movement-related pain): this type of pain is related to speciﬁc events and can be subclassiﬁed into three categories: 1. volitional—pain is precipitated by a voluntary act (e.g., walking); 2. nonvolitional—pain is precipitated by an involuntary act (e.g., coughing); and 3. procedural—pain is related to a therapeutic intervention (e.g., wounddressing change). • End-of-dose failure: this type of pain is related to analgesic dosing (i.e., declining, subtherapeutic analgesic blood levels). To create a clinical context for the categorization of breakthrough pain subtypes presented in Table 1.2, case histories from patients with the different types of breakthrough pain are exempliﬁed in Boxes 2.1–2.3. Breakthrough pain can also be classiﬁed according to the underlying pathophysiology of the pain: • Nociceptive pain: this type of pain is triggered by activation of somatic or visceral nociceptors (usually as a result of noxious mechanical, thermal, or inﬂammatory stimuli) and can be subclassiﬁed into two categories: 1. somatic pain—pain originates from the cutaneous and musculoskeletal tissues of the body; and 2. visceral pain—pain originates from the organs of the body.

13

Classiﬁcation

Uncontrolled Baseline Pain

Breakthrough Pain

nt Pain

Basal Persiste

Pain Intensity

Basal Analgesic Pain Intensity

Time

B Pain Intensity

Basal Analgesic

Time

Intermittent Pain

Breakthrough Pain

nt Pain

Basal Persiste

Pain Intensity

Clinical features CHAPTER 2

A

C

Time

Rescue Dose Around-the-Clock Medication “Breakthrough” Pain Episode Pain Intensity

14

Time

nt Pain

Basal Persiste

Time

Figure 2.1 Patterns of pain. (A) Control of baseline (basal persistent) pain reveals breakthrough pain. (B) By deﬁnition, breakthrough pain requires the presence, and control, of baseline (basal persistent) pain. Intermittent episodic acute pain requires diagnosis and treatment but does not require around-the-clock (basal analgesic) opioid therapy. (C) Treating temporal patterns of pain with pharmacokinetically matched analgesic therapies for optimal pain control.

• Neuropathic pain: this type of pain results from injury or pathological

changes in peripheral or central neural structures. • Mixed pain: this refers to a combination of nociceptive and neuropathic pain.

Table 1.3 shows the breakdown of the different pathophysiologies of breakthrough pain in studies that have applied standard criteria for diagnosing breakthrough pain (Portenoy and Hagen, 1990; Portenoy et al., 1999; Zeppetella et al., 2000; Hanks et al., 2004).

Box 2.1 Case history of patient with spontaneous-type breakthrough pain Mr. PW is a 50-year-old man with localized Ewing’s sarcoma of the sacrum. His chief complaint was excruciating pain in the penis/scrotum that was determined to be referred from tumor encroachment. This pain was intermittent in nature, occurring 3 to 4 times per hour, and lasting <1 minute per episode. There were no precipitating or aggravating factors. He also complained of moderate pain in the gluteal area and legs. This pain was persistent in nature. The patient had been receiving acetaminophen and low doses of gabapentin for the pain. Tramadol 50 mg was added (one to two tablets up to four times per day), which resulted in good control of the persistent pain without adverse effects, but there was no improvement in spontaneous pains, then categorized as breakthrough pains. The gabapentin was titrated upward to a total dose of 900 mg TID, which resulted in good control of the spontaneous pain. During this period, the patient also received an epidural injection of steroid (which had little effect on the pain) and a course of radical radiotherapy to the sacrum (which initially aggravated the pain). In due course, following completion of his multimodal oncological therapy, the patient was able to discontinue all of the aforementioned analgesics. Reprinted with permission, Davies, 2006.

Box 2.2 Case history of patient with incident-type breakthrough pain Mr. ML was a 64-year-old man with advanced renal cell carcinoma. He had widespread bone metastases, including disease in the thoracic spine, lumbar spine, and pelvis (particularly the left acetabulum). He complained of low back and hip pains, which were present at rest but were more severe on movement. As a result of the incident pain, he was rendered bedbound. Moreover, movement in the bed also resulted in signiﬁcant pain. He was unable to use NSAIDs due to a history of severe peptic ulcer disease. He was started on immediate-release oxycodone tablets due to concern about accumulation of toxic morphine metabolites in view of his reduced creatinine clearance, and the dose was gradually titrated upward in an attempt to control the pain. The pain at rest was well controlled, and he was able to sleep comfortably. However, the pain on transference from bed to chair or during short walks continued to cause severe pain, and further upward titration of the oxycodone dose resulted in the development of excessive sedation. A dose of oxycodone continuous-release formulation (60 mg q12h) was well tolerated. Fentanyl buccal tablet, starting at 100 µg and titrated to 200 µg, was used 15 minutes prior to the patient’s getting out of bed and several times throughout the day to encourage and facilitate ambulation. This provided satisfactory prevention and relief of his incident breakthrough pain. Subsequently, following a course of palliative radiotherapy to the lumbar spine, the dose of oxycodone was able to be reduced to 20 mg q12h, but he continued to use FBT 200 µg up to QID for breakthrough pain. Reprinted with permission, Davies, 2006.

Clinical features CHAPTER 2

Box 2.3 Case history of patient with end-of-dose failure Mr. GT is a recently retired accountant with insulin-dependent diabetes who has maintained fastidious control over his blood sugars for many years. Nevertheless, he has developed painful peripheral neuropathy involving his feet that interferes with his daily activities. Until recently he had been quite active, but he has had to curtail his long-standing enjoyment of twice-weekly golf outings with his friends and evening walks with his wife due to pain. His inability to exercise routinely has caused his blood sugar control to become more erratic, and he is feeling depressed. The pain was constant and was aggravated by walking, and it persisted even after Mr. GT sat down. He was able to tolerate duloxetine 30 mg BID, and he then added sustained-release morphine 15 mg po q12h (after titration with immediate-release hydrocodone/acetaminophen) to get baseline pain levels throughout most of the day and night down from 6- to 8/10 to 2/10 in intensity. He used a senna preparation to maintain satisfactory bowel function. With this, his mood and usual daily activity regimen improved greatly, but he still felt “down” and “tired out” by a recrudescence of severe pain toward the late afternoon and severe pain that would cause early-morning awakening. His sustained-release morphine was increased to an every-8hours dosing schedule, eliminating the periods of end-of-dose-failure breakthrough pain.

16

Reprinted with permission, Davies, 2006.

General features As a group, breakthrough pain is not a single entity but rather a spectrum of very different entities. The clinical features vary from individual to individual and may vary within an individual over time (Portenoy, 1997). However, the clinical features of an individual’s breakthrough pain are often related to the clinical features of the background pain (Portenoy et al., 1999). Table 2.1 shows some of the characteristics of breakthrough pain described in English-language studies that have applied standard criteria for diagnosing breakthrough pain (Portenoy and Hagen, 1990; Fine and Busch, 1998; Portenoy et al., 1999 ; Zeppetella et al., 2000; Gomez-Batiste et al., 2002; Hwang et al., 2003; Hanks et al, 2004). The diagnosis of breakthrough pain depends on the presence of wellcontrolled background pain, and so the initial presentation of the breakthrough pain often coincides with the successful management of the background pain. The differential diagnosis of breakthrough pain includes the progression of underlying pathology or the development of new pathology (e.g., pathological fracture in cancer patients, vertebral compression fracture in degenerative spine disease patients) (Patt and Ellison, 1998; Hadjistavropoulos et al., 2007). The development and progression of breakthrough pain also may signify problems related to the analgesic regimen (e.g., reduced duration of action or development of tolerance) (Patt and Ellison, 1998; Fine and Herr, 2006). In addition to these aforementioned causes, there appears to be an association between the presence of breakthrough pain and the intensity of the background pain insofar as patients with breakthrough pain often have more severe background pain (Portenoy et al., 1999; Caraceni et al., 2004). Indeed, break-

Table 2.1A Characteristics of breakthrough pain in studies applying standard criteria for breakthrough pain Study Portenoy and Hagen, 1990

Fine and Busch, 1998 Portenoy et al., 1999 Zeppetella et al., 2000 Gomez-Batiste et al., 2002 Hwang et al., 2003 Portenoy et al., 2006

BTP connected to background pain 96%

Number of types of BTP 1 pain: 78% 2 pains: 20% 3 pains: 2%

—

—

100%

1 pain: 83.1% 2 pains: 14.5% 3 pains: 2.4% Mean 2 pains (range 1 to 5) —

89% — 75% —

BTP: breakthrough pain. Updated with permission from Davies, 2006.

1 pain: 79% ≥2 pains: 21% —

Number of episodes of BTP (episodes/day) Median 4 (range 1 to 3600)

Comments The patient with 3600 episodes/day had a rib fracture and a persistent cough.

Mean 2.9 (range 1 to 5.5) Median 6 (range 1 to 60) Mean 4 (range 1 to 14) Mean 1.5 (range 0 to 5) Median 5 (range 1 to 50) Mean 2.4 Median 2.0

Data based on initial assessment of patients. Chronic (noncancer) pain patients; majority with chronic low back pain

Table 2.1B Additional characteristics of breakthrough pain in studies applying standard criteria for breakthrough pain Study Portenoy and Hagen, 1990

Fine and Busch, 1998

Duration of BTP (min) Median duration: 30 (range 1 to 240)

Portenoy et al., 1999

Mean duration: 52 (range <1 to 240) —

Zeppetella et al., 2000

73% episodes ≤ 30

Gomez-Batiste et al., 2002

Mean duration: 33.8 (range 1 to 180)

Hwang et al., 2003

Median duration: 15 (range 1 to 120)

Portenoy et al., 2006

Median duration: 60 Mean duration: 107.4 (range 1 to 720) [33% episodes < 30 ]

BTP:breakthrough breakthroughpain. pain. Updated with permission from Davies, 2006. BTP: Updated with permission from Davies, 2006.

Characteristics of BTP (temporal) Rapid onset: 43% Gradual onset: 57% — Median time to peak intensity: 3 min (range 1 s to 30 min) Rapid onset: 49% Gradual onset: 51%

Rapid onset: 60% Gradual onset: 39% (Not recorded: 1%) Rapid onset: 62% Gradual onset: 38% Rapid onset: 55% Gradual onset: 45%

Characteristics of BTP (intensity) Severe/excruciating: 100%

Mean intensity: 7/10 (range 3/10 to 10/10) Severe/excruciating: 100%

Slight: 16% Moderate: 46% Severe: 36% Excruciating: 2% Median intensity: 8 /10 (range 2/10 to 10/10) Severe/excruciating: 94%

Severe: 50% Excruciating: 50%

Comments Only patients with severe or excruciating pain classiﬁed as having BTP — Only patients with severe or excruciating pain classiﬁed as having BTP —

—

Only patients with severe or excruciating pain classiﬁed as having BTP Chronic (noncancer) pain patients; majority of patients with chronic low back pain

Other features Chronobiology of breakthrough pain It appears that there is a circadian variation in the intensity of background pain in patients with cancer (Labrecque and Vanier, 1995). Studies have demonstrated a reduction in the intensity of background pain during the night/early morning (Wilder-Smith and Wilder-Smith, 1992; Wilder-Smith et al., 1992). Similarly, there also appears to be circadian variation in the occurrence of breakthrough pain in patients with cancer. For example, in a mixed population of hospice patients (i.e., patients with end-stage, terminal diseases), 86% experienced breakthrough pain during the day, but only 45% of patients experienced breakthrough pain during the night (Fine and Busch, 1998). In addition, various studies have demonstrated a reduction in the use of breakthrough-pain medication during the night and early morning (Bruera et al., 1992; Citron et al., 1992). The reasons for the circadian variation in breakthrough pain have yet to be elucidated, but because most people are generally less active during the night, it is logical that patients whose breakthrough pain is precipitated by speciﬁc (e.g., weight-bearing) activities would be less likely to experience incident pain during this time. Furthermore, there appears to be a circadian variation in the metabolism of certain analgesics (e.g., morphine), which may be of signiﬁcance with regard to pain control (Gourlay et al., 1995). Interestingly, delirium results in an alteration in the circadian variation in breakthrough pain. In support of this, Gagnon et al. (2001) reported that patients without delirium used breakthrough medication more often during the

Clinical features CHAPTER 2

19

through pain has been reported to be associated with poor overall pain control (Mercadante et al., 1992; Bruera et al., 1995) and, not surprisingly, with decreased satisfaction with overall pain control (Zeppetella et al., 2000). Early reports revealed no relationship among the various clinical features of breakthrough pain and its different etiologies (i.e., spontaneous pain, incident pain, end-of-dose failure) (Portenoy and Hagen, 1990). More recently, it has been reported that incident pains tend to be more rapid in onset (incident pain: 76%; spontaneous pain: 52%; end-of-dose failure: 24%) and tend to have a shorter median duration of action (incident pain: 20 minutes; spontaneous pain: 30 minutes; end-of-dose failure: 30 minutes) (Gomez-Batiste et al., 2002). Similarly, neuropathic breakthrough pains have a shorter duration of action (neuropathic pain: 91% < 30 minutes; somatic: 69% < 30 minutes; visceral: 62% < 30 minutes) (Zeppetella et al., 2000). These temporal patterns and relationships have important implications for prevention and effective treatment, which are elaborated on in later chapters. It should be noted that patients with different pain pathophysiologies tend to report similar pain qualities. For example, patients with nociceptive causes for their pain report “burning,” “scalding,” “shooting,” and “pricking” pains as much as patients with neuropathic pain, which can confound diagnosis and treatment (Rasmussen et al., 2004).

Clinical features CHAPTER 2

20

day, while patients with delirium used breakthrough medication more often during the evening. It should be noted that patients with delirium are often more active—or more restless—during the evening/night, and so more likely to experience incident pain at these times. Also, their behaviors (e.g., crying out, moaning) may be interpreted, accurately or inaccurately, as being precipitated by pain (Hadjistavropoulos and Fine, 2007).

Complications of breakthrough pain Breakthrough pain can result in a number of physical, psychological, and social sequelae: • Physical complications: Breakthrough pain may be associated with a variety of physical problems, particularly in patients with volitional (movementrelated) incident pain. Such patients have difﬁculty mobilizing, which may lead to pain-related reduction in functional capacities (see next point) (Portenoy et al., 1999; Hwang et al., 2003). Sleep and mood disorders commonly result from poorly treated pain (Portenoy et al., 1999; Hwang et al., 2003). • As a result of decreased mobility, patients may develop a range of other physical problems, including muscle wasting, joint stiffness, pressure sores, constipation, deep vein thrombosis, and pneumonia. • Psychological complications: The presence of breakthrough pain has been linked to the presence of mood disturbances (Hwang et al., 2003), most notably anxiety and depression (Portenoy et al., 1999) (see Fig. 2.2). Inadequately treated pain of any type may extend into the broader realm of “suffering” due to its impact on personal integrity. The “meaning” of the pain (i.e., its implications), the physical complications of pain, and its treatmentrelated adverse effects (e.g., constipation, nausea, cognitive impairment, etc.), combined with the social complications of chronic or ongoing pain (e.g., change in work status, identity, stigmatization, etc.), create complex psychological challenges that must be recognized by the practitioner in order to optimize therapy. • Social complications: Breakthrough pain may be associated with a variety of social problems, particularly in patients with volitional (movementrelated) incident pain. Such patients may have difﬁculty undertaking essential activities of daily living, which may necessitate increased caregiver support. Moreover, patients may be unable to engage in their usual social and workrelated activities, which may result in ﬁnancial hardship for them and their dependents (Portenoy et al., 1999; Hwang et al., 2003). • Societal complications: Indirect costs of breakthrough pain are difﬁcult to calculate, although medical expenses, including physician visits and hospitalizations, have been reported to be appreciably greater in patients experiencing breakthrough pain compared to those who are not (Fortner et al., 2002) (see Table 2.2). One can extrapolate, then, from the evidence of breakthrough pain leading to increased medical utilization and decreased patient satisfaction that indirect costs (costs to society) would likely increase.

30

24.8

20

16.7

18.2 12.8

17.9

Beck Depression

Beck Anxiety

16.7

9.9

10 0 Total Score

Clinical features

Pain Interference

34.2

Patients with BTP

CHAPTER 2

Patients without BTP 40

Background Pain Intensity

Figure 2.2 Effect of breakthrough pain (BTP) on mood (cancer patients). Adapted from Portenoy et al., 1999.

Patients with BTP* Patients without BTP

Frequency of hospitalization 36.9% 22.5%

Cost of hospitalization (millions of dollars) 1.7 0.192

BTP: breakthrough pain. * Signiﬁcant at the 0.02 level. Extracted with permission from Fortner et al., 2002.

It can be concluded that the presence of breakthrough pain can have a signiﬁcant and negative impact on quality of life (Portenoy et al., 1999; Hwang et al., 2003). The degree of interference seems to be related to the characteristics of the breakthrough pain, with patients who experience spontaneous pain (Portenoy et al., 1999) and patients with more severe pain (Swanwick et al., 2000) being prone to more problems. In addition, the ability to cope with breakthrough pain seems to be related to the underlying etiology of the breakthrough pain. Patients with cancer-related pain (with all its associated implications) may have more problems coping than do patients with cancer-treatment-related pain (Foley, 1985).

References Bruera E, Macmillan K, Kuehn N, Miller MJ. Circadian distribution of extra doses of narcotic analgesics in patients with cancer pain: A preliminary report. Pain. 1992; 49:311–314. Bruera E, Schoeller T, Wenk R, et al. A prospective multicenter assessment of the Edmonton Staging System for cancer pain. Journal of Pain and Symptom Management. 1995;10:348–355.

21

Table 2.2 Costs associated with breakthrough pain

Clinical features CHAPTER 2

22

Caraceni A, Martini C, Zecca E, et al. Breakthrough pain characteristics and syndromes in patients with cancer pain. An international survey. Palliative Medicine. 2004;18:177–183. Citron ML, Kalra JM, Seltzer VL, Chen S, Hoffman M, Walczak MB. Patient-controlled analgesia for cancer pain: A long term study of inpatient and outpatient use. Cancer Investigation. 1992;10:335–341. Davies A. Current thinking in cancer breakthrough pain management. European Journal of Palliative Care. 2005;12(Suppl):4–6. Davies A. Cancer-Related Breakthrough Pain. Oxford, UK: Oxford University Press, 2006. Fine PG, Busch MA. Characterization of breakthrough pain by hospice patients and their caregivers. Journal of Pain and Symptom Management. 1998;16:179–183. Fine PG, Herr KA. Efﬁcacy, safety and tolerability of pharmacotherapy for management of persistent pain in older persons. Annals of Long-term Care: Clinical Care and Aging. 2006;14(3):25–33. Foley KM. The treatment of cancer pain. New England Journal of Medicine. 1985;313:84–95. Fortner BV, Okon TA, Portenoy RK. A survey of pain-related hospitalizations, emergency department visits, and physician ofﬁce visits reported by cancer patients with and without history of breakthrough pain. Journal of Pain. 2002;3:38–44. Gagnon B, Lawlor PG, Mancini IL, Pereira JL, Hanson J, Bruera ED. The impact of delirium on the circadian distribution of breakthrough analgesia in advanced cancer patients. Journal of Pain and Symptom Management. 2001;22:826–833. Gómez-Batiste X, Madrid F, Moreno F, et al. Breakthrough cancer pain: Prevalence and characteristics in patients in Catalonia, Spain. Journal of Pain and Symptom Management. 2002;24:45–52. Gourlay GK, Plummer JL, Cherry DA. Chronopharmacokinetic variability in plasma morphine concentrations following oral doses of morphine solution. Pain. 1995;61: 375–381. Hadjistavropoulos T, Fine PG. Chronic pain in older persons: Prevalence, assessment, and management. Reviews in Clinical Gerontology. 2007;16:1–11. Hadjistavropoulos T, Herr K, Turk D, et al. An interdisciplinary expert consensus statement on assessment of pain in older persons. Clinical Journal of Pain. 2007;23:S1–S43. Hwang SS, Chang VT, Kasimis B. Cancer breakthrough pain characteristics and responses to treatment at a VA medical center. Pain. 2003;101:55–64. Labrecque G, Vanier MC. Biological rhythms in pain and in the effects of opioid analgesics. Pharmacology and Therapeutics. 1995;68:129–147. Mercadante S, Maddaloni S, Roccella S, Salvaggio L. Predictive factors in advanced cancer pain treated only by analgesics. Pain. 1992;50:151–155. Patt RB, Ellison NM. Breakthrough pain in cancer patients: Characteristics, prevalence, and treatment. Oncology (Huntington). 1998;12:1035–1052. Portenoy RK. Treatment of temporal variations in chronic cancer pain. Seminars in Oncology. 1997;5(S16):7–12. Hanks G, Portenoy RK, Forbes K. Difﬁcult pain problems: An integrated approach. In Doyle D, Hanks G, Cherny N, Calman K (eds.), Oxford Textbook of Palliative Medicine (3rd ed., pp. 438–458). Oxford, UK: Oxford University Press, 2004. Portenoy RK, Hagen NA. Breakthrough pain: Deﬁnition, prevalence and characteristics. Pain. 1990;41:273–281.

Clinical features CHAPTER 2

23

Portenoy RK, Payne D, Jacobsen P. Breakthrough pain: Characteristics and impact in patients with cancer pain. Pain. 1999;81:129–134. Rasmussen PV, Sindrup SH, Jensen TS, Bach FW. Symptoms and signs in patients with suspected neuropathic pain. Pain. 2004;110:461–469. Swanwick M, Haworth M, Lennard RF. The prevalence of episodic pain in cancer: A survey of hospice patients on admission. Palliative Medicine. 2001;15:9–18. Wilder-Smith CH, Schimke J, Bettiga A. Circadian pain responses with tramadol (T), a short-acting opioid and alpha-adrenergic agonist, and morphine (M) in cancer pain. Presented at the 5th International Conference on Chronopharmacology, July 1992. Wilder-Smith CH, Wilder-Smith OH. Diurnal patterns of pain in cancer patients during treatment with long-acting opioid. Presented at the 5th International Conference on Chronopharmacology, July 1992. Zeppetella G, O’Doherty CA, Collins S. Prevalence and characteristics of breakthrough pain in cancer patients admitted to a hospice. Journal of Pain and Symptom Management. 2000;20:87–92.

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Chapter 3

Assessment

25

The successful management of breakthrough pain depends on adequate assessment, appropriate treatment, and adequate reassessment (i.e., determination of whether therapeutic goals have been reached without excessive adverse effects from the treatment) (Davies, 2002). Inadequate assessment may lead to ineffective treatment, or even inappropriate treatment. Similarly, inadequate reassessment may lead to continuance of ineffective or harmful treatment. The objectives of assessment are to determine the etiology of the pain (e.g., cancer- related, non-cancer-related), the pathophysiology of the pain (i.e., nociceptive, neuropathic, mixed), and factors that would support, or contraindicate, particular treatment strategies. The assessment of breakthrough pain is similar to the assessment of background pain, but the two must be differentiated.

Assessment procedure The assessment of pain primarily depends on basic clinical skills (i.e., taking a history and performing an examination) (Davies, 2002). It is important to take a general history as well as a pain history. In particular, patients should be screened for psychological, spiritual, and social factors that may be contributing to their experience of pain (Dworkin et al., 2005). Similarly, it is important to perform a general physical examination as well as a physical examination of the painful area, including a “functional exam”—that is, one that either leads to the symptoms elaborated in the history or demonstrates that the analgesic regimen is adequate. Corroborating imaging studies (e.g., plain radiographs, MRI, bone scans) can be extremely useful in the assessment of a pain complaint or a new ﬁnding that evokes pain on clinical examination. However, caution must be exercised in not overinterpreting results, whether negative or positive, insofar as imaging studies, especially of the spine, may correlate poorly with the presence or absence of pain (Weiner et al., 1994). A detailed pain history should be taken for all patients. The features of the pain that need to be determined include the following (Foley, 2004): • onset of pain • temporal pattern of pain (see Fig. 2.1) • site of pain • radiation of pain • quality (character) of pain

Assessment CHAPTER 3

26

intensity (severity) of pain exacerbating factors (what makes the pain start or get worse?) relieving factors (what prevents the pain or makes it better?) response to analgesics (including attitudes and concerns about opioids) response to other interventions (including use of “complementary and alternative” [CAM] medicines and therapies) • associated physical symptoms (The presence of other symptoms may help to determine the etiology of the pain. For example, the presence of neurological symptoms suggests an underlying neuropathic component to the pain [e.g., sensory disturbance] [Bennett, 2001].) • associated psychological symptoms • interference with activities of daily living (It is important to ascertain the global impact of the pain. Activities of daily living can be used as a surrogate marker of the response to treatment.) A thorough physical examination must be performed on all patients. The examination should include a neurological examination of the relevant area, because the presence of neurological signs suggests an underlying neuropathic component to the pain (Bennett, 2001). It can be useful to reproduce the patient’s pain by using provocative maneuvers (e.g., palpation, passive movement, active functional evaluation) (Hagen, 1999). However, it is important that the beneﬁts of such maneuvers (i.e., improved understanding of the pain) outweigh the costs of these maneuvers (i.e., causation of the pain) incurred by the patient. To assess for incident breakthrough pain, it may be illuminating both to reproduce an activity that incites pain (e.g., weight-bearing or walking) and to determine the effectiveness (pain reduction and tolerability) of a proposed treatment. To do so, it is important to have the treatment ready for use by the patient in the clinical setting. This may require preplanning, such as writing a prescription for the patient in advance of the appointment. It should be noted that many patients have more than one type of breakthrough pain (Portenoy and Hagen, 1990; Portenoy et al., 1999). Each breakthrough pain should be individually assessed, because each breakthrough pain may require a different form or timing of treatment. • • • • •

Reassessment procedure The primary objective of reassessment is to determine the efﬁcacy and tolerability of any therapeutic intervention. A further objective of reassessment is the identiﬁcation of signiﬁcant changes in the breakthrough pain. For example, increasing pain in a bone may represent impending fracture of that bone, which may necessitate a more intensive therapeutic intervention, such as surgical stabilization. Various outcome measures have been used to assess the efﬁcacy of therapeutic interventions, including (a) intensity of pain, (b) distress of pain, (c) pain

A

Assessment CHAPTER 3

relief, (d) satisfaction with treatment, (e) improvement in function, and (f ) improvement in quality of life (Davies, 2002). The different outcome measures relate to different aspects of the pain. Consequently, there is often a poor correlation between the results obtained with different outcome measures. For example, in one study involving cancer patients, the percentage of subjects who were “inadequately treated” varied from 16% to 91% depending on the speciﬁc outcome measure used (deWit et al., 1999).

Unidimensional Pain Assessment Scales Visual Analog Scale Worst possible pain

No pain Verbal Pain Intensity Scale No pain

Mild pain

Moderate pain

Severe pain

Very severe pain

Worst possible pain

0-10 Numeric Pain Intensity Scale 1

2

3

4

5 Moderate pain

6

7

Pain Thermometer Pain as bad as it could be Extreme pain Moderate pain Severe pain Mild pain Slight pain No pain

B

8

9

10 Worst possible pain

27

0 No pain

Adult Pain Faces

Multidimensional Pain Assessment Instruments

• Brief Pain Inventory (BPI) Resource-intensive and time-consuming Evaluates effects on function and QoL

–

Useful for both initial patient evaluation and evaluating/modifying ongoing treatment

–

More reliable than recall memory

–

Requires significant time commitment to interpret

10 9 8 7 6 5 4 3 2 1 0

X X X XX XX X X X X X X X XX X X X X X X X X XX XXX XX X X X X X XXX X X X X X X X X X X X X X XX X XX X

X X X X X X X X X X X X X X

X

6 am 7 8 9 10 11 12 pm 1 2 3 4 5 6 pm 7 8 9 10 11 12 am 1 2 3 4 5

• Pain Diary

Daily Pain Log Daily Pain Chart

– –

1 Oxycodone 51R 15 1 2 Senna-S 3 4 5

X Leg Burning

0

0

X Back

5

X Knee

5.5

5 5 5 1

X Shooting & Leg

Figure 3.1 Example of pain measurement scales. (A) Adapted with permission from Elsevier (Daut et al., 1983; Fishman et al., 1987; Bierri et al., 1990; Herr and Mobily, 1993; Collins and McQuay, 1997). (B) Reproduced with permission (Herr and Mobily, 1993; Cleeland et al., 1994).

Assessment CHAPTER 3

28

All of the aforementioned outcome measures have limitations. For example, pain relief is related to the change in pain intensity over a period of time; that is, it is dependent on the patient’s recollection of the baseline pain intensity. There is little consensus on the speciﬁc outcome measure that should be used to assess treatment response (deWit et al., 1999). Nevertheless, it is important that patient-appropriate outcome measure(s) be used to assess treatment responses in all patients (Davies, 2002; Dworkin et al., 2005). Outcome measures are most commonly obtained through verbal, numerical, or visual analogue scales, with pictorial variations having been created and validated for patients unable to use these other tools (Fig. 3.1A). Studies have shown good correlation between the results obtained with these different scales (McQuay and Moore, 1998). Multidimensional scales (Fig. 3.1B) further elucidate the impact of pain on activity, mood, and other quality-of-life indicators, in addition to providing insight into sensory and temporal characteristics of pain. Patients with advanced illness, severe frailty, or cognitive impairment may have difﬁculty in completing assessment tools. For example, in one study involving palliative care inpatients, 45% of the subjects were unable to complete any of the outcome measures (mainly because of cognitive impairment) (Shannon et al., 1995). On the more sanguine side, in a mixed-diagnosis population of hospice patients, the majority were able to complete a quality-of-life survey tool that used a Likert scale within 2 weeks prior to their deaths (Fine and Busch, 1998). It should be noted that studies suggest that the formal measurement of pain leads to the improved management of pain. For example, in one study involving oncology outpatients, subjects whose outcome measures were reviewed were more likely to have had an improvement in their background pain intensity at follow-up than were subjects whose outcome measures were unavailable for review (Trowbridge et al., 1997).

Assessment tools A number of different tools have been developed for the assessment of cancerrelated and noncancer chronic pain (Melzack, 1987; Cleeland and Ryan, 1994; Caraceni et al., 2002). However, these tools focus on the background pain rather than on the presence or absence of breakthrough pain. Portenoy and Hagen (1990) developed the Breakthrough Pain Questionnaire to speciﬁcally assess breakthrough pain in cancer patients. In various forms, and with modiﬁcation over the years, this scale has been used in several clinical studies involving cancer and noncancer populations (Portenoy and Hagen, 1990; Portenoy et al., 1999; Portenoy et al., 2006). The Breakthrough Pain Questionnaire enables the health-care professional to identify patients with breakthrough pain as well as collect information about the nature of the breakthrough pain and of the background pain. The criteria for diagnosing breakthrough pain are (a) the presence of background pain (i.e., the

Box 3.1 Breakthrough pain assessment algorithm This algorithm is designed for patients with controlled, persistent baseline pain. The nature of the baseline pain is assessed. Those with controlled baseline pain are then asked about ﬂares of breakthrough pain. The nature of the breakthrough pain is assessed. Note that the deﬁnition of controlled baseline pain depends in part on whether patients are taking opioids more than 12 hours per day (Scenario A) or less than 12 hours per day (Scenario B). Opioid therapy will be known of prior to beginning the assessment, and it is expected that most patients will be taking opioids more than 12 hours per day. Determining the presence of persistent baseline pain (determined at screening) 1. Does your pain currently have a component you would describe as “constant” or “almost constant”, or would it be constant or almost constant if not for the treatment you are receiving? 0 = No 1 = Yes a) If Yes, go to question #2A or #2B b) If No, STOP. Patient does not have persistent baseline pain. Scenario A: Patient taking opioids greater than or equal to 12 hours per day (screening) 2A. Have you had any pain during the past week? 0 = No 1 = Yes a) If Yes, go to question #3A. b) If No, patient has controlled baseline pain; skip to question #5. 3A. How would you judge your baseline pain on average during the past week? 1 = Mild 2 = Moderate 3 = Severe 4 = Excruciating a) If severe or excruciating, STOP. Patient has uncontrolled baseline pain. b) If mild or moderate, patient has controlled baseline pain. Continue to question #5. Scenario B: Patients taking opioid less than 12 hours per day (screening) 2B. Have you had any pain during the past week? 0 = No 1 = Yes a) If Yes, go to question #3B b) If No, STOP. Patient does not have baseline pain. 3B. Did you feel this pain for more than half the time that you were awake? 0 = No 1 = Yes a) If Yes, go to question #4B b) If No, STOP. Patient has transient pains. 4B. How would you judge your baseline pain on average during the past week? 1 = Mild 2 = Moderate 3 = Severe 4 = Excruciating a) If severe or excruciating, STOP. Patient has uncontrolled baseline pain. b) If mild or moderate, patient has controlled baseline pain. Continue to question #5. 5. Assessing the nature of the baseline pain. a) Where is this pain? (indicate “right”, “left”, or “both” if appropriate). 1. head 2. face 3. neck 4. shoulder (R,L,B) 5. chest 6. arm (R,L,B) 7. abdomen 8. upper back 9. lower back 10. leg (R,L,B) 11. buttock (R,L,B) 12. pelvis (R,L,B) 13. anorectal area 14. genitalia 15. other:________________________________________________________ b) How long have you experienced this pain? (in weeks) ____________________

Box 3.1 (Continued) c) What does it feel like? (indicate one or more description): 1. sharp 2. aching 3. crampy 4. radiating or shooting 5. pressing, squeezing, or tight 6. burning 7. throbbing 8. stabbing 9. other (describe): _________________________________________________ b) How long have you experienced this pain? (in weeks) ______________________ c) What does it feel like? (indicate one or more description): 1. sharp 2. aching 3. crampy 4. radiating or shooting 5. pressing, squeezing, or tight 6. burning 7. throbbing 8. stabbing 9. other (describe): ________________________________________________ d) Does anything that you do reduce your pain? 0 = No 1 = Yes e) If Yes, please describe what reduces your pain: _________________________________________________________________ f ) Does anything that you do make your pain worse? 0 = No 1 = Yes g) If Yes, please describe what makes your pain worse: _________________________________________________________________ Question 6 probes for the presence of breakthrough pain and question 7 assesses the nature of the breakthrough pain. 6. Do you also experience temporary ﬂares of severe or excruciating pain? 0 = No 1 = Yes a) If Yes, patient has breakthrough pain. Continue with the remainder of the questionnaire to characterize the breakthrough pain. b) If No, STOP. Patient has controlled baseline pain without breakthrough pain. 7. Assessing the nature of the breakthrough pain. a) How many different types of temporary ﬂare-ups do you have? ________________ If you had one kind of severe pain ﬂare-up during the past 24 hours, the following questions refer to the worst ﬂare-up you have had during the past 24 hours. Patients can then describe the second- and third-worst ﬂare-ups. b) Where is this pain? (indicate “right”, “left”, or “both” if appropriate). 1. head 2. face 3. neck 4. shoulder (R,L,B) 5. chest 6. arm (R,L,B) 7. abdomen 8. upper back 9. lower back 10. leg (R,L,B) 11. buttock (R,L,B) 12. pelvis (R,L,B) 13. anorectal area 14. genitalia 15. other:________________________________________________________ c) What does it feel like? (indicate one or more description): 1. sharp 2. aching 3. crampy 4. radiating or shooting 5. pressing, squeezing, or tight 6. burning 7. throbbing 8. stabbing 9. other (describe): _________________________________________________ d) When your pain ﬂare becomes as bad as it gets, would you say it is: 1 = Severe 2 = Excruciating e) From the time that you ﬁrst feel this pain start to ﬂare until it gets to be as bad as it gets, how long does it take (in minutes)? ____________________ f ) When the pain ﬂare comes on, does it start mildly and gradually get worse, or does it immediately start out severe? 1 = Gradual 2 = Severe g) If the pain ﬂare starts slowly and gradually gets worse, how long does it take from the time that you ﬁrst start to feel the pain coming on until it goes away? ______

Adapted with permission, Portenoy et al., 2006.

patient has pain that has been there for more than half of his or her waking time during the previous week, or the patient has been taking regular opioid analgesics to control persistent pain for more than half the days during the previous week); (b) the presence of controlled background pain (i.e., the patient has pain that has been rated as “absent,” “mild,” or “moderate” [but not “severe”] for more than half the time); and (c) the occurrence of one or more “severe or excruciating episodes of pain” during the previous day (Portenoy et al., 1999). The most recent version of the breakthrough pain assessment algorithm is shown in Box 3.1 (Portenoy et al., 2006). It should be noted that patients with no background (baseline, persistent) pain but who have severe or excruciating episodes of pain are classiﬁed as having “transitory pains” (Portenoy et al., 1999). Similarly, patients who have poorly controlled background pain and who have severe or excruciating episodes of pain are simply classiﬁed as having “uncontrolled pain” (Portenoy et al., 1999). Other investigators have also developed tools to speciﬁcally assess breakthrough pain. For example, Zeppetella produced an episodic (breakthrough) pain documentation sheet (Zeppetella and Ribeiro, 2002) (Fig. 3.2).

Assessment CHAPTER 3

h) How many times a day do you get this speciﬁc kind of pain ﬂare? _____________ i) Does your pain ﬂare usually come on within a certain amount of time after you have taken your pain medication? 0 = No 1 = Yes Describe _____________________________________________________ j) Do you kow what causes your pain ﬂare to come on? 0 = No 1 = Yes k) If Yes, please describe what causes your pain ﬂare: ____________________________________________________________________ l) How well can you predict when your pain ﬂare will occur? 1 = Can never predict when it will occur 2 = Can sometimes predict when it will occur 3 = Can often predict when it will occur 4 = Can almost always predict when it will occur 5 = Can always predict when it will occur m) Does anything help to lessen your painful episode? 0 = No 1 = Yes n) If Yes, please describe what reduces your pain: ____________________________________________________________________ o) If you do know of something that lessens your pain, how sure are you that it will work? Does it work successfully each time you try it? 0 = No 1 = Yes Describe________________________________________________________________

31

Box 3.1 (Continued)

Location

Severity Mild Moderate Severe Excruciating

CHAPTER 3

Assessment

Patient name: ____________________________________________ Date: ________________ Each pain should be marked on a separate sheet

Type A. No background pain [ ] B. Controlled background pain [ ] C. Uncontrolled background pain [ ] Temporal characteristics Daily frequency: ___________________ Onset:

Gradual [ ]

[ [ [ [

] ] ] ]

0. No scheduled analgesia 1. Insufficient scheduled analgesia 2. Sufficient scheduled analgesia

[ ] [ ] [ ]

Weekly frequency (if less than daily) ______

Sudden [ ]

Time course Time to max intensity (minutes) ______ [ ] [ ] [ ]

Predictable Yes No

[ ] [ ]

32

Precipitating event None (spontaneous) Incident Non-volitional

Total duration (minutes) ________________ Pathophysiology Somatic Visceral Neuropathic Mixed Unknown

[ [ [ [ [

Aetiology Disease related Treatment related Unrelated to disease/treatment

[ ] [ ] [ ]

] ] ] ] ]

Notes

Figure 3.2 Episodic pain documentation sheet. Reproduced with permission from Zeppetella & Ribeiro, 2002.

References Bennett M. The LANSS Pain Scale: The Leeds assessment of neuropathic symptoms and signs. Pain. 2001;92:147–157. Caraceni A, Cherny N, Fainsinger R, et al. Pain measurement tools and methods in clinical research in palliative care: Recommendations of an Expert Working Group of the European Association of Palliative Care. Journal of Pain and Symptom Management. 2002;23:239–255. Cleeland CS, Ryan KM. Pain assessment: Global use of the Brief Pain Inventory. Annals of the Academy of Medicine. 1994;23:129–138. Davies A. The assessment and measurement of physical pain. In Hillier R, Finlay I, Miles A (Eds.), The Effective Management of Cancer Pain (2nd ed., pp. 23–28). London: Aesculapius Medical Press, 2002.

Assessment CHAPTER 3

33

de Wit R, van Dam F, Abu-Saad HH, et al. Empirical comparison of commonly used measures to evaluate pain treatment in cancer patients with chronic pain. Journal of Clinical Oncology. 1999;17:1280–1287. Dworkin RH, Turk DC, Farrar JT, et al. Core outcome domains for chronic pain clinical trials: IMMPACT recommendations. Pain. 2005;113:9–19. Fine PG, Busch MA. Characterization of breakthrough pain by hospice patients and their caregivers. Journal of Pain and Symptom Management. 1998;16:179–183. Foley KM. Acute and chronic cancer pain syndromes. In Doyle D, Hanks G, Cherny N, Calman K (Eds.), Oxford Textbook of Palliative Medicine (3rd ed., pp. 298–316). Oxford: Oxford University Press, 2004. Hagen NA. Reproducing a cancer patient’s pain on physical examination: Bedside provocative maneuvers. Journal of Pain and Symptom Management. 1999;18:406–411. Herr KA, Mobily PR. Comparison of selected pain assessment tools for use with the elderly. Applied Nursing Research. 1993;6:39–46. McQuay HJ, Moore RA. An Evidence-Based Resource for Pain Relief. Oxford: Oxford University Press, 1998. Melzack R. The short-form McGill Pain Questionnaire. Pain. 1987;30:191–197. Portenoy RK, Bennett DS, Rauck R, et al. Prevalence and characteristics of breakthrough pain in opioid-treated patients with chronic noncancer pain. Journal of Pain. 2006;7:583–591. Portenoy RK, Hagen NA. Breakthrough pain: Deﬁnition, prevalence and characteristics. Pain. 1990;41:273–281. Portenoy RK, Payne D, Jacobsen P. Breakthrough pain: Characteristics and impact in patients with cancer pain. Pain. 1999;81:129–134. Rasmussen PV, Sindrup SH, Jensen TS, Bach FW. Symptoms and signs in patients with suspected neuropathic pain. Pain. 2004;110:461–469. Shannon MM, Ryan MA, D’Agostino N, Brescia FJ. Assessment of pain in advanced cancer patients. Journal of Pain and Symptom Management. 1995;10:274–278. Trowbridge R, Dugan W, Jay SJ, et al. Determining the effectiveness of a clinical-practice intervention in improving the control of pain in outpatients with cancer. Academic Medicine. 1997;72:798–800. Weiner DK, Distell B, Studenski S, et al. Does radiographic osteoarthritis correlate with ﬂexibility of the lumbar spine? Journal of the American Geriatrics Society. 1994; 42:257–263. Zeppetella G, Ribeiro MD. Episodic pain in patients with advanced cancer. American Journal of Hospice and Palliative Care. 2002;19:267–276.

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Chapter 4

Breakthrough pain is not a single entity but rather a manifestation of myriad pain-producing disorders. Therefore, the effective treatment of breakthrough pain depends on a variety of factors that relate to the expression and experience of pain: biomedical, psychological, and social. From a medical perspective, the etiology, pathophysiology, and characteristics of the pain will point the way toward potentially beneﬁcial therapeutic options. Moreover, treatment needs to be informed by a variety of patient-speciﬁc factors, including the stage of the disease and the performance status of the patient (Mercadante and Arcuri, 1998). Thus, treatment is highly individualized (Patt and Ellison, 1998). The management of breakthrough pain involves (a) assessment, (b) treatment of the cause of the pain, (c) treatment of the pain per se (symptomatic—or palliative—treatment), and (d) reassessment. Chapter 3 described the assessment of breakthrough pain in detail. This chapter discusses the general principles of the treatment of breakthrough pain. Subsequent chapters describe speciﬁc approaches to the symptomatic treatment of breakthrough pain in detail.

Management strategies The optimal treatment for all types of breakthrough pain is management of the underlying disease and the underlying pathological processes that are causing pain, whenever possible. Whereas disease-modifying interventions have been shown to be very effective in managing background pain, breakthrough pain has not been an outcome measure in studies evaluating the results of the use of radiotherapy, chemotherapy, bisphosphonates, anti-inﬂammatory medications, injection therapies, and so forth (Mercadante et al., 2002). Nevertheless, there is anecdotal evidence and considerable practice experience that some of these interventions may also be effective in managing some instances of breakthrough pain (Mercadante et al., 2001). The symptomatic management of breakthrough pain includes both pharmacological and nonpharmacological treatments.

Pharmacological treatment of pain 1. Modiﬁcation of the background analgesic regimen a) Increase dose of analgesic drugs b) Addition of opioid analgesic drugs

35

Principles of management

Principles of management CHAPTER 4

36

c) Addition of nonopioid analgesics (e.g., NSAIDs, which some consider to be co-analgesics, or anticonvulsants, which some consider to be adjuvant analgesics) 2. Use of breakthrough (“rescue”) analgesics a) Nonopioid analgesics b) Opioid analgesics c) Other classes of pain-attenuating agents (e.g., nitrous oxide, subanesthetic ketamine, baclofen, clonazapam, propofol)

Nonpharmacological treatment of pain A variety of nonpharmacological methods may be useful in treating breakthrough pain, such as rubbing/massage, application of heat (Fine and Busch, 1998; Swanwick et al., 2001), application of cold (Fine and Busch, 1998; Petzke et al., 1999), transcutaneous nerve stimulation (TENS) (Zeppetella and Ribeiro, 2003), distraction techniques (Portenoy, 1997; Petzke et al., 1999), and relaxation techniques (Portenoy, 1997; Fine and Busch, 1998). Table 4.1 shows the relieving factors reported by patients in studies applying standard criteria for the diagnosis of breakthrough pain (Portenoy and Hagen, 1990; Portenoy et al., 1999; Hwang et al., 2003). In these surveys, without speciﬁc attention to amelioration of breakthrough pain, it can be seen that only 44% to 61% of patients reported that their medication relieved breakthrough pain. With attention to breakthrough pain, Hwang et al. (2003) have shown that alterations in medication can lead to dramatic improvements. In their study, 54% of patients reported that their medication relieved breakthrough pain at baseline, while 83% of patients reported that their medication relieved breakthrough pain after 1 week of intervention. Similar to the relief of persistent pain, multimodal approaches to the relief of breakthrough pain, combining pharmacotherapy with nonpharmacological interventions, lead to improved outcomes (Portenoy and Hagen, 1990; Swanwick et al., 2001).

Table 4.1 Relieving factors of breakthrough pain in studies applying recognized criteria for breakthrough pain Study

Portenoy and Hagen, 1990 Portenoy et al., 1999 Hwang et al., 2003

Relieving factors Other No relieving Medication strategies factors 44% 44% 12% 61%

26%

13%

54%

26%

20%

Reproduced with permission from Davies, 2006.

Comments

Some patients had more than one relieving factor.

Data refer to initial assessment.

Management of incident pain The management of incident pain includes both treatment of precipitants of the pain and symptomatic treatment of the pain. The precipitants of incident pain are extremely varied (Table 1.2), and only some of these precipitants are amenable to speciﬁc treatment (e.g., opioids to suppress coughing) (Portenoy, 1997). Movement-related (volitional incident) pain due to osteoarthritis, degenerative spine disease, or metastatic bone disease is a common phenomenon with these disorders. This can be a very refractory type of breakthrough pain to

Principles of management CHAPTER 4

The symptomatic management of spontaneous pain primarily involves modiﬁcation of the background analgesic regimen in order to reduce the frequency and intensity of spontaneous pains. Use of breakthrough medication supplements the “around-the-clock” regimen. The options for modiﬁcation of the background analgesia are as follows: • Increase the dose of the around-the-clock analgesic. This strategy can be effective in reducing the frequency and/or severity of breakthrough pain, and it has been suggested that the dose be increased by 25% to 50% in order to determine efﬁcacy and tolerability (Portenoy, 1997). If dose-limiting side effects predominate, a different strategy, such as the consideration of an alternative around-the-clock analgesic, is recommended (Fine and Portenoy, 2007). One of the major restrictions to increasing the dose of opioid analgesics is the development of opioid-related drowsiness. Bruera et al. (1992) reported that this problem can be relieved by the concurrent use of a psychostimulant, such as methylphenidate. An alternative strategy would be opioid switching (also known as opioid rotation) (Cherny et al., 2001). It should be noted that opioid switching may also be useful in managing other opioid-related side effects (Cherny et al., 2001). • Addition of analgesic drugs. The rationale for this strategy is that the addition of another analgesic drug may result in a better effect/side-effect proﬁle than increasing the dose of the original analgesic drug. O Short-acting opioids may be used to increase analgesic effects for a period of time commensurate with the episode of breakthrough pain. O Other drugs may be added that have either direct (independent analgesia) or indirect analgesic effects. This strategy utilizes drugs that may be termed co-analgesics or adjuvants and can be effective in reducing the frequency and/or severity of speciﬁc types of breakthrough pain. Most commonly, spontaneous pains that derive from neuropathic disorders may be eased in many cases by certain anticonvulsant or antidepressant drugs (Portenoy et al., 2004).

37

Management of spontaneous pain

Principles of management CHAPTER 4

38

manage (Hwang et al., 2003). In cases of malignancy where medical management has not been effective, it may be possible to perform surgical stabilization or use an orthotic device to stabilize the relevant tissues(s) (Mercadante et al., 2002; Mercadante and Arcuri, 1998) (Figs. 4.1 and 4.2). In all cases where skeletal disease is the underlying cause of incident pain and where internal or external prostheses or ﬁxation/stabilization are not feasible, patients will beneﬁt from adaptive strategies, including assistive devices and environmental modiﬁcations. When feasible, the provision of additional practical support with activities of daily living through the use of home-care or hospice services is of great value (Mercadante and Arcuri, 1998; Fine and Davis, 2006). • The symptomatic management of incident pain rarely involves modiﬁcation of the background (around-the-clock) opioid analgesic regimen because this usually creates an excessive burden of opioid-related side effects during the majority of the time when incident pain is absent. An exception to this was found by Mercadante et al. (2004) in a study of patients with metastatic bone pain. These investigators reported that increasing the dose of regular opioid was effective in managing movement-related (volitional incident) pain in a group of patients with bone metastases without undue adverse effects. When there is a pharmacological rationale for modifying underlying pathology that leads to incident pain, then maximizing that analgesic regimen (e.g., anti-

(a)

(b)

Figure 4.1 Radiographs demonstrating surgical stabilization of a lytic bone metastasis. Reprinted with permission from Davies, 2006.

Principles of management CHAPTER 4

inﬂammatory drugs) makes sense as long as adverse effects are monitored, managed, and tolerated. • Addition of other analgesic drugs—see “Management of spontaneous pain.” In most cases, though, the effective pharmacological approach to incident pain relies on the use of breakthrough medication. In those cases where pain is predictable, it is possible to take the breakthrough pain medication in advance. The timing of preventative medication use must match the onset of the medication and timing of the activity so there is overlap of peak medication effect and paininducing events. For example, the time to onset of oral morphine is 20 to 30 minutes (Twycross et al., 1998), and the time to maximum effect is 60 minutes (Mercadante et al., 2002). Thus oral morphine should be given at least 30 minutes, and probably 60 minutes, before the relevant activity. The same parameters generally exist for most of the immediate-release opioid analgesics (e.g., tramadol, hydrocodone, hydromorphone, oxycodone, oxymorphone), although there is considerable variability—and unpredictability—based upon stomach contents and gastrointestinal absorption and transit time. The rapidonset formulations of buccal fentanyl (oral transmucosal fentanyl citrate [OTFC; ﬂavored lozenge on a stick]; fentanyl effervescent buccal tablet [FEBT]) have consistently meaningful onset of analgesic effects in 10 to 15 minutes (Fine et al., 1991; Portenoy et al., 2006; Portenoy et al., 2007).

Management of end-of-dose failure The management of end-of-dose failure involves modiﬁcation of the background analgesic regimen (Mercadante et al., 2002). The options are as follows: • Increase the dose of the analgesic. This strategy has been recommended as a first-line approach for treating end-of-dose failure with most opioid analgesics

39

Figure 4.2 Orthotic device (Polysling) for supporting/immobilizing upper arm. Reprinted with permission from Davies, 2006.

Principles of management CHAPTER 4

40

(Hanks et al., 2001). This strategy is invariably effective, although the increase in dosage may lead to an increase in side effects that may not be tolerable (Simmonds, 1999). • Increase the frequency of the analgesic. This is a recommended strategy for treating end-of-dose failure when dose increases are not tolerated or the patient’s past experience with dose escalation suggests that adverse effects will be problematic (Breitbart et al., 2000; Hanks et al., 2001). Duration of action for all opioids—and notably the controlled-release formulations—can vary enough from patient to patient that individualization of the dosing interval should always be considered during the course of treatment. For instance, the fentanyl transdermal patch was designed and tested in clinical trials for a 72-hour duration of action. Nevertheless, in up to 43% of patients the duration of action of transdermal fentanyl is somewhere between 48 and 72 hours (Payne et al., 1995; Grond et al., 1997). It has been recommended that patients whose pain is controlled for 48 hours but who require breakthrough medication at between 48 and 72 hours replace their patch every 48 hours rather than every 72 hours instead of increasing the dose of the patch to obviate breakthrough pain (Breitbart et al., 2000). • Provision of nonopioid analgesic drugs, opioid switching, or other pain relief methods. In some cases, the aforementioned strategies are either not possible or lead to intolerable side effects. In such cases, the provision of nonopioids (e.g., NSAIDs, corticosteroids, anticonvulsants, etc.), switching to a different opioid (opioid rotation), or nonpharmacological pain relief methods are optimal for controlling the background pain. If opioid rotation ﬁts the clinical circumstances as the most reasonable option, use of an established algorithm is recommended (Indelicato and Portenoy, 2003) (Box 4.1). Note that particular care must be taken when converting from an opioid to methadone; older doseconversion tables may be inaccurate and could lead to dangerous overdosing. Box 4.1 Recommendations for opioid rotation • Calculate the equianalgesic dose of the new opioid based on an accepted equianalgesic table. • If switching to any opioid other than methadone or fentanyl, decrease the equianalgesic dose by 25% to 50%. • If switching to methadone, reduce the dose by 75% to 90%. • If switching to transdermal fentanyl, do not reduce the equianalgesic dose. • Consider further changes in the adjusted equianalgesic dose based on medical condition and pain. If the patient is elderly or has signiﬁcant cardiopulmonary, hepatic, or renal disease, consider further dose reduction. If the patient has severe pain, consider a lesser dose reduction. • Calculate a rescue dose as 5% to 15% of the total daily opioid dose and administer at an appropriate interval. • Reassess and titrate the new opioids. Adapted with permission from ASCO (Indelicato and Portenoy, 2003).

Principles of management CHAPTER 4

In theory, any fast-acting analgesic can be used to treat breakthrough pain (i.e., nonopioid analgesics, opioid analgesics, adjuvant analgesics) (Mercadante and Arcuri, 1998). Due to their predictable analgesic effects, opioid preparations have become the mainstay of the pharmacological management of breakthrough pain. However, opioid preparations will only be effective if the breakthrough pain is an opioid-responsive pain. Moreover, individual opioid preparations will only be effective if the pharmacokinetic proﬁle of the preparation mirrors the temporal pattern of the pain. It should be noted that effectiveness (efﬁcacy, tolerability) to individual opioid preparations varies from person to person and may vary over time within the same person. The oral and transdermal routes are most commonly used for around-theclock opioid therapy in the management of chronic, continuous pain. These routes pose problems in the treatment of breakthrough pain. The oral route is associated with a delayed onset of action (⬇20 to 30 minutes for oral morphine) (Twycross et al., 1998), and a delayed peak effect (⬇60 minutes for oral morphine) (Mercadante et al., 2002), and there is not a transdermal system available yet that allows for rescue dosing with an ample variety of doses. In an attempt to overcome these issues, a variety of alternative routes have been utilized, including the oral transmucosal (Gardner-Nix, 2001), intravenous (Mercadante et al., 2004a), subcutaneous (Enting et al., 2005), intranasal (Pavis et al., 2002), and intrapulmonary (Zeppetella, 2000) routes. All of these routes have been shown to be very effective, but only the oral transmucosal (buccal) route both has commercially available preparations for its use and is realistic for most patients in an outpatient setting. Subsequent chapters describe these routes of administration in more detail. In the past, it has been recommended that the opioid used to treat breakthrough pain should be the same as the opioid used to treat background pain (Patt and Ellison, 1998). However, there are no data to support using the same opioid, and the decision to use an opioid should be based primarily on its pharmacokinetic proﬁle, the prescriber’s knowledge and comfort with the drug, and the patient’s past experience with the drug. Moreover, in the past, it has been recommended that the dose of opioid to treat breakthrough pain should be a ﬁxed ratio of the daily dose of opioid being used to treat the background pain (Patt and Ellison, 1998). However, the recommended ratio has varied signiﬁcantly among various guidelines (e.g., one-twenty-fourth to one-sixth of the daily dose) (Cleary, 1997). Data from recent studies suggest that there is no relationship between the dose of opioid required to control breakthrough pain and the dose of opioid required to control background pain (Coluzzi et al., 2001). Thus the dose of breakthrough medication should be titrated in a manner that balances safety and efﬁcacy (Mercadante et al., 2002). For oral agents, a starting dose equivalent to 10% to 15% of the usual 24-hour total opioid dose is recommended; for buccal delivery systems, the

41

Breakthrough (rescue/supplemental) medication

Principles of management CHAPTER 4

recommended starting dose of OTFC is 200 µg, and for FEBT it is 100 µg (Fine and Portenoy, 2007). The potential side effects associated with taking a breakthrough dose of opioid are similar to those associated with taking any dose of opioid (e.g., somnolence, nausea, vomiting, dizziness, and respiratory depression) (Coluzzi et al., 2001; Portenoy et al., 2006). Due to risks of sedation and somnolence, certain guidelines on driving and opioid medication state that in view of the risk of somnolence, “you must not drive on days where you have had to take extra (breakthrough or rescue) doses of a strong painkiller” (Pease et al., 2004). Prescribing clinicians need to determine what they believe is the best balance between public safety and patients’ interests based on their assessment of drug effects and the duration of action of breakthrough pain medications.

Other issues

42

Prescription of breakthrough medication Studies suggest that patients are frequently not prescribed breakthrough medication. For example, Ferrell et al. (1999) reported that 27% of patients with chronic pain involved in their study had not been prescribed breakthrough medication. Other authors have reported even higher levels of inattention to breakthrough pain (38% to 57%) (Weber and Huber, 1999; Zeppetella et al., 2000; Lawrie et al., 2003). Ferrell et al. (1999) also reported that patients in their study who had been prescribed breakthrough medication had arbitrary limitations imposed on the frequency of use of the breakthrough medication, regardless of frequency of breakthrough pain episodes or demonstrated effectiveness of treatment.

Adherence to breakthrough medication recommendations Nonadherence to prescribed medication instructions is common. For example, Zeppetella et al. (1999) reported that 44% of home-care patients they questioned were not taking their medication as prescribed. In particular, patients were not taking their analgesics as prescribed (i.e., nonopioids, opioids). Similarly, Ferrell et al. (1999) reported that only 3% of patients they questioned were taking their breakthrough medication as prescribed. Overall, 96% of patients were taking too low a dose, 3% were taking the prescribed dose, and 1% were taking too high a dose; the mean dose taken was only 21% of the dose prescribed (Ferrell et al., 1999). It is unclear what the reasons for this nonadherence were in the aforementioned studies, although other studies have reported that patients do not take their medication because of lack of effect, adverse events, concerns about adverse events, difﬁculty in taking the medication, and lack of knowledge about the medication (Zeppetella, 1999). Other authors have reported that the use of breakthrough medication depends on the type of breakthrough pain, with patients experiencing incident pain

One of the factors that may affect adherence is the acceptability of the breakthrough medication. Table 4.2 shows the acceptability of various routes of administration to palliative care patients if their pain were rated as “severe” (Walker et al., 2003). It should be noted that patients were informed that the onset of pain relief was 5 minutes for the intravenous route; 10 minutes for the nasal, sublingual, transmucosal, inhaled, subcutaneous, and intramuscular

Principles of management

Acceptability of breakthrough medication

CHAPTER 4

being less likely to use breakthrough medication than patients with spontaneous pain or end-of-dose failure (Gomez-Batiste et al., 2002). One plausible reason for this, although purely speculative, is that incident pain is perceived to be more controllable by the patient (without requiring medication) than spontaneous pain or end-of-dose failure. However, this may lead to unnecessary—and potentially problematic—self-imposed restrictions in activities and functions.

Table 4.2 Acceptability of different routes of administration of breakthrough medication for severe pain Acceptability of route for severe pain Yes (%) Possibly (%) No (%) 88 4 8 48 10 42

Nasal

68

14

18

Sublingual

75

11

14

Transmucosal

63

12

25

Inhaled

75

9

16

Subcutaneous Intramuscular Intravenous

87 76 83

8 12 8

5 12 9

Adapted from Walker et al., 2003.

Reasons for unacceptability Slow onset of action Slow onset of action, dignity, previous bad experience, localized pain/disease, difﬁcult to administer, unpleasant/uncomfortable Localized pain/disease, difﬁcult to administer, catches in back of throat, fear of bad taste/nausea, unfamiliar with/dislike idea Slow onset of action, previous bad experience, fear of bad taste/nausea, unfamiliar with/dislike idea Localized pain/disease, fear of bad taste/nausea, “childlike,” unfamiliar with/dislike idea Previous bad experience, localized pain/disease, difﬁcult to administer, fear of bad taste/nausea, unfamiliar with/dislike idea Dislike of injections Dislike of injections Previous bad experience, dislike of injections

43

Route Oral Rectal

Principles of management CHAPTER 4

44

routes; and 30 minutes for the oral and rectal routes. It can be seen that the likelihood that the patient will accept an invasive route of administration is related to the severity of pain (Walker et al., 2003). The advent of potent, rapidly acting opioid formulations that have the time-of-onset characteristics of invasive therapies obviates the need for this exchange of burdens for beneﬁts.

References Breitbart W, Chandler S, Eagel B, et al. An alternative algorithm for dosing transdermal fentanyl for cancer-related pain. Oncology (Huntington). 2000;14:695–705. Bruera E, Fainsinger R, MacEachern T, Hanson J. The use of methylphenidate in patients with incident cancer pain receiving regular opiates. A preliminary report. Pain. 1992;50:75–77. Cherny N, Ripamonti C, Pereira J, et al. Strategies to manage the adverse effects of oral morphine: an evidence-based report. Journal of Clinical Oncology. 2001;19:2542–2554. Cleary JF. Pharmacokinetic and pharmacodynamic issues in the treatment of breakthrough pain. Seminars in Oncology. 1997;24(Suppl 16):13–19. Coluzzi PH, Schwartzberg L, Conroy JD Jr, et al. Breakthrough cancer pain: A randomized trial comparing oral transmucosal fentanyl citrate (OTFC) and morphine sulfate immediate release (MSIR). Pain. 2001;91:123–130. Davies A. Cancer-Related Breakthrough Pain. Oxford, UK: Oxford University Press, 2006. Enting RH, Mucchiano C, Oldenmenger WH, et al. The “Pain Pen” for breakthrough cancer pain: A promising treatment. Journal of Pain and Symptom Management. 2005;29:213–217. Ferrell BR, Juarez G, Borneman T. Use of routine and breakthrough analgesia in home care. Oncology Nursing Forum. 1999;26:1655–1661. Fine PG, Busch MA. Characterization of breakthrough pain by hospice patients and their caregivers. Journal of Pain and Symptom Management. 1998;16:179–183. Fine PG, Davis M. Hospice: Comprehensive care at the end of life. Anesthesiology Clinics. 2006;24:181–204. Fine PG, Marcus M, DeBoer AJ, Van der Oord B. An open label study of oral transmucosal fentanyl citrate (OTFC) for the treatment of breakthrough cancer pain. Pain. 1991;45:149–153. Fine PG, Portenoy RK. A Clinical Guide to Opioid Analgesia (2nd ed.). New York: Vendome, 2007. Gardner-Nix J. Oral transmucosal fentanyl and sufentanil for incident pain. Journal of Pain and Symptom Management. 2001;22:627–630. Gómez-Batiste X, Madrid F, Moreno F, et al. Breakthrough cancer pain: Prevalence and characteristics in patients in Catalonia, Spain. Journal of Pain and Symptom Management. 2002;24:45–52. Grond S, Zech D, Lehmann KA, Radbruch L, Breitenbach H, Hertel D. Transdermal fentanyl in the long-term treatment of cancer pain: A prospective study of 50 patients with advanced cancer of the gastrointestinal tract or the head and neck region. Pain. 1997;69:191–198. Hanks GW, de Conno F, Cherny N, et al. Morphine and alternative opioids in cancer pain: The EAPC recommendations. British Journal of Cancer. 2001;84:587–593.

Mercadante S, Arcuri E. Breakthrough pain in cancer patients: Pathophysiology and treatment. Cancer Treatment Reviews. 1998;24:425–432. Mercadante S, Radbruch L, Caraceni A, et al. Episodic (breakthrough) pain. Consensus conference of an Expert Working Group of the European Association for Palliative Care. Cancer. 2002;94:832–839. Mercadante S, Villari P, Ferrera P, Bianchi M, Casuccio A. Safety and effectiveness of intravenous morphine for episodic (breakthrough) pain using a ﬁxed ratio with the oral daily morphine dose. Journal of Pain and Symptom Management. 2004a; 27:352–359.

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Lawrie I, Lloyd-Williams M, Waterhouse E. Breakthrough strong opioid analgesia prescription in patients using transdermal fentanyl admitted to a hospice. American Journal of Hospice and Palliative Care. 2003;20:229–230.

CHAPTER 4

Hwang SS, Chang VT, Kasimis B. Cancer breakthrough pain characteristics and responses to treatment at a VA medical center. Pain. 2003;101:55–64. Indelicato RA, Portenoy RK. Opioid rotation in the management of refractory cancer pain. Journal of Clinical Oncology. 2003;21(Suppl):87s–91s.

Mercadante S, Villari P, Ferrera P, Casuccio A. Optimization of opioid therapy for preventing incident pain associated with bone metastases. Journal of Pain and Symptom Management. 2004b;28:505–510.

Patt RB, Ellison NM. Breakthrough pain in cancer patients: Characteristics, prevalence, and treatment. Oncology (Huntington). 1998;12:1035–1052. Pavis H, Wilcock A, Edgecombe J, et al. Pilot study of nasal morphine-chitosan for the relief of breakthrough pain in patients with cancer. Journal of Pain and Symptom Management. 2002;24:598–602. Payne R, Chandler S, Einhaus M. Guidelines for the clinical use of transdermal fentanyl. Anti-Cancer Drugs. 1995;6(Suppl 3):50–53. Pease N, Taylor H, Major H. Driving advice for palliative care patients taking strong opioid medication. Palliative Medicine. 2004;18:663–665. Petzke F, Radbruch L, Zech D, Loick G, Grond S. Temporal presentation of chronic cancer pain: Transitory pains on admission to a multidisciplinary pain clinic. Journal of Pain and Symptom Management. 1999;17:391–401. Portenoy RK, Hagen NA. Breakthrough pain: Deﬁnition, prevalence and characteristics. Pain. 1990;41:273–281. Portenoy RK. Treatment of temporal variations in chronic cancer pain. Seminars in Oncology. 1997;5(S16):7–12. Portenoy RK, Payne D, Jacobsen P. Breakthrough pain: Characteristics and impact in patients with cancer pain. Pain. 1999;81:129–134. Portenoy RK, Forbes K, Lussier D, Hanks G. Difﬁcult pain problems: An integrated approach. In Doyle D, Hanks G, Cherny N, Calman K (Eds.), Oxford Textbook of Palliative Medicine (3rd ed., pp. 438–458). Oxford: Oxford University Press, 2004. Portenoy RK, Taylor D, Messina J, Tremmel L. A randomized, placebo-controlled study of fentanyl buccal tablet for breakthrough pain in opioid-treated patients with cancer. Clinical Journal of Pain. 2006;22:805–811.

45

Mercadante S, Villari P, Ferrera P, Dabbene M. Pamidronate in incident pain due to bone metastases. Journal of Pain and Symptom Management. 2001;22:630–631.

Principles of management CHAPTER 4

46

Portenoy RK, Messina J, Xie F, Peppin J. Fentanyl buccal tablet (FBT) for relief of breakthrough pain in opioid-treated patients with chronic low back pain: A randomized, placebo-controlled study. Current Medical Research Opinions. 2007;23:223–233. Simmonds MA. Management of breakthrough pain due to cancer. Oncology (Huntington). 1999;13:1103–1108. Swanwick M, Haworth M, Lennard RF. The prevalence of episodic pain in cancer: A survey of hospice patients on admission. Palliative Medicine. 2001;15:9–18. Twycross R, Wilcock A, Thorp S. Palliative Care Formulary. Abingdon: Radcliffe Medical Press, 1998. Walker G, Wilcock A, Manderson C, Weller R, Crosby V. The acceptability of different routes of administration of analgesia for breakthrough pain. Palliative Medicine. 2003;17:219–221. Weber M, Huber C. Documentation of severe pain, opioid doses, and opioid-related side effects in outpatients with cancer: A retrospective study. Journal of Pain and Symptom Management. 1999;17:49–54. Zeppetella G. How do terminally ill patients at home take their medication? Palliative Medicine. 1999;13:469–475. Zeppetella G. Nebulized and intranasal fentanyl in the management of cancer-related breakthrough pain. Palliative Medicine. 2000;14:57–58. Zeppetella G, O’Doherty CA, Collins S. Prevalence and characteristics of breakthrough pain in cancer patients admitted to a hospice. Journal of Pain and Symptom Management. 2000;20:87–92. Zeppetella G, Ribeiro MD. Pharmacotherapy of cancer-related episodic pain. Expert Opinion on Pharmacotherapy. 2003;4:493–502.

Chapter 5

Pain treatment guidelines recommend the least invasive route for opioid use in the management of chronic pain, and this is usually the oral route (World Health Organization [WHO], 1996; American Geriatrics Society [AGS], 2002; British Pain Society [BPS], 2005; Miaskowski et al., 2005). However, although the oral route is generally effective in the management of background pain, it is often less effective in the management of breakthrough pain. This is because oral opioids have a relatively delayed and highly variable interindividual and intraindividual onset of action and time to peak effect. These properties make them less than ideal for the management of breakthrough pain. Nevertheless, due to convenience, practice habits, and cost, oral opioids remain the cornerstone of the symptomatic management of breakthrough pain. This chapter focuses on those oral opioid preparations that are suitable for treating breakthrough pain (so-called normal-release, immediate-release, or short-acting opioids). This chapter concentrates on opioids for moderate to severe pain (formerly “strong opioids”) (WHO, 1996; Fine, 2005). Nevertheless, combination opioid products that are customarily used to treat mild to moderate pain (formerly given the misnomer “weak opioids”) may be used to treat breakthrough pain, but the dose is limited by the co-compounded analgesic (acetaminophen, aspirin, or ibuprofen). There are a number of different combination oral opioids that are usually prescribed for acute pain. The relevant ones that are available in the United States are shown in Table 5.1. In addition, some basic clinical and pharmacokinetic data on these opioids are shown in Tables 5.2 and 5.3. For patients who require higher doses of around-the-clock opioids (i.e., more than 50 to 100 mg oral morphine equivalents per day), the maximum safe doses of combination-product opioids may not provide sufﬁcient analgesia to control breakthrough pain. Also, routine use of acetaminophen, aspirin, or other NSAIDs may be contraindicated in certain patients who require one or more doses of a breakthrough pain analgesic per day (e.g., those with renal or hepatic dysfunction, hypertension, heart failure, gastropathy, or peptic ulcer disease) (AGS, 2002).

Route considerations The advantages and disadvantages of the oral route for treating breakthrough pain include the following (Patt and Ellison, 1998; Hanks et al., 2004):

47

Oral opioid analgesics

Oral opioid analgesics CHAPTER 5

Table 5.1 Combination oral opioids available in the United States for the treatment of breakthrough pain Generic name Hydrocodone + acetaminophen or ibuprofen

Opioid doses 5, 7.5, 10 mg

Oxycodone + acetaminophen or aspirin Tramadol + acetaminophen

5, 7.5, 10, 15 mg

37.5 mg

Comments In healthy adults, maximum daily dose of acetaminophen is 4000 mg. In patients with liver disease or a history of moderate or greater alcohol ingestion, or in frail, elderly individuals, restrict maximum acetaminophen doses to 1500 mg. See above

See above

Note: Codeine combination formulations are generally not recommended. Adapted from Fine and Portenoy, 2007.

48

Table 5.2 Basic clinical data for combination opioids commonly used for acute pain in the United States Drug Hydrocodone Oxycodone Tramadol

Onset of pain relief 30 to 60 min 30 min 30 min

Peak pain relief 60 to 120 min 60 to 120 min 180 min

Duration of pain relief 3 to 6 h 3 to 6 h 4 to 6h

From Fine and Portenoy, 2007; Twycross et al., 2002; Grond and Sablotzki, 2004.

Table 5.3 Basic pharmacokinetic data for combination opioids commonly used for acute pain in the United States Drug Hydrocodone Oxycodone Tramadol

Peak plasma level 1 to 2 h 1 to 2 h 2h

Half-life 2 to 3 h 3 to 4 h 6 h*

* Active metabolite has longer half-life (7.4 hours). From Fine and Portenoy, 2007; Twycross, 2002.

• Advantages

1. Familiar/acceptable to patients (Walker et al., 2003) 2. Convenient for patients 3. Familiar/acceptable to health-care professionals 4. Convenient for health-care professionals 5. Large variety of oral opioid drugs available 6. Large variety of oral opioid formulations available • Disadvantages 1. Not suitable for patients with dysphagia 2. Not suitable for patients with nausea and vomiting 3. Not suitable for patients with dysfunction of the upper gastrointestinal tract

Oral opioid analgesics

Commonly used oral opioids There are a number of µ opioid agonists that are used for the treatment of breakthrough pain. The relevant ones that are available in the United States are shown in Table 5.4, along with some basic clinical and pharmacokinetic data (Prommer, 2006; Fine and Portenoy, 2007). It should be noted that although there is a signiﬁcant amount of data about the pharmacokinetic proﬁles of these opioids, there is a limited amount of data about their associated clinical effects (e.g., time to onset of pain relief, time to maximum pain relief ) for the treatment of breakthrough pain. This information needs to be extrapolated from pharmacokinetic and acute pain studies. By convention and convenience only, the opioid used for breakthrough pain is usually the same as the opioid used for background pain (Mercadante et al., 2002). However, an alternative opioid may be just as or more suitable for treating breakthrough pain. Furthermore, in certain circumstances, an alternative opioid is the only option for treating breakthrough pain. For example, there is no oral preparation of fentanyl to offer a patient being treated with transdermal fentanyl for whom an oral opioid is preferred for breakthrough pain.

Drug formulation The oral immediate-release opioids commonly used to treat breakthrough pain (Table 5.4) are all available in tablet form. Morphine, oxycodone, and methadone are commercially available in liquid form, and the other agents can be extemporaneously prepared in a liquid form by a compounding pharmacy, if needed. The choice of preparation depends on a number of patient-related facTable 5.4 Basic clinical data for oral µ opioids that can be used for breakthrough pain Drug Morphine Hydromorphone Methadone* Oxycodone Oxymorphone

Onset of pain relief 20 to 30 min 30 min 30 min 20 to 30 min 20 to 30 min

Peak pain relief 60 to 120 min 60 to 120 min 60 to 120 min 60 to 120 min 30 to 60 min

Duration of pain relief 3 to 6 h 3 to 6 h 6 to 8 h 3 to 6 h 4 to 6 h

Half-life 2 to 3 h 2 to 3 h 8 to 150 h 2 to 3 h 8h

* Pharmacokinetics of methadone are complex due to a highly variable and long half-life; use for breakthrough pain in addition to baseline pain control can lead to dose accumulation and potentially lifethreatening respiratory depression. From Fine and Portenoy, 2007; Prommer, 2006.

CHAPTER 5

Drug considerations

49

4. Variation in oral bioavailability 5. Relatively slow onset of action 6. Relatively long duration of action

Plasma concentration (ng/ml)

Oral opioid analgesics CHAPTER 5

25 Oral tablet 20 mg

20

Oral solution 20 mg 15 10 5 0

0

3

6

9

12

Time (hr)

50

Figure 5.1 Mean plasma morphine sulfate (ms) concentrations following oral administration of 20 mg tablet of morphine and 20 mg oral solution of morphine (Napp Pharmaceuticals Ltd., data on ﬁle). Reprinted with permission from Davies, 2006.

tors (e.g., patient preference, presence of dysphagia, presence of enteral feeding tube) and a number of drug-related factors (e.g., taste, alcohol content, sucrose content). There is no evidence that the formulation of the opioid affects the clinical/pharmacokinetic proﬁle of the opioid (Collins et al., 1998) (Fig. 5.1). Some commercial and extemporaneously compounded liquid preparations contain alcohol, which makes them unsuitable for use in patients with certain physiological contraindications or religious beliefs, so it is worthwhile to make this determination prior to prescribing. Furthermore, some patients report that the alcohol-containing preparations cause oral and/or esophageal discomfort on ingestion. Similarly, if sucrose is used in oral solutions, diabetic patients must be made aware of this.

Drug dose The “correct” dose of breakthrough medication is the dose that provides maximal analgesia with minimal side effects (Zeppetella and Ribeiro, 2002). There is an absence of scientiﬁc data supporting speciﬁc recommendations for a ﬁxed ratio of the baseline opioid dose. An Expert Working Group of the European Association for Palliative Care has recommended using one-sixth of the daily dose of background opioid analgesia (Hanks et al., 2001). However, the same document stated that “it may be that the optimal dose for breakthrough pain can only be determined by titration” (Hanks et al., 2001). Other authorities have recommended using between 5% and 15% of the daily dose of background opioid analgesia (Cherny and Portenoy, 1993; Indelicato and Portenoy, 2003). Coluzzi et al. (2001) examined the use of oral morphine for the treatment of breakthrough pain within the context of a double-blind, randomized, controlled trial of oral transmucosal fentanyl citrate. The trial showed that there was no relationship between the dose of oral morphine (or oral transmucosal fentanyl citrate) needed to control the breakthrough pain and the dose of opioid

Oral opioid analgesics

45

30

15 y = 0.03x + 28 R2 = 0.084 0

45

30

15 y = 0.07x + 23 R2 = 0.095 0

0

200

400

800

600

0

Fixed schedule oral opioid dose morphine equivalent (mg/day)

CHAPTER 5

60

Successful MSIR dose (mg)

Successful MSIR dose (mg)

60

50 100 150 200 250 300 Transdermal fentanyl fixed schedule dose (g/hr)

Figure 5.3 Relationship between successful dose of breakthrough oral morphine (MSIR) and background dose of transdermal fentanyl. Reproduced with permission from Coluzzi et al., 2001.

Figure 5.2 Relationship between successful dose of breakthrough oral morphine (MSIR) and background dose of oral opioid. Reproduced with permission from Coluzzi et al., 2001.

51

3 OTFC *

MSIR

Pain relief score

* *

2 * 1

*p ⱕ0.009 0 0

15

30 Minutes

45

60

Figure 5.4 Timing of breakthrough pain relief with oral morphine (MSIR) vs. oral transmucosal fentanyl citrate (OTFC). Reproduced with permission from Coluzzi et al, 2001.

needed to control the background pain (Figs. 5.2 and 5.3). Furthermore, the trial also conﬁrmed that the time to maximum pain relief is at least 60 minutes after oral administration of morphine (Fig. 5.4). On the basis of the above, it would seem reasonable to initially prescribe tablets (or liquid formulation) that is equivalent to 5% of the daily dose of back-

Oral opioid analgesics CHAPTER 5

52

ground opioid analgesia, and then to titrate the dose upward according to the response achieved. Obviously, if the pain is not relieved and side effects are troublesome, then an alternative treatment should be prescribed.

Drug usage The usefulness of oral opioids for treating breakthrough pain depends on a number of factors: 1. The pain must be opioid-responsive. 2. The clinical and pharmacokinetic characteristics of the opioid need to match the temporal characteristics of the pain. 3. The patient must be able to use the oral route (see earlier section). Unfortunately, the clinical and pharmacokinetic characteristics of oral opioids often do not match the temporal characteristics of a patient’s breakthrough pain pattern. As evidenced by the various surveys evaluating onset times of breakthrough pain, an appreciable number of these pains arise rapidly and last less than 1 hour (Table 2.1B). As such, the oral agents peak too slowly and last too long to meet the needs of many patients with breakthrough pain. The role of oral opioids in treating breakthrough pain also depends on the particular subtype of breakthrough pain: • Spontaneous pain—oral opioids are taken at the ﬁrst sign of pain. However, once the pain has ﬂared, it is usually too late for oral agents to work effectively. • Incident pain—in cases of nonvolitional pain, oral opioids are given once the pain has begun. However, in cases of volitional pain or procedural pain, oral opioids can be given in advance of the precipitating event in order to try to prevent or ameliorate the incident pain. It is important that the opioids are given far enough in advance of the precipitating event. For example, in the case of oral morphine, the dose needs to be given at least 30 minutes (time to onset of pain relief ), and probably 60 minutes (time to maximum pain relief ), in advance of the precipitating event. Predictable (volitional) incident pain may be the most appropriate application of the oral route of administration. • End-of-dose failure—immediate-release oral opioids can be given to relieve pain during the dose-titration phase of initiating around-the-clock opioid therapy or prior to modiﬁcation of an existing background analgesic regimen.

Other considerations Drug acceptability In a survey looking at the acceptability of different routes of administration for breakthrough medication, 97% of patients stated that the oral route was acceptable for “mild to moderate” pain, while 88% of patients stated that the oral route was acceptable for “severe” pain (Walker et al., 2003) (see Tables 4.2 and 4.3).

The oral route is considered to be relatively cost effective (Patt and Ellison, 1998). However, although oral opioids are relatively inexpensive to purchase, they will only be truly cost effective if they actually relieve the breakthrough pain. Unrelieved breakthrough pain is associated with an increased use of health-care services (i.e., increased outpatient visits, increased inpatient admissions) (Fortner et al., 2002). The impact of the increased use of health-care services is an increase in direct (e.g., prescription costs, laboratory studies) and indirect (e.g., transportation costs, time off from work) costs for patients and their caregivers, employers, and insurers (Fortner et al., 2003).

Oral opioid analgesics

Drug costs

CHAPTER 5

The only concern about the oral route involved the time to onset of effect (i.e., 30 minutes). The speed-of-onset factor seems to be signiﬁcant insofar as in headto-head comparisons, it appears that patients prefer rapid-onset formulations (OTFC, FEBT) of fentanyl over oral opioids (Coluzzi et al., 2001; Webster et al., 2006).

American Geriatrics Society (AGS) Panel on Persistent Pain in Older Persons. The management of persistent pain in older persons. Journal of the American Geriatrics Society. 2002;50:S205–S224. British Pain Society (BPS). Recommendations for the Appropriate Use of Opioids for Persistent Non-Cancer Pain. London: British Pain Society, 2005. Cherny NI, Portenoy RK. Cancer pain management. Current strategy. Cancer. 1993;72(11 Suppl):3393–3415. Collins SL, Faura CC, Moore A, McQuay HJ. Peak plasma concentrations after oral morphine: A systematic review. Journal of Pain and Symptom Management. 1998;16:388–402. Coluzzi PH, Schwartzberg L, Conroy JD Jr, et al. Breakthrough cancer pain: A randomized trial comparing oral transmucosal fentanyl citrate (OTFC) and morphine sulfate immediate release (MSIR). Pain. 2001;91:123–130. Davies A. Cancer-Related Breakthrough Pain. Oxford, UK: Oxford University Press, 2006. Fine PG. The evolving and important role of anesthesiology in palliative care. Anesthesia and Analgesia. 2005;100:183–188. Fine PG, Portenoy RK. Clinical Guide to Opioid Analgesia (2nd ed.). New York: Vendome, 2007. Fortner BV, Demarco G, Irving G, et al. Description and predictors of direct and indirect costs of pain reported by cancer patients. Journal of Pain and Symptom Management. 2003;25:9–18. Fortner BV, Okon TA, Portenoy RK. A survey of pain-related hospitalizations, emergency department visits, and physician ofﬁce visits reported by cancer patients with and without history of breakthrough pain. Journal of Pain. 2002;3:38–44. Grond S, Sablotzki A. Clinical pharmacology of tramadol. Clinical Pharmacokinetics. 2004;43:879–923.

53

References

Oral opioid analgesics CHAPTER 5

54

Hanks GW, de Conno F, Cherny N, et al. Morphine and alternative opioids in cancer pain: The EAPC recommendations. British Journal of Cancer. 2001;84:587–593. Hanks G, Roberts CJ, Davies AN. Principles of drug use in palliative medicine. In Doyle D, Hanks G, Cherny N, Calman K (Eds.), Oxford Textbook of Palliative Medicine (3rd ed., pp. 213–225). Oxford: Oxford University Press, 2004. Indelicato RA, Portenoy RK. Opioid rotation in the management of refractory cancer pain. Journal of Clinical Oncology. 2003;21(Suppl):87s–91s. Leow KP, Smith MT, Williams B, Cramond T. Single-dose and steady-state pharmacokinetics and pharmacodynamics of oxycodone in patients with cancer. Clinical Pharmacology and Therapeutics. 1992;52:487–495. Mercadante S, Radbruch L, Caraceni A, et al. Episodic (breakthrough) pain. Consensus conference of an Expert Working Group of the European Association for Palliative Care. Cancer. 2002;94:832–839. Miaskowski C, Cleary J, Burney R, et al. Guideline for the Management of Cancer Pain in Adults and Children, APS Clinical Practice Guidelines Series, No. 3. Glenview, IL: American Pain Society, 2005. Patt RB, Ellison NM. Breakthrough pain in cancer patients: Characteristics, prevalence, and treatment. Oncology (Huntington). 1998;12:1035–1052. Prommer E. Oxymorphone: A review. Supportive Care in Cancer. 2006;14:109–115. Twycross R, Wilcock A, Charlesworth S, Dickman A. Palliative Care Formulary (2nd ed.). Abingdon: Radcliffe Medical Press, 2002. Walker G, Wilcock A, Manderson C, Weller R, Crosby V. The acceptability of different routes of administration of analgesia for breakthrough pain. Palliative Medicine. 2003;17:219–221. Webster L, Taylor D, Peppin J, Niebler G. Open-label study of fentanyl effervescent buccal tablets in patients with chronic noncancer pain and breakthrough pain: Patient preference assessment. Journal of Pain (abstracts from the 2006 annual scientiﬁc conference). World Health Organization (WHO). Cancer Pain Relief (2nd ed.). Geneva: World Health Organization, 1996. Zeppetella G, Ribeiro MD. Episodic pain in patients with advanced cancer. American Journal of Hospice and Palliative Care. 2002;19:267–276.

Chapter 6

The ideal treatment for breakthrough pain is an analgesic with good efﬁcacy, a rapid onset of action, a short duration of action, and minimal adverse effects. As discussed in Chapter 5, the oral route may not be suitable for many patients with breakthrough pain because the pharmacokinetic proﬁle of orally delivered drugs does not closely mirror the characteristics of breakthrough pain, resulting in only partially effective treatment and/or troublesome adverse effects. In an effort to deliver more effective treatment, various other routes of administration have been explored, including the transmucosal routes of administration. The transmucosal routes include ocular, nasal, buccal, sublingual, pulmonary, rectal, and vaginal. This chapter elaborates on the role of the oral transmucosal routes (buccal, sublingual), and Chapter 7 outlines the role of certain other transmucosal routes (nasal, pulmonary, rectal) in the management of breakthrough pain.

Oral mucosa The oral mucosa refers to the lining of the oral cavity. It is composed of an outer layer of stratiﬁed squamous epithelium, below which lies the basement membrane and then the lamina propria (connective tissue layer). The total surface area of the oral mucosa is ⬇200 cm2, which is relatively small compared with the gastrointestinal tract (⬇350,000 cm2) (Zhang et al., 2002). The lamina propria is highly vascular tissue, so drugs diffusing into the oral mucosa have access to the systemic circulation via its capillaries and venous drainage (internal jugular vein). The rate of blood ﬂow through the oral mucosa is substantial; it is 0.97 mL/min/cm2 in the sublingual mucosa and 2.4 mL/min/cm2 in the buccal mucosa. The oral mucosa is covered by a layer of saliva, which is secreted by the three pairs of major salivary glands (parotid, submandibular, sublingual) and the hundreds of minor salivary glands distributed throughout the mouth. The composition of the epithelium varies depending on the site in the oral cavity. For example, the hard palate, the gingiva, and the dorsal surface of the tongue are covered by a layer of keratinized cells, whereas the epithelium covering the soft palate, the buccal mucosa, and the sublingual mucosa is nonkeratinized. (Nonkeratinized epithelium is more permeable to water than keratinized

55

Oral transmucosal opioid analgesics

Oral transmucosal opioid analgesics CHAPTER 6

56

epithelium.) Similarly, the thickness of the epithelium varies according to the site: for example, the buccal mucosa is approximately 3 times as thick as the sublingual mucosa (500 to 600 µm versus 100 to 200 µm [Lee, 2001]). As a result of these characteristics, the permeability of the sublingual mucosa is greater than that of the buccal mucosa, which is greater than that of the remainder of the oral mucosa (Shojaei, 1998). The absorption of drugs across the oral mucosa involves a process of passive absorption and may involve either the transcellular route, the paracellular route (via the intercellular spaces), or a combination of the two routes (Hao and Hang, 2003). Lipophilic drugs are predominantly absorbed using the transcellular route, while hydrophilic drugs are predominantly absorbed using the paracellular route. It should be noted that lipophilic drugs also need a degree of hydrophilicity in order to transverse the inner part of the cell (Zwang et al., 2002). Paracellular absorption is limited by the small surface area available for this type of absorption (Hao and Hang, 2003). A number of drug factors affect the absorption of drugs across the oral mucosa, including the lipophilicity of the drug as described earlier, the nonionized fraction of the drug (a property that is taken advantage of in the newer modiﬁed-release-delivery fentanyl buccal tablet [FBT]), and the duration of contact with the mucosa (Hao and Hang, 2003). Due to surface-area limitations, the amount of drug that can be absorbed at any one time is relatively small compared with oral ingestion, so only potent drugs are suitable for administration via the oral transmucosal route (Zwang et al., 2002). Patients with oral mucosal disease may have altered oral transmucosal absorption (Hao and Hang, 2003), and such patients may have either decreased absorption of drugs (mucosal thickening) or increased absorption of drugs (mucosal inﬂammation). Patients with salivary-gland dysfunction may also have altered oral transmucosal absorption (Hao and Hang, 2003). Saliva is important in maintaining the pH of the oral cavity, which can affect the ionized fraction of the drug (Hao and Hang, 2003). Moreover, saliva may be necessary to dissolve the drug formulation (tablets, lozenges).

Oral transmucosal administration The oral transmucosal route offers several advantages over the gastrointestinal tract and other alternative routes of administration (Zhang et al., 2002): • Acceptable to patients (noninvasive) (Walker et al., 2003) • Convenient for patients • Convenient for health-care professionals • Suitable for patients with dysphagia • Suitable for patients with nausea and vomiting • Suitable for patients with dysfunction of the upper gastrointestinal tract • Potentially fast onset of action

Opioids approved for oral transmucosal administration Many opioids have been subject to oral transmucosal administration. However, most of these opioids are not very lipophilic and, therefore, not suited for buccal or sublingual administration due to limited absorption across the oral mucosa. Figure 6.1 shows the percentage absorption for selected opioids administered via the sublingual route (Weinberg et al., 1988). A number of pharmaceutical companies are developing oral transmucosal preparations of fentanyl for the management of breakthrough pain, including various sublingual sprays and buccal patches. In addition, several authors have reported success with the sublingual administration of the parenteral preparation of fentanyl (Gardner-Nix, 2001; Zeppetella, 2001; Duncan, 2002). Currently, though, there are only two drugs for which applications have been submitted and speciﬁcally approved by the U.S. Food and Drug Administration (FDA) for the treatment of breakthrough pain: oral transmucosal fentanyl citrate (OTFC) (Actiq) and FBT (Fentora). The current indications as set forth in the FDA approvals—and thus the indications for which these drugs can be promoted by the companies that make and market them—are limited to opioidtolerant patients with cancer-related breakthrough pain. These formulations have been tested in randomized, controlled trials of patients experiencing breakthrough pain from causes unrelated to cancer (e.g., chronic low back pain, neuropathic pain syndromes), and their use has extended to these types of patients since the drugs have become commercially available (Portenoy et al., 2007; Taylor et al., 2007).

Oral transmucosal opioid analgesics CHAPTER 6

Oral transmucosal drug delivery does not require expertise, preparation, technical equipment, or supervision of patients (except in circumstances where dose initiation might best be monitored in particularly vulnerable patients). Overall, oral transmucosal administration is convenient for patients and for health-care professionals, and it is more cost effective than invasive (e.g., parenteral) routes of administration (Zhang et al., 2002). Furthermore, oral transmucosal administration of certain drugs can provide patients with an onset of action approaching that seen with intravenous administration. The disadvantages of the oral transmucosal route include the following (Zhang et al., 2002): • Not suitable for patients with dryness of mouth • Not suitable for patients with pathology of the mouth • Limited number of suitable drugs • Limited number of suitable formulations • Variation in oral transmucosal bioavailability

57

• Avoidance of degradation by gastric acid/enzymes • Avoidance of ﬁrst-pass metabolism by liver enzymes

Mean absorption (%)

50 40 30 20 10 F (0 ent .0 an 5 yl m Bu g) pr en (0 o .1 rp m hin g) e

M e (0 thad .8 o m ne g)

M o (5 rph in m H g) e yd ro m (1 or m ph g) on e D iam (2 or .5 ph m in g) e

0 O x (2 yco .5 do m ne g)

Oral transmucosal opioid analgesics CHAPTER 6

60

Opioid (dose)

58

Figure 6.1 Absorption of opioid analgesics after sublingual administration. Adapted from Weinberg et al, 1988.

Fentanyl Drug class and characteristics Fentanyl is a synthetic opioid and a pure agonist at the µ opioid receptor. Compared with morphine, it is relatively lipophilic and approximately 50 to 100 times more potent (Gauthier and Fine, 1997). In the United States, fentanyl is available for intravenous administration (50 µg/mL); as a transdermal patch (dose strengths of 12, 25, 50, 75, and 100 µg/h); as a lozenge (dose strengths of 200, 400, 600, 800, 1200, and 1600 µg); and as a buccal tablet (dose strengths of 100, 200, 400, 600, and 800 µg).

Transmucosal fentanyl: Commercially available products Oral transmucosal fentanyl citrate

OTFC (Fig. 6.2A) consists of a hardened, sweetened, and ﬂavored fentanylimpregnated lozenge on a plastic handle (Fig. 6.2). OTFC is rubbed against the inside of the cheek, which allows the lozenge to be dissolved by the saliva and the fentanyl to be absorbed through the buccal mucosa. It takes about 15 minutes to dissolve the lozenge. However, dry-mouthed patients may take longer or be unable to dissolve the lozenge. It is recommended that the lozenge be removed from the mouth if the pain is relieved before the lozenge has completely dissolved, and the partly consumed lozenge should not be recycled but should be dissolved under hot running water (Fine, 1997). Fentanyl buccal tablet

The FBT formulation (Fig. 6.2B) uses OraVescent drug delivery technology to produce an effervescent reaction that enhances the rate and extent of fentanyl

Oral transmucosal opioid analgesics CHAPTER 6

59 Figure 6.2 (A) Oral transmucosal fentanyl citrate (Actiq). Reprinted with permission from Davies, 2006. (B) Fentanyl buccal tablet (Fentora).

absorption (Fig. 6.3). FBT is placed next to the buccal mucosa between the upper third molar area and the cheek, in the oral buccal pouch. When it comes in contact with saliva, a reaction takes place, resulting in transient changes in pH. As the pH decreases, dissolution is facilitated. As CO2 is released, the pH rises, enhancing the absorption of fentanyl through the mucosa by altering the ionic charge and making it more lipophilic (Durfee et al., 2006). The pharmacokinetics of FBT in human subjects can be seen in Table 6.1.

Pharmacokinetic Proﬁle Fentanyl is highly lipid soluble and is 80% nonionized, making it ideally suited for transmucosal absorption. The bioavailability of OTFC is 47% to 50%: 25% is rapidly absorbed through the buccal mucosa, while 25% is more slowly absorbed through the gastrointestinal mucosa as a result of swallowing the drug (Hanks, 2001; Darwish, 2007a). In comparison, the absolute biovailability of FBT is 65%:

Fentanyl buccal tablets are formulated to create a reaction that releases carbon dioxide when the tablet comes in contact with saliva – Transient pH changes accompanying this reaction are believed to optimize dissolution (at a lower pH) and membrane permeation (at a higher pH) Lower pH

Higher pH

High pH

High pH

Low pH

Low pH

Enhancing Dissolution When the tablet comes in contact with saliva, a combination of acid and bicarbonate forms carbonic acid

This drives down the pH and may enhance the dissolution of ionized fentanyl Enhancing Absorption Carbonic acid dissociates into CO2 and H2O – CO2 bubbles out of solution or is absorbed across oral mucosa H2CO3 carbonic acid

The loss of CO2 results in an increase in pH, which may favor the absorption of nonionized fentanyl Figure 6.3 OraVescent Drug Delivery Technology.

Darwish et al., 2005

FBT 200 (n = 25) FBT 500 (n = 26) FBT 810 (n = 27) FBT 1080 (n = 27) FBT 100 (n = 31) FBT 200 (n = 31) FBT 400 (n = 31) FBT 800 (n = 31) FBT 1080 (n = 40) OTFC 1600 (n = 40) FBT 400, one tablet (n = 27) FBT 100, four tablets (n = 27) FBT 400 (n = 26) FBT 800, oral (n = 26) OTFC 800 (n = 26) Fentanyl 400 IV (n = 26) FBT 400 singledose (n = 21) FBT 400 multiple doses (n = 21)

Darwish et al., 2006a

Darwish et al., 2006b Darwish et al., 2006c

Darwish et al., 2007a

Darwish et al., 2007b

Tmax (min)

Cmax (ng/mL)

45.6 45.0 59.4 45.0 45.0 40.2 34.8 40.2 60 120 45.0

0.62 1.5 2.3 2.7 0.25 0.40 0.97 1.59 2.7 2.2 0.94

AUC0-Tmax’ (ng• h/mL) 0.37 0.91 1.4 1.6 0.09 0.13 0.34 0.52 1.5 0.8 0.34

AUC0-inﬁnity (ng• h/mL) 3.5 9.7 15.0 19.0 0.98 2.11 4.72 9.05 18.0 18.0 6.15

45.0

1.03

0.36

6.30

46.8 90.1

1.02 0.98

0.40 0.11

6.48 6.60

90.8 NA

1.26 3.00

0.28 1.43

9.58 10.29

52.2

0.88

0.35

6.07

49.8

1.77

1.09

NR

NA: not applicable; NR: not reported. * All values are expressed as means, with the exception of Tmax (median). † All studies were randomized and open-label and featured a crossover design. ‡ Numbers of patients evaluable for pharmacokinetic analysis may differ from total number of enrolled patients reported in text.

48% is rapidly absorbed through the buccal mucosa while 17% is absorbed enterally (Darwish, 2007a).

Clinical Data: OTFC and FBT OTFC can provide pain relief within 10 to 15 minutes, with the peak effect occurring within 20 to 30 minutes (Hanks, 2001), whereas FBT has been shown to provide meaningful pain relief in 5 to 10 minutes with similar time course for peak effect (Darwish et al., 2007b; Slatkin et al., 2007) (Fig. 6.4). The duration of analgesia is ⬇2 hours for both formulations (Hanks, 2001; Portenoy et al., 2006). The onset of action is dependent on the absorption of fentanyl through the buccal mucosa because the drug rapidly crosses the blood–brain barrier once it enters the systemic circulation. With OTFC, patients who suck the lozenge, rather than rub the lozenge against the inside of the cheek, will experience a delayed and reduced effect.

Oral transmucosal opioid analgesics

Dose in µg (n)

CHAPTER 6

Study

61

Table 6.1 Pharmacokinetic parameters of fentanyl buccal tablet (FBT) obtained from studies in healthy volunteers*†‡

1.0 Mean Plasma Fentanyl Concentration (ng/mL)

0.8 0.6 0.4 0.2

FBT median Tmax

0 0

15

30

45 60 Time (min)

OTFC median Tmax

90

120

Figure 6.4 Oral transmucosal fentanyl citrate (OTFC) vs. fentanyl buccal tablet (FBT) mean plasma concentrations. Adapted from Darwish, 2007.

OTFC MSIR

Pain relief score

Oral transmucosal opioid analgesics CHAPTER 6

62

There have been numerous studies of the use of OTFC in the management of cancer-related breakthrough pain (Mystakidou et al., 2005). Table 6.2 shows some data from the randomized trials of OTFC (Christie et al., 1998; Farrar et al., 1998; Portenoy et al., 1999; Coluzzi et al., 2001). There have been more recent trials of OTFC in non-cancer-related breakthrough pain (Taylor et al., 2007) and with FBT in both cancer-related and non-cancer-related breakthrough pain (Portenoy et al., 2006; Fine et al., 2007; Portenoy et al., 2007). Both formulations of transmucosal fentanyl have been found to be effective in treat-

*pⱕ0.009

Minutes

Figure 6.5 Pain relief scores with oral transmucosal fentanyl citrate (OTFC) and immediate-release oral morphine sulphate (MSIR). Reproduced with permission from Coluzzi et al., 2001.

Table 6.2A Randomized trials of oral transmucosal fentanyl citrate Study Christie et al., 1998

Methodology Multicenter, double-blind, randomized dose-titration study of OTFC

62 cancer patients using transdermal fentanyl for background analgesia

Portenoy et al., 1999

Multicenter, double-blind, randomized dose-titration study of OTFC 65 cancer patients using oral opioids for background analgesia

OTFC: oral transmucosal fentanyl citrate.

Principal outcomes • 76% of patients titrated to an effective dose of OTFC. • No relationship was found between the successful dose of OTFC and the dose of background transdermal fentanyl. • OTFC produced signiﬁcantly quicker/better pain relief than usual breakthrough analgesic. • Global satisfaction signiﬁcantly higher for OTFC than usual breakthrough analgesic. • The most common adverse effects of OTFC were somnolence, nausea, dizziness, and vomiting. • 74% of patients titrated to an effective dose of OTFC. • No relationship was found between the successful dose of OTFC and the dose of background oral opioid. • OTFC produced signiﬁcantly quicker/better pain relief than usual breakthrough analgesic. • Global satisfaction signiﬁcantly higher for OTFC than usual breakthrough analgesic. • The most common adverse effects of OTFC were somnolence, dizziness, nausea, and headache.

Table 6.2B Randomized trials of oral transmucosal fentanyl citrate Study Farrar et al., 1998

Methodology Multicenter, double-blind, randomized, controlled crossover trial of OTFC vs. placebo 92 cancer patients using oral opioids or transdermal fentanyl for background analgesia Patients only eligible for main trial if they responded to OTFC

Coluzzi et al., 2001

Multicenter, double-blind, randomized, controlled crossover trial of OTFC vs. oral morphine 93 cancer patients using oral opioids or transdermal opioid for background analgesia Patients only eligible for main trial if they responded to OTFC

OTFC: oral transmucosal fentanyl citrate.

Principal outcomes • OTFC produced signiﬁcantly quicker/better pain relief than placebo. • Global performance of OTFC better than placebo. • Patients required signiﬁcantly less additional rescue medication when using OTFC. • Most patients chose to continue with OTFC following the trial. • The most common adverse effects of OTFC were dizziness, nausea, somnolence, constipation, and asthenia. • No relationship was found between the successful dose of OTFC and the dose of background oral opioid or transdermal opioid (Figs. 6.5 and 6.6). • OTFC produced signiﬁcantly quicker/better pain relief than oral morphine (Figs. 6.3 and 6.4). • Global performance of OTFC better than placebo. • Most patients chose to continue with OTFC following the trial. • The most common adverse effects of OTFC were somnolence, nausea, constipation, and dizziness.

70 60 51† 50 40

35

30

25

24* 20 10

16 8

6

65

Percentage of Distribution

64†

Oral transmucosal opioid analgesics

80

CHAPTER 6

Pain Intensity Response ⱖ50% Improvement

0 15

45

30

60

Time (min)

*P < 0.05 †P < 0.0001 Figure 6.6 Breakthrough pain intensity improvement by treatment episode. FBT: fentanyl buccal tablet. Adapted with permission from Portenoy et al., 2006. FENTORA (package insert). Frazer, PA: Cephalon, Inc., 2007.

ing these difﬁcult-to-control, debilitating, episodic pains (Figs. 6.5 and 6.6) and to be well tolerated. Dose-ﬁnding studies have demonstrated that there is no correlation between the dose of opioid needed to control the background pain and the dose of OTFC or FBT needed to control the breakthrough pain (i.e., the dose requires individual titration) (Christie et al., 1998; Portenoy et al., 1999; Coluzzi et al., 2001; Portenoy et al., 2006) (Figs. 6.7, 6.8, and 6.9). Figure 6.10 shows a titration schedule for FBT and OTFC that has been safe and effective (Fentora Package Insert, 2007; Zeppetella, 2005). More rapid titration schedules have been developed, but this is not advised unless performed under circumstances where monitoring can detect and lead to immediate reversal of untoward adverse effects (e.g., respiratory depression) (Zeppetella, 2005; Fine and Portenoy, 2007). The side effects of OTFC and FBT are similar to those of other opioid preparations and include somnolence, nausea, dizziness, and headache (Christie et al.,

Successful OTFC dose (µg)

1600 1400 1200 1000 800 600 400 200

y = 0.47x + 807 R2 = 0.024

0 0 200 400 600 800 Fixed schedule oral opioid dose morphine equivalent (mg/day)

Figure 6.7 Relationship between successful dose of oral transmucosal fentanyl citrate (OTFC) and background dose of oral opioid. Reproduced with permission from Coluzzi et al., 2001.

Figure 6.8 Relationship between successful dose of oral transmucosal fentanyl citrate (OTFC) and background dose of transdermal fentanyl. Reproduced with permission from Coluzzi et al., 2001.

12%

13%

100

200

20%

400

600

800

67

Figure 6.9 Titration of the fentanyl buccal tablet (FBT) Pivotal Cancer Trials. Distribution of successful doses of FBT following titration (N = 167). Successful dose = dose strength that provided adequate analgesia (sufﬁcient pain relief within 30 minutes after placing a single tablet of that dose strength in the buccal cavity for each of two consecutive episodes of breakthrough pain (BTP) in cancer patients that occurred at least 4 hours apart) without unacceptable adverse effects; no correlation was found between baseline opioid dose and BTP dose. Source: Cephalon, Inc., Frazer, PA.

Oral transmucosal opioid analgesics

33% 22%

CHAPTER 6

% of Patients

30% 25% 20% 15% 10% 5% 0%

1998; Farrar et al., 1998; Portenoy et al., 1999; Coluzzi et al., 2001; Portenoy et al., 2006). Respiratory depression is a potential hazard, but this has been a very rare occurrence when these formulations have been titrated appropriately. Limitations to the use of OTFC include patients who cannot actively rub the preparation against the buccal membrane (e.g., patients who are severely disabled, fatigued, or cognitively impaired.) Dry mouth is one of the main reasons cited for not being able to use OTFC or FBT. However, it is usually possible to treat the dry mouth in order to facilitate use of these formulations when deemed appropriate (Davies and Vriens, 2005). Severe oral pathology may alter absorption or result in painful application, so these situations must be managed on a case-by-case basis. Unique to FBT is the potential for application-site irritation from the effervescent reaction. Similarly, there are anecdotal reports of dental caries from frequent OTFC use. Fentanyl is metabolized mainly via the human cytochrome P450 3A4 isoenzyme system (CYP3A4); thus, potential interactions may occur when it is given concurrently with agents that affect CYP3A4 activity. Particular caution should be exercised for patients receiving CYP3A4 inhibitors, and the lowest possible dose of fentanyl-containing formulations should be used in these patients (e.g., dexamethasone, dextromethorphan, ﬂuoxetine, paroxetine [weak inhibitor], sertraline, venlafaxine) (Inturrisi, 2002). Patients receiving OTFC or FBT and moderate or potent CYP3A4 inhibitors should be carefully monitored for an extended period of time, and dosage increases should be conservative (Fine and Portenoy, 2007).

Patients considered opioid-tolerant are those who are taking: – At least 60 mg of oral morphine daily – At least 25 µg of transdermal fentanyl per hour – At least 30 mg of oxycodone daily – At least 8 mg of oral hydromorphone daily – An equianalgesic dose of another opioid for 1 week or longer FBT: Start dosing at 100 µg OTFC: Start dosing at 200 µg

1. Patient waits 15 to 30 minutes after complete dissolution of either drug formulation. If inadequate analgesia results, patient applies/consumes a second FBT/OTFC unit of the same strength. 2. Patient tries this FBT/OTFC dose for consecutive episodes of breakthrough pain. With FBT, 100 µg tablets can be placed concurrently on either side of the mouth to use up the initial prescription.

Did patient achieve adequate pain relief with one FBT/OTFC unit?

Yes Successful dose determined

No Increase dose to next strength

Figure 6.10 Titration protocol for transmucosal formulations of fentanyl (fentanyl buccal tablet [FBT] and oral transmucosal fentanyl citrate [OTFC]) in opioid-tolerant patients with breakthrough pain. Adapted from Zeppetella, 2005, and Fentora package insert.

Buprenorphine Drug characteristics Buprenorphine is a semisynthetic opioid and is a partial agonist at the µ receptor.

Product characteristics Buprenorphine, an analgesic used primarily for addiction therapy in the United States, has a very high afﬁnity for the µ receptor. As a partial agonist, it can compete for the receptor and has antagonist properties in opioid-sensitized individuals, and it also is difﬁcult to displace from the receptor once bound. Oral sublingual buprenorphine is now available in the United States for ofﬁce-based substitution treatment of opioid addiction, but it is also being studied for use in chronic pain. A transdermal buprenorphine formulation is also being studied for use in chronic pain (Fine and Portenoy, 2007). Buprenorphine is available as a sublingual tablet and may become available in the United States as a transdermal patch and a parenteral preparation, formulations that are currently available in the United Kingdom. In the United Kingdom, the sublingual tablet is licensed for the management of moderate to severe pain; the sublingual tablet is primarily used in the management of background pain but is also recommended for use in the management of breakthrough pain in patients prescribed the transdermal patch (Anonymous, 2005).

Pharmacokinetic proﬁle Buprenorphine is highly lipophilic and is well absorbed across mucosal membranes. The percentage absorption is ⬇55% after sublingual administration (Weinberg et al., 1988) (Fig. 6.1), although it is somewhat less after buccal administration

Oral transmucosal opioid analgesics

Alfentanil is a synthetic opioid analgesic that is chemically similar to fentanyl. It is less lipophilic than fentanyl but has a more rapid onset of action and shorter duration of action when given parenterally (Scholz et al., 1996). For example, when given intravenously, the onset of action is < 2 minutes, and the duration of action is 10 minutes (Twycross et al., 2002). These characteristics suggest that alfentanil could be particularly helpful in the management of breakthrough pain. A parenteral preparation of alfentanil was reported to be effective and well tolerated when administered bucally/sublingually in a small case series of patients with cancer-related breakthrough pain (Duncan, 2002). Interestingly, patients preferred buccal administration of the preparation. It should be noted that the main reason for choosing alfentanil in this series was the availability of a suitable (concentrated) preparation of alfentanil (i.e., only small volumes of alfentanil were required to be administered).

CHAPTER 6

Alfentanil

69

Other opioids for oral transmucosal administration

Oral transmucosal opioid analgesics CHAPTER 6

70

(Davis, 2005). However, the rate of systemic absorption can be slow: peak plasma concentrations occur 0.5 to 3 hours after sublingual administration (Davis, 2005).

Clinical data The reported onset of action of sublingual buprenorphine is ⬇15 to 30 minutes, the peak analgesic effect is at ⬇60 to 120 minutes, and the duration of action is ⬇8 hours (Thompson, 1990). The delayed peak analgesic effect and the long duration of action make this preparation of questionable value for the treatment of breakthrough pain. There have been numerous studies of the use of sublingual buprenorphine in the management of cancer-related pain (Davis, 2005). The majority of these studies report its use for background pain, but some studies also report its use for breakthrough pain, especially when used with the transdermal buprenorphine patch (Sittl et al., 2003; Sorge and Sittl, 2004). However, there are no studies speciﬁcally designed to evaluate the effectiveness of sublingual buprenorphine in the management of breakthrough pain. The adverse effects encountered with buprenorphine are typical of those encountered with opioid analgesics. Buprenorphine is reported to cause more dizziness, nausea, and vomiting than morphine. However, it is reported to cause less respiratory depression and constipation than morphine (Davis, 2005). It should be noted that the effects of buprenorphine are only partially reversed by opioid antagonists (e.g., naloxone), an issue of particular concern should there be accidental overdose (Anonymous, 2005).

Hydromorphone Hydromorphone has a relatively low lipid solubility, which results in limited transmucosal absorption (Weinberg et al., 1988) (see Fig. 6.1). The low bioavailability and long duration of action of hydromorphone (⬇4 hours) mean that this drug is not suited for the treatment of breakthrough pain.

Methadone Methadone is a lipophilic drug that is well absorbed across mucosal membranes. The percentage absorption is 35% after sublingual administration (Weinberg et al., 1988) (see Fig. 6.1). Sublingual methadone has been reported to be effective in the management of pain in adults, and the sublingual bioavailability is reported to be similar to the oral bioavailability, with the time to maximum peak concentration reported to be similar for the two routes (McQuay et al., 1986). In view of the comparable pharmacokinetic proﬁles of oral and sublingual methadone, it would seem reasonable to suppose that the clinical proﬁle is similar for sublingual and oral methadone. Oral methadone is reported to have an onset of action of 30 to 60 minutes, a peak analgesic effect at 30 to 120 minutes, and a duration of action of 6 to 8 hours (Thompson, 1990). However, a recent study of oral methadone for breakthrough pain stated that some patients reported an analgesic effect at 10 minutes following ingestion of the oral methadone (Fisher et al., 2004).

Oxycodone Oxycodone has a very low lipid solubility, which results in very limited transmucosal absorption (Weinberg et al., 1988) (see Fig. 6.1). Again, the low bioavailability and long duration of action of oxycodone (⬇4 hours) mean that this drug is not ideally suited for the treatment of breakthrough pain. Nevertheless, there are reports of buccal administration of oxycodone in the management of background pain (Parodi et al., 1997).

Sufentanil Sufentanil is another synthetic opioid analgesic and is chemically similar to fentanyl. It is more lipophilic and about 10 times more potent than fentanyl, with a more rapid onset of action and shorter duration of action when given parenterally (Scholz et al., 1996). Again, these characteristics suggest that sufentanil could be particularly helpful in the management of breakthrough pain.

Oral transmucosal opioid analgesics

Among opioids, morphine is relatively hydrophilic, and 90% of its molecules are ionized at the normal oral pH (Coluzzi, 1998). Thus the physicochemical properties of morphine are not favorable for oral transmucosal absorption (Weinberg et al., 1988) (see Fig. 6.1). In addition, the time to maximum peak concentration and the maximum peak concentration are reported to be similar for the sublingual and oral routes (McQuay et al., 1986). A review of the literature on the use of sublingual morphine stated that “the limited clinical data do not provide compelling evidence for the effectiveness of sublingual morphine for the rapid relief of pain in cancer patients” (Coluzzi, 1998). Nothwithstanding these ﬁndings, oral morphine concentrate (20 mg/mL) is commonly used for “rescue analgesia” or breakthrough pain in hospice and palliative care settings. This is most likely a matter of convention, convenience, and cost. There may be a desire to avoid invasive parenteral drug delivery devices (e.g., patient-controlled analgesia pumps) or an inability to pay for the appreciably higher cost of rapid-onset noninvasive drug delivery systems (i.e., OTFC or FBT) compared to oral morphine solution under the ﬁnancial constraints of the Medicare Hospice Beneﬁt (Fine and Davis, 2006).

CHAPTER 6

Morphine

71

The fast onset of action and relatively low cost of sublingual methadone could be viewed as advantageous. Nonetheless, the pharmacology of methadone has been shown to differ so substantially from other opioids as to pose unique risks related to its metabolism, protein binding, excretion, arrhythmogenesis, and unpredictable eqianalgesic dosing (Fishman et al., 2002). Likewise, methadone has a uniquely shorter analgesic half-life compared to its rather long plasma half-life (8 to 150 hours), which potentially complicates its dosing. Overall, it can be concluded that the risks of dose accumulation due to the very long half-life of methadone simply outweigh any potential beneﬁts for treatment of breakthrough pain in most cases.

Oral transmucosal opioid analgesics CHAPTER 6

72

There have been a number of published reports supporting the role of sublingual sufentanil in the management of breakthrough pain (Kunz et al., 1993; Gardner-Nix, 2001). In the study by Gardner-Nix, the onset of action was reported to be between 4 and 6 minutes, and the duration of action was 35 minutes (Gardner-Nix, 2001). In fact, in some patients the duration of action was so brief that they required a combination of the short-acting sufentanil and a longer-acting oral opioid (i.e., morphine or hydromorphone) to control some longer episodes of breakthrough pain. Although sufentanil has a very suitable proﬁle for breakthrough pain, as of yet no commercially available transmucosal formulations of sufentanil have been approved for this indication.

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Parodi B, Russo E, Caviglioli G, Vallarino M, Fusco F, Henriquet F. Buccoadhesive oxycodone hydrochloride disks: Plasma pharmacokinetics in healthy volunteers and clinical study. European Journal of Pharmaceutics and Biopharmaceutics. 1997;44:137–142. Portenoy RK, Messina J, Xie F, Peppin F. Fentanyl buccal tablet (FBT) for relief of breakthrough pain in opioid-treated patients with chronic low back pain: A randomized, placebo-controlled study. Current Medical Research Opinion. 2007;23:223–233. Portenoy RK, Payne R, Coluzzi P, et al. Oral transmucosal fentanyl citrate (OTFC) for the treatment of breakthrough pain in cancer patients: A controlled dose titration study. Pain. 1999;79:303–312. Portenoy RK, Taylor D, Messina J, Tremmel LA. Randomized, placebo-controlled study of fentanyl buccal tablet for breakthrough pain in opioid-treated patients with cancer. Clinical Journal of Pain. 2006;22:805–811. Scholz J, Steinfath M, Schulz M. Clinical pharmacokinetics of alfentanil, fentanyl and sufentanil. An update. Clinical Pharmacokinetics. 1996;31:275–292. Shojaei AH. Buccal mucosa as a route for systemic drug delivery: A review. Journal of Pharmacy and Pharmaceutical Sciences. 1998;1:15–30. Sittl R, Griessinger N, Likar R. Analgesic efﬁcacy and tolerability of transdermal buprenorphine in patients with inadequately controlled chronic pain related to cancer and other disorders: A multicenter, randomized, double-blind, placebo-controlled trial. Clinical Therapeutics. 2003;25:150–168. Slatkin NE, Xie F, Messina J, Segal TJ. Fentanyl buccal tablet for relief of breakthrough pain in opioid-tolerant patients with cancer-related chronic pain. Supportive Oncology. 2007;5(7):327–334. Sorge J, Sittl R. Transdermal buprenorphine in the treatment of chronic pain: Results of a phase III, multicenter, randomized, double-blind, placebo-controlled study. Clinical Therapeutics. 2004;26:1808–1820. Taylor DR, Webster LR, Chun SY, et al. Impact of breakthrough pain on quality of life in patients with chronic, noncancer pain: Patient perceptions and effect of treatment with oral transmucosal fentanyl citrate (OTFC, ACTIQ®). Pain Medicine. 2007;8:281–288. Thompson JW. Clinical pharmacology of opioid agonists and partial agonists. In Doyle D (Ed.), Opioids in the Treatment of Cancer Pain (pp. 17–38). London: Royal Society of Medicine Services, 1990. Twycross R, Wilcock A, Charlesworth S, Dickman A. Palliative Care Formulary (2nd ed.). Abingdon: Radcliffe Medical Press, 2002. Walker G, Wilcock A, Manderson C, Weller R, Crosby V. The acceptability of different routes of administration of analgesia for breakthrough pain. Palliative Medicine. 2003;17:219–221. Weinberg DS, Inturrisi CE, Reidenberg B, et al. Sublingual absorption of selected opioid analgesics. Clinical Pharmacology and Therapeutics. 1988;44:335–342. Zeppetella G. Sublingual fentanyl citrate for cancer-related breakthrough pain: A pilot study. Palliative Medicine. 2001;15:323–328. Zeppetella J. Is the recommended titration schedule for OTFC too conservative? European Journal of Palliative Care. 2005;12(Suppl):6–7. Zhang H, Zhang J, Streisand JB. Oral mucosal drug delivery: Clinical pharmacokinetics and therapeutic applications. Clinical Pharmacokinetics. 2002;41:661–680.

Chapter 7

Ideally, breakthrough pain should be treated with a self-manageable method that consistently provides a rapid onset of action, a short duration of action, good efﬁcacy, and good tolerability. Furthermore, the method must be acceptable and affordable. By convention and convenience, the majority of patients with breakthrough pain are treated with oral opioids. However, as discussed in Chapter 5, the oral route of administration is not ideally suited to the treatment of breakthrough pain. Furthermore, there are a number of clinical conditions that contraindicate the oral route of administration (e.g., dysphagia, nausea, and vomiting). Opioids can be delivered via a number of other routes, including the rectal, intravenous, intramuscular, subcutaneous, transdermal, oral transmucosal, intranasal, and intrapulmonary routes (Stevens and Ghazi, 2000). Some of these routes have become more commonly used to manage breakthrough pain (e.g., subcutaneous, oral transmucosal), while others are still being investigated for their utility (e.g., intranasal, intrapulmonary). The suitability of different opioids for delivery via certain routes depends on a number of physicochemical factors (i.e., drug-speciﬁc factors) and pharmaceutical factors (i.e., product formulation factors). For example, methadone— regardless of its long half-life and beneﬁt-to-risk ratio as a breakthrough pain drug—is not ideally suited to intranasal administration because it causes irritation of the nasal mucosa (Dale et al., 2002b). On the other hand, fentanyl and its congeners (e.g., sufentanil) have been tested via the intranasal route, but no formulation has been submitted for U.S. Food and Drug Administration (FDA) approval, let alone made commercially available, for such use (Duncan, 2002).

Enteral routes Oral administration A comprehensive discussion of oral administration is given in Chapter 5. However, some comparative aspects of oral versus other routes of administration are shown in Table 7.1.

75

Opioid analgesics via other routes

Table 7.1 Characteristics of different routes of administration Characteristic First-pass metabolism Bioavailability Onset of action Invasive method Self-administered method Duration of usage

Oral route ++ Variable >30 min − +

Rectal route (+) Variable >30 min − +

Intravenous route − Maximum 5 min + −**

Intramuscular route − High 10 to 15 min ++ −

Subcutaneous route − Medium to high 10 to 15 min + +

Transmucosal routes* − Medium to high 10 min − +

Intrapulmonary route − Medium to high 5 min − +

Unlimited

Medium term

Long term

Short term

Long term

Unlimited

Undetermined

* Oral transmucosal, intranasal ** Except for intravenous PCA (patient-controlled analgesia)

Opioid analgesics via other routes CHAPTER 7

The rectum is ⬇15 to 19 cm in length and has a surface area available for drug absorption of ⬇200 to 400 cm2. The upper part of the rectum drains into the portal vein, while the lower part of the rectum drains into the inferior vena cava (and thus circumvents ﬁrst-pass metabolism through the liver). However, there are anastomoses between the two venous systems (van Hoogdalem et al., 1991; Warren, 1996). Drug transport across the rectal mucosa occurs predominantly via passive diffusion. Absorption is mostly dependent on the amount of surface area and duration of contact of the drug with the rectal mucosa. Stool in the rectum may prevent the absorption of all or some portion of the drug. Furthermore, defecation will obviate the absorption of the drug, and reﬂex expulsion will occur if signiﬁcant volumes of solubilized formulations of medications are inserted into the rectum (i.e., 10 to 25 mL) (van Hoogdalem et al., 1991; Warren, 1996). Rapidity and amount of drug absorption from the rectum also depend to a high degree on the formulation used (e.g., liquid enemas tend to be more rapidly absorbed than solid suppositories). Rectal administration may result in a faster onset of action than oral administration, due to the time taken for the drug to reach the site of absorption for the oral route (i.e., the small bowel). For example, it has been shown in healthy volunteers that there is more rapid uptake of methadone after rectal administration (Dale et al., 2004). In addition, rectal administration of an opioid may result in a higher bioavailability than oral administration of the same drug for those that undergo extensive ﬁrst-pass metabolism (e.g. morphine, fentanyl). However, rectal bioavailability can be extremely variable, for the reasons discussed earlier (Hanks et al., 2004). Although the rectal route has been suggested as being potentially suitable for the treatment of breakthrough pain, there are no speciﬁc studies of the use of the rectal route for this purpose (Mercadante et al., 2002). Nonetheless, in those rare cases where other routes are simply not acceptable or accessible, rectal administration may be an option (Mercadante and Fulfaro, 1999). The rectal route is simple, does not require any equipment, and can be used by both patients and their nonprofessional caregivers (Hanks et al., 2004). However, the rectal route may be inappropriate in patients with local disease of the rectum and may be difﬁcult to use in patients who are not cooperative. In addition, many patients do not ﬁnd the rectal route to be an acceptable route of administration for drugs. For example, in a study by Walker et al. (2003), only 48% or patients thought that rectal administration of analgesics was acceptable for pain that was severe in nature. A variety of different reasons were given for rejecting this route (see Table 4.2).

77

Rectal administration

Opioid analgesics via other routes CHAPTER 7

78

Parenteral routes Intravenous administration The intravenous (IV) route is associated with a 100% bioavailability (by deﬁnition) and a very rapid onset of action (⬇5 minutes). Mercadante et al. (2004) reported on the use of IV morphine to treat breakthrough pain episodes in patients receiving oral morphine. Intravenous morphine was found to be effective, well tolerated, and safe (in the inpatient setting). In addition, other authors have reported on the use of IV morphine to treat breakthrough pain episodes in patients receiving continuous infusions of morphine (i.e., IV patient-controlled analgesia [PCA]) (Swanson et al., 1989; Wagner et al., 1989). The IV route requires appropriate venous access, some basic equipment (for bolus injections), and some training in performing the technique and caring for the IV site. This route can be used in community settings, and the technique can be taught to patients and their caregivers. However, in practice, this route is generally restricted to inpatient settings (with the exception of home-based post-acute care), palliative care, and hospice situations, where IV PCA has been successfully used (Swanson et al., 1989; Wagner et al., 1989). Intravenous administration has high acceptability when the pain is severe in intensity (83% acceptability) (Walker et al., 2003) and there are no other reasonable alternatives presented. The main objections to the use of this route are its invasiveness and previous bad experiences with this route. In patients without a permanent IV access device (e.g., Broviac catheter), it goes without saying that in the vast majority of cases, use of this route is temporary and labile until other modalities (e.g., oral transmucosal formulations) can take over.

Intramuscular administration The intramuscular (IM) route of administration is not recommended for the treatment of breakthrough pain because of the discomfort associated with IM injection (Mercadante et al., 2002). Indeed, the IM route of administration is not acceptable to many patients because of their dislike for injections (and particularly IM injections) (Walker et al., 2003). Nevertheless, in certain crisis circumstances, there may be no alternative to the IM route of administration (Hanks et al., 2004). Proper planning and anticipation of needs are the best means of preventing such a crisis, obviating the need for unscheduled emergency/urgent care and preventing the suffering and costs associated with it (Ferrell and Grifﬁth, 1994).

Subcutaneous administration The subcutaneous (SC) route is the most commonly used parenteral route of administration in palliative care (Hanks et al., 2004). The SC route is associated with a relatively high bioavailability: for example, a pharmacokinetic study in healthy volunteers showed that SC morphine has a bioavailability of 80% to 100% (higher for continuous infusion than for bolus doses) (Stuart-Harris et al., 2000). The SC route is also associated with a relatively rapid onset of action

Transdermal administration Transdermal administration has had no role to play in the treatment of breakthrough pain due to the very slow egress of drug through the skin. However, new patch technology using iontophoresis may alter that rate-limiting barrier. A fentanyl hydrochloride patient-activated transdermal system (Ionsys) has recently been developed and FDA approved for the treatment of acute postoperative pain in hospitalized patients. The system uses a low-intensity direct current to transport fentanyl from the reservoir in the patch into the SC tissues, where it is then absorbed into the systemic circulation (Sinatra, 2005). The system is patient activated, delivers a 40 µg bolus of fentanyl over 10 minutes, and has a 10-minute “lock-out” period. Each patch is operational for 24 hours and delivers a maximum of 80 boluses of fentanyl. The system compared favorably to conventional PCA in recent studies of postoperative pain (Viscusi et al., 2004; Viscusi et al., 2006). No studies as of yet have been designed to evaluate this system for breakthrough pain, although the technology lends itself to this indication.

Other routes Intranasal administration Although the nose has a relatively small surface area for absorption (⬇150 to 180 cm2), the nasal epithelium is very permeable and highly perfused with blood. These factors help to facilitate the absorption of drugs. A special feature of the nose is its close connection to the brain in the olfactory area (i.e., an absence of

Opioid analgesics via other routes CHAPTER 7

79

(⬇10 to 15 minutes) depending on site, state of hydration, peripheral perfusion, and use of absorption-enhancing agents (e.g., hyaluronidase). Subcutaneous administration of hydromorphone via a “pain pen”—an adapted insulin injection pen—has been reported to treat breakthrough pain (Enting et al., 2005). Other studies are being planned to conﬁrm the efﬁcacy, tolerability, and safety of this approach. In addition, other authors have reported on the use of SC morphine to treat breakthrough pain episodes in patients receiving continuous infusions of morphine (i.e., SC PCA) (Swanson et al., 1989; Wagner et al., 1989). The SC route requires some basic equipment for bolus injections or administration via PCA pump, as well as some training in performing the technique. It is used successfully in community settings, and the technique can be taught rapidly to cooperative patients and responsible, capable caregivers (Swanson et al., 1989; Wagner et al., 1989). Subcutaneous administration has high acceptability when pain is severe in intensity (87% acceptability) (Walker et al., 2003). The main objection to the use of this route was the dislike of injections. With the availability of rapid-onset oral transmucosal opioid formulations, it is anticipated that this route will have little long-term utility but may be useful in selected cases as a transition to less invasive routes or when other routes are precluded by clinical circumstances.

Opioid analgesics via other routes CHAPTER 7

80

the normal blood–brain barrier); this may enable a fraction of the drug to enter the intrathecal space directly (Dale et al., 2002a). The nose can accommodate only volumes of 150 to 200 µL in each nostril, which restricts the opioid formulations suitable for intranasal administration. In addition, there is a continuous turnover/ﬂow of mucus within the nose, which limits the time available for the drug to be absorbed (⬇15 minutes). The pharmacokinetics of relevant opioids following nasal administration have been studied in groups of healthy volunteers (Dale et al., 2002a). The intranasal route of administration is well established in other areas of medicine (e.g., otolaryngology). In addition, several explorative studies have looked at the use of intranasal opioids for the treatment of breakthrough pain (Zeppetella, 2000; Pavis et al., 2002; Fitzgibbon et al., 2003; Kendall et al., 2003). Morphine (Pavis et al., 2002; Fitzgibbon et al., 2003), diamorphine (Kendall et al., 2003), fentanyl (Zeppetella, 2000; Duncan, 2002), and alfentanil (Duncan, 2002) have all been reported to be useful for intranasal administration. Methadone has been reported to be too irritating for intranasal administration (Dale et al., 2002b). Zeppetella reported on a small, open-label, ﬁxed-dose study of intranasal fentanyl (Zeppetella, 2000). The patient population consisted of 12 hospice inpatients, and the treatment regimen consisted of 20 µg of fentanyl citrate (administered as 0.2 mL solution to each nostril, using two separate nasal spray bottles). Eight (67%) patients reported good or very good pain relief, and pain relief invariably occurred within 5 to 10 minutes. Moreover, nine (75%) patients reported that the pain relief with the intranasal fentanyl was greater than the pain relief with oral morphine. Two patients reported nasal discomfort/nasal itching, which subsided with ongoing use of the spray. No patients reported systemic opioid side effects, and no side effects were noted by the medical staff caring for the patients. The intranasal route is simple, does not require particularly specialized equipment, and can be used by patients alone or with assistance from their nonprofessional caregivers. Opioids can be delivered by traditional nasal spray bottles and by syringes ﬁtted with atomizers (Fig. 7.1). Newer methods of delivery include devices that increase the deposition of the spray in the deeper parts of the nose and incorporate a lock-out function (Djupesland et al., 2004). The intranasal route may be inappropriate for patients with local disease of the nose and could be difﬁcult to use in patients who are uncooperative. A major limitation associated with the intranasal administration of opioids is the small volume of drug that can be administered, making this approach most suitable for potent, concentrated formulations. The addition of absorptionfacilitating agents may overcome this potential problem (Pavis et al., 2002). Other problems relate to local side effects such as irritation (nose, pharynx) and taste disturbance. It should be noted that little is known about the risks of longterm adverse effects from repeated intranasal administration of opioids, such as mucosal/septal erosion, polyp formation, or rhinorrea (Dale et al., 2002a). Based on current literature and experience, it can be concluded that the intranasal route is only moderately attractive for the treatment of breakthrough pain, regardless of setting or clinical circumstances. Even though 68% of pallia-

Bronchopulmonary administration The lungs have an extremely large surface area for absorption. Moreover, the alveolar surface is highly permeable and highly perfused with blood. The lungs are the most highly perfused organs in the body. All of these factors help to facilitate the absorption of drugs. The inhalational route of administration is well established in other areas of medicine (e.g., respiratory medicine, anesthetics, and, most recently, diabetes with the advent of inhaled insulin). Furthermore, it has been used to deliver opioids for the treatment of dyspnea in palliative care settings and to deliver opioids for the treatment of pain in the postoperative setting (Thipphawong et al., 2003). However, there are few data on the use of intrapulmonary opioids for the treatment of breakthrough pain. Zeppetella (2000) reported on a small case series involving intrapulmonary fentanyl. The ﬁrst patient was treated with 25 µg fentanyl, achieved good pain control within 15 minutes, and did not develop any local or systemic adverse effects. The second patient was treated with 125 µg fentanyl (dose titrated), also achieved good pain control within 15 minutes, and also did not develop any local or systemic adverse effects. In both cases, treatment was continued until either discharge (Patient 2) or death (Patient 1). The intrapulmonary route is simple and does not require particularly specialized equipment, but it does require a relatively cooperative and capable patient. Opioids can be delivered by traditional nebulizers; newer methods of delivery

CHAPTER 7

Opioid analgesics via other routes

tive care patients surveyed thought that the route was acceptable for pain that was severe in nature (Walker et al., 2003), this does not account for the host of potential problems that could be associated with long-term use that have yet to be fully appreciated. Even so, a number of different reasons were given for not wanting to use the intranasal route (see Table 4.3).

81

Figure 7.1 Atomization device (MAD™) for intranasal administration of drugs. Reprinted with permission from Davies, 2006.

Opioid analgesics via other routes CHAPTER 7

include breath-activated delivery systems that produce small particle sizes, deliver the particles to the distal parts of the lung, and incorporate a lock-out function (Thipphawong et al., 2003). It should be noted that efﬁcient delivery of the drug requires that the particle sizes are of the order of 1 to 3 µm in diameter. The intrapulmonary route may be inappropriate for patients with respiratory ailments or pulmonary disease. The intrapulmonary route is reasonably attractive for the treatment of breakthrough pain for chronic pain and palliative care patients. Use of inhalers of one sort or another for self-treatment has become a familiar and acceptable practice in our society. In one survey, 75% of patients thought that the route was acceptable for pain that was severe in nature (Walker et al., 2003). As is the case with all routes, there is a fraction of the population who ﬁnds this route to be unacceptable (see Table 4.3). Given the diversity of patients and their individual circumstances—and thus the need to be able to tailor therapies—and the range of routes by which opioids can be effectively administered and absorbed concordant with the time frame necessary to prevent or treat breakthrough pain, the future bodes well for imminent improvements in this area.

82

References Dale O, Hjortkjaer R, Kharasch ED. Nasal administration of opioids for pain management in adults. Acta Anaesthesiologica Scandinavica. 2002a;46:759–770. Dale O, Hoffer C, Sheffels P, Kharasch ED. Disposition of nasal, intravenous, and oral methadone in healthy volunteers. Clinical Pharmacology and Therapeutics. 2002b;72:536–545. Dale O, Sheffels P, Kharasch ED. Bioavailabilities of rectal and oral methadone in healthy subjects. British Journal of Clinical Pharmacology. 2004;58:156–162. Davies A. Cancer-Related Breakthrough Pain. Oxford, UK: Oxford University Press, 2006. Djupesland PG, Skretting A, Windren M, Holand T. Bi-directional nasal delivery of aerosols can prevent lung deposition. Journal of Aerosol Medicine. 2004;17:249–259. Duncan A. The use of fentanyl and alfentanil sprays for episodic pain. Palliative Medicine. 2002;16:550. Enting RH, Mucchiano C, Oldenmenger, et al. The “pain pen” for breakthrough cancer pain: A promising treatment. Journal of Pain and Symptom Management. 2005;29:213–217. Ferrell BR, Grifﬁth H. Cost issues related to pain management: Report from the Cancer Pain Panel of the Agency for Health Care Policy and Research. Journal of Pain and Symptom Management. 1994;9(4):221–234. Fitzgibbon D, Morgan D, Dockter D, Barry C, Kharasch ED. Initial pharmacokinetic, safety and efﬁcacy evaluation of nasal morphine gluconate for breakthrough pain in cancer patients. Pain. 2003;106:309–315. Hanks G, Roberts CJ, Davies AN. Principles of drug use in palliative medicine. In Doyle D, Hanks G, Cherny N, Calman K (Eds.), Oxford Textbook of Palliative Medicine (3rd ed., pp. 213–225). Oxford, UK: Oxford University Press, 2005. Kendall CE, Davies AN, Forbes K. Nasal diamorphine for “breakthrough pain” in palliative care—a promising approach to a difﬁcult problem [abstract 509, p. 92]. In Proceedings

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of 8th Congress of the European Association for Palliative Care, 2003 April 2–5, Hague, the Netherlands. Mercadante S, Radbruch L, Caraceni A, et al. Episodic (breakthrough) pain. Consensus conference of an Expert Working Group of the European Association for Palliative Care. Cancer. 2002;94:832–839. Mercadante S, Villari P, Ferrera P, Bianchi M, Casuccio A. Safety and effectiveness of intravenous morphine for episodic (breakthrough) pain using a ﬁxed ratio with the oral daily morphine dose. Journal of Pain and Symptom Management. 2004;27:352–359. Pavis H, Wilcock A, Edgecombe J, et al. Pilot study of nasal morphine-chitosan for the relief of breakthrough pain in patients with cancer. Journal of Pain and Symptom Management. 2002;24:598–602. Sinatra R. The fentanyl HCl patient-controlled transdermal system (PCTS): An alternative to intravenous patient-controlled analgesia in the postoperative setting. Clinical Pharmacokinetics. 2005;44(Suppl 1):1–6. Stevens RA, Ghazi SM. Routes of opioid analgesic therapy in the management of cancer pain. Cancer Control. 2000;7:132–141. Stuart-Harris R, Joel SP, McDonald P, Currow D, Slevin ML. The pharmacokinetics of morphine and morphine glucuronide metabolites after subcutaneous bolus injection and subcutaneous infusion of morphine. British Journal of Clinical Pharmacology. 2000;49:207–214. Swanson G, Smith J, Bulich R, New P, Shiffman R. Patient-controlled analgesia for chronic cancer pain in the ambulatory setting: A report of 117 patients. Journal of Clinical Oncology. 1989;7:1903–1908. Thipphawong JB, Babul N, Morishige RJ, et al. Analgesic efﬁcacy of inhaled morphine in patients after bunionectomy surgery. Anesthesiology. 2003;99:693–700. van Hoogdalem E, de Boer AG, Breimer DD. Pharmacokinetics of rectal drug administration, Part I. General considerations and clinical applications of centrally acting drugs. Clinical Pharmacokinetics. 1991;21:11–26. Viscusi ER, Reynolds L, Chung F, Atkinson LE, Khanna S. Patient-controlled transdermal fentanyl hydrochloride vs intravenous morphine pump for postoperative pain: A randomized controlled trial. Journal of American Medical Association. 2004;291:1333–1341. Viscusi ER, Reynolds L, Tait S, Melson T, Atkinson LE. An iontophoretic fentanyl patientactivated analgesic delivery system for postoperative pain: A double-blind, placebocontrolled trial. Anesthesia Analgesia. 2006;102:188–194. Wagner JC, Souders GD, Coffman LK, Horvath JL. Management of chronic cancer pain using a computerized ambulatory patient-controlled analgesia pump. Hospital Pharmacy. 1989;24:639–644. Walker G, Wilcock A, Manderson C, Weller R, Crosby V. The acceptability of different routes of administration of analgesia for breakthrough pain. Palliative Medicine. 2003;17:219–221. Warren DE. Practical use of rectal medications in palliative care. Journal of Pain and Symptom Management. 1996;11:378–387. Zeppetella G. Nebulized and intranasal fentanyl in the management of cancer-related breakthrough pain. Palliative Medicine. 2000;14:57–58. Zeppetella G. An assessment of the safety, efﬁcacy, and acceptability of intranasal fentanyl citrate in the management of cancer-related breakthrough pain: A pilot study. Journal of Pain and Symptom Management. 2000;20:253–258.

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Chapter 8

Breakthrough pains have diverse characteristics, as they span all pain-related etiologies. This inherent diversity means that the management of breakthrough pain can potentially involve every class of pain-modifying drug. In most cases, the relevant drugs are analgesics in their own right, although their analgesic activity may not be their primary indication (so-called adjuvant analgesics) (Lussier and Portenoy, 2004). In other cases, the relevant drugs may not be analgesics at all, in which case their analgesic activity is an indirect result of their primary function (e.g., antibiotics may reduce pain by treating the underlying cause of inﬂammation) (Bruera and MacDonald, 1986). This chapter focuses on prescribed nonopioid drugs that are commonly used in the management of cancer and noncancer chronic pain. The ﬁrst part of the chapter examines the evidence for nonopioid drugs in the management of relevant pain syndromes (i.e., neuropathic pain, bone pain), and the second part of the chapter examines evidence for the use of speciﬁc nonopioid drugs in the treatment of breakthrough pain episodes (e.g., benzodiazapines, nitrous oxide).

Role of nonopioids Nonopioids may improve pain via a variety of different mechanisms: • Acting as independent analgesics. Nonopioid analgesics are crucial for treating pain that is poorly responsive to opioids. • Supplementing opioid analgesic use. Nonopioid drugs can be used as an opioid-sparing measure, thereby avoiding the need to increase the opioid dose, and possibly even allowing a decrease in the opioid dose. • Facilitating opioid analgesic use. Nonopioid drugs can be used to combat opioid side effects, thereby avoiding the need to decrease the opioid dose, and possibly even allowing an increase in the opioid dose (e.g., psychostimulants for sedation). In addition, nonopioid drugs may be used in a variety of different ways: • Around-the-clock—the drugs are taken regularly, and their role is to treat the underlying pathological process and so reduce the frequency/severity of breakthrough pain episodes.

85

Nonopioid pharmacotherapy

Nonopioid pharmacotherapy CHAPTER 8

86

• As needed—the drugs are taken intermittently for breakthrough pain, and

two distinct scenarios are applicable: 1. “Rescue” analgesia—the drugs are given once the breakthrough pain has started, and their role is to minimize the breakthrough pain episode (i.e., spontaneous pain episodes, nonvolitional incident pain episodes). 2. “Anticipatory” analgesia—the drugs are given in advance of the precipitating event for the breakthrough pain, and their role is to prevent/ameliorate the breakthrough pain episode (i.e., volitional incident pain episodes, procedural pain).

Nonopioid drugs for neuropathic pain The standard treatment of neuropathic pain involves using evidence- and consensus-based clinical guidelines (Dworkin et al., 2003). Studies suggest that while many patients with neuropathic pain respond to conventional analgesics (e.g., opioids), a signiﬁcant number of patients also require the use of other analgesics (often referred to as adjuvant analgesics) and/or the use of other interventions (e.g., anesthetic techniques) (Grond et al., 1999; Fine, 2001). A range of nonopioid analgesics have been used in the treatment of neuropathic pain, including corticosteroids, certain antidepressants, anticonvulsants, local anesthetics, antiarrhythmic drugs, baclofen, clonidine, capsaicin, ketamine, and magnesium sulfate (Lussier and Portenoy, 2004; Argoff et al., 2006). However, the most commonly used drugs are antidepressants and anticonvulsants (Table 8.1). Making a selection from the bewildering range of options available is difﬁcult, because of the limited data available on the effectiveness of individual drugs and the even more limited data available on the relative effectiveness of different drugs. Notwithstanding the need for head-to-head trials and more guiding data, it is believed that most neuropathic analgesics share essentially the same efﬁcacy potential. In practice, the choice of a neuropathic analgesic is therefore not largely made on the basis of efﬁcacy but more on the basis of safety, tolerability, and ease Table 8.1 Treatment guidelines for peripheral neuropathic pain Agent type First tier

Reason for recommendation ≥2 RCTs in DPN

Second tier

1 RCT in DPN and ≥1 in other painful neuropathies Mechanism of action ≥1 RCTs in other painful neuropathies or other evidence

Topical Other

Agent names Duloxetine, oxycodone CR, pregabalin, TCAs Carbamazepine, gabapentin, lamotrigine, tramadol, venlafaxine ER (Effexor) Capsaicin, lidocaine Bupropion (Wellbutrin), citalopram (Celexa), methadone (Dolophine), paroxetine (Paxil), phenytoin (Dilantin), topiramate (Topamax)

CR = controlled release; DPN = diabetic peripheral neuropathy; ER = extended release; RCT = randomized controlled trial; TCAs = tricyclic antidepressants.

Nonopioid pharmacotherapy

The tricyclic antidepressants (TCAs) are commonly used in the management of neuropathic pain. Their analgesic effect has been considered to be a result of the prevention of presynaptic reuptake of serotonin and norepinephrine, although other mechanisms (e.g., sodium channel–blocking effects) may be more relevant (Twycross et al., 2002). There is a reasonable amount of data on the use of TCAs, and particularly on the use of amitriptyline, in the management of neuropathic pain. Most of the data derive from studies of postherpetic neuralgia and diabetic neuropathy, but extensive clinical experience supports its use in the management of other neuropathic pain conditions, including those associated with malignancy. This same experience also suggests that TCAs have a narrow window of safety relating to their complex pharmacology that involves activity at multiple ion channel and receptor systems. Caution must therefore be used in prescribing TCAs in susceptible populations (e.g., older patients and those with cardiac conduction abnormalities). These provisos also apply to many of the other adjuvant drugs used in the management of neuropathic pain, especially the anticonvulsants. A systematic review of the literature calculated an overall number needed to treat (NNT) of two for amitriptyline (Saarto and Wiffen, 2005). The NNT refers to the number of patients who need to receive a drug for one patient to achieve at least 50% relief of pain compared with placebo (Moore et al., 2003). The NNT was lower for diabetic neuropathy (1.3) than for postherpetic neuralgia (2.2), and amitriptyline did not appear to be effective in HIV-related neuropathy (Saarto and Wiffen, 2005). The number needed to harm (NNH) for minor adverse effects was 4.6, while the NNH for major adverse effects (requiring withdrawal from the study) was 16 (Saarto and Wiffen, 2005). The side effects of amitriptyline mostly derive from its multiplicity of receptor effects including anticholinergic, anti-α-adrenergic, and antiserotonergic effects as well as sodium channel blockade. These effects often lead to adverse effects such as drowsiness, dry mouth, blurred vision, constipation, urinary retention, heart block, and arrhythmias (Saarto and Wiffen, 2005). Indeed, side effects are often the major barrier to the use of amitriptyline, if not all TCAs, in the management of neuropathic pain. Other tricyclic drugs have also been used in the management of neuropathic pain (e.g., imipramine, desipramine, nortriptyline). The data on other tricyclic drugs are much more limited, but the data that are available suggest that they may have a similar efﬁcacy to amitriptyline, although the secondary

CHAPTER 8

Antidepressants Tricyclic antidepressants

87

of use. For example, amitriptyline may be a good choice for a patient with insomnia, but it would not be a good choice for an older patient with balance problems, risk of urinary retention, or cardiac arrhythmias. There is great interindividual variation in patient response to these medications in terms of both efﬁcacy and adverse effects, and a trial-and-error approach is often necessary.

Nonopioid pharmacotherapy CHAPTER 8

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amines (desipramine, nortriptyline) have fewer anticholinergic effects and therefore may be better tolerated (Saarto and Wiffen, 2005) (Fig. 8.1).

Selective norepinephrine serotonin reuptake inhibitors The selective norepinephrine-serotonin reuptake inhibitors (NSRIs) have also been used in the management of neuropathic pain. Their analgesic effect is also thought to be related to the combined prevention of presynaptic reuptake of serotonin and norepinephrine (Terneus, 2007). Comparatively, the selective serotonin reuptake inhibitors (SSRIs) have not been found to be particularly beneﬁcial in the treatment of neuropathic pain (Saarto and Wiffen, 2005) other than as an adjuvant in treating related depressive illness. The data on NSRIs in the management of neuropathic pain are currently relatively limited. Two drugs of this class, venlafaxine and duloxetine, are currently available in the United States, and duloxetine is approved by the U.S. Food and Drug Administration (FDA) for the treatment of peripheral diabetic neuropathy. Duloxetine is formulated for once-daily dosing and is available in 20, 30, and 60 mg strengths. It is contraindicated in patients with uncontrolled narrow-angle glaucoma and patients taking monoamine oxidase inhibitors (MAOIs). Caution should be exercised in the setting of alcoholism or preexisting liver disease. Common adverse effects include nausea, diarrhea, constipation, dizziness, drowsiness, anxiety, nervousness, and insomnia, but with slow titration, most patients are able to ﬁnd an acceptable dose (Fishbain et al., 2006). The mechanism of action for the neuropathic analgesic properties of NSRIs is not known for certain. However, recent ﬁndings that suggest that analgesia is usually not achieved until reaching higher dosages associated with predominance of norepinephrine reuptake effects suggest that the mechanism is more related to presynaptic reuptake of norepinephrine than serotonin. This would be consistent with the lack of independent analgesia seen with SSRIs as a drug class.

• Commonly reported AEs (generally anticholinergic): – – –

blurred vision cognitive changes constipation

– – –

dry mouth orthostatic hypotension sedation

– –

sexual dysfunction tachycardia

–

urinary retention

Fewest AEs

• Desipramine • Nortriptyline • Imipramine • Doxepin • Amitriptyline

Most AEs

Figure 8.1 Tricyclic antidepressants and their adverse effects (AEs).

Results of systematic reviews 1. Carbamazepine

89

A systematic review of the use of carbamazepine in the management of neuropathic pain calculated an NNT of 1.8 for trigeminal neuralgia but was unable to calculate an NNT for other conditions because of lack of suitable data (Wiffen et al., 2005c). The NNH for minor harm was 3.7, while the NNH for major harm was not statistically different from that of a placebo (Wiffen et al., 2005c). The side effects of carbamazepine include nausea, vomiting, dizziness, drowsiness, headache, ataxia, confusion, agitation, and visual disturbances (e.g., double vision), and serious, although rare, adverse effects include the syndrome of inappropriate antidiuretic hormone (SIADH), aplastic anemia, and liver failure.

Nonopioid pharmacotherapy

A variety of different drugs have been used to treat seizure disorders, and a few of them have also been found to have some efﬁcacy in the treatment of neuropathic pain (Wiffen et al., 2005). The putative mechanism of action is via selective inhibition of sodium and voltage-gated calcium channels (Tremont-Lukats, 2000). There have been clinical trials, case reports, and conventional usage of several agents (Backonja, 2002), but currently, only carbamazapine, gabapentin, and pregabalin are FDA approved for neuropathic pain indications (Table 8.2).

CHAPTER 8

Anticonvulsants

2. Gabapentin

A further (related) systematic review of the use of gabapentin in the management of neuropathic pain calculated a combined NNT of 4.3 (Wiffen et al., 2005b). (The NNT was 2.9 for diabetic neuropathy and 3.9 for postherpetic neuralgia.) The NNH for minor harm was 3.7, while the NNH for major harm was not statistically different from that of a placebo (Wiffen et al., 2005b). The undesirable effects of gabapentin include sedation and mental clouding, diarrhea, dry mouth, dyspepsia, nausea, and vomiting.

Table 8.2 Anticonvulsant drugs for neuropathic pain disorders • Postherpetic neuralgia – gabapentin* – pregabalin* • Diabetic neuropathy – carbamazepine – gabapentin – lamotrigine – phenytoin – pregabalin* *Approved by FDA for this use. HIV = human immunodeﬁciency virus.

• HIV-associated neuropathy – lamotrigine • Trigeminal neuralgia – carbamazepine* – lamotrigine – oxycarbazepine • Central poststroke pain – lamotrigine • Cancer-related neuropathic pain disorders – All of the above agents

Nonopioid pharmacotherapy CHAPTER 8

3. Other drugs

Other anticonvulsant drugs that are commonly used to treat neuropathic pain include sodium valproate (limited evidence of efﬁcacy), phenytoin (limited evidence of efﬁcacy), and pregabalin (increasing evidence of efﬁcacy; Rosenstock et al., 2004; Terneus, 2007).

Nonopioid drugs for bone pain The standard treatment of bone pain associated with malignant diseases involves using the World Health Organization analgesic guidelines (WHO, 1996). A range of adjuvant analgesics have been used in the treatment of cancer-related bone pain, including corticosteroids, bisphosphonates, calcitonin, and drugs for neuropathic pain (see earlier sections) (Lussier and Portenoy, 2004).

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Bisphosphonates Bisphosphonates are indicated for the management of osteoporosis, Paget’s disease, bone metastases, and hypercalcemia (Anonymous, 2005). Bisphosphonates have a number of mechanisms of action, but their main mechanism of action relates to inhibition of osteoclast activity (leading to inhibition of bone resorption) (Fine and Bellamy, 2005). A systematic review of the literature concluded that long-term (≥6 months) bisphosphonate therapy reduces skeletal morbidity associated with cancer (i.e., reduces the need for radiotherapy, reduces the incidence of fractures, and reduces the incidence of hypercalcemia) (Ross et al., 2003). The evidence of effectiveness is so compelling that the authors concluded that bisphosphonate therapy should commence as soon as bone metastases are diagnosed and continue until “it is no longer clinically relevant” (Ross et al., 2003). A systematic review that focused on the pain literature concluded that bisphosphonate therapy provides analgesia in cancer-related bone pain (Wong and Wiffen, 2002). The NNT was 11 at 4 weeks, improving to an NNT of 7 at 12 weeks. The NNH for major side effects (leading to discontinuation of treatment) was 16. The authors stated that “there was insufﬁcient evidence to recommend bisphosphonates for immediate effect,” and “bisphosphonates should be considered where analgesics and/or radiotherapy are inadequate for the management of painful bone metastases” (Wong and Wiffen, 2002). On the basis of the data, it would seem reasonable to prescribe bisphosphonates to patients who have already experienced morbidity as a result of bone metastases, with the primary aim of preventing further morbidity and the secondary aim (if relevant) of treating pain. As such, this class of drugs may have a prophylactic effect against bone-related breakthrough pain, but there is no role for bisphosphonates in the active treatment of breakthrough pain.

Nonopioid pharmacotherapy

Nonsteroidal anti-inﬂammatory drugs (NSAIDs) are approved for the treatment of variety of painful conditions, including inﬂammatory diseases (e.g., rheumatoid arthritis), degenerative conditions (e.g., osteoarthritis), other painful conditions (e.g., dysmenorrhoea), and postoperative pain (Anonymous, 2005). Their analgesic action appears to be related to inhibition of prostaglandin production both at the site of injury/disease (reducing inﬂammation) and in the central nervous system (reducing central sensitization) (Twycross et al., 2002). NSAIDs inhibit prostaglandin production by inhibiting the enzyme cyclooxygenase (COX). COX is present in a number of different forms (Dickman and Ellershaw, 2004). Conventional NSAIDs are nonselective, inhibiting both COX1 and COX-2, while the newer class of NSAIDs, the coxibs, speciﬁcally inhibit COX-2. It was thought that COX-2 was an inducible (by inﬂammation) enzyme and that inhibition of COX-2 would be associated with minimal systemic adverse events. However, it is now known that COX-2 is also a constitutive enzyme and that inhibition of COX-2 is associated with signiﬁcant systemic adverse events (discussed in a later section). In chronic conditions, NSAIDs are generally used as around-the-clock medications, although they may be used as supplemental medications when continual use is either not tolerated or excessively risky. In the management of acute pain and in advanced medical illness, NSAIDs have an established role as an opioid-sparing maneuver (Mercadante and Portenoy, 2001). Systematic reviews of oral NSAIDs have conﬁrmed beneﬁts in cancer pain (Eisenberg et al., 1994; McNichol et al., 2005). In the original systematic review, NSAIDs were found to be more effective than placebo, and there appeared to be no beneﬁt to the combination of a NSAID and an opioid for mild to moderate pain (Eisenberg et al., 1994). In the subsequent systematic review, NSAIDs were again found to be more effective than placebo, and there appeared to be a slight beneﬁt to the combination of an NSAID and an opioid (McNichol et al., 2005). However, the authors of this review were unable to comment on the relative efﬁcacy (i.e., calculate NNTs) or tolerability (i.e., calculate NNHs) of individual NSAIDs (McNicol et al., 2005). Data from acute pain studies suggest NNTs of 2 to 3 for a single dose of the common oral NSAIDs (e.g., diclofenac, ibuprofen) (Moore et al., 2003). It should be noted that the NNTs for NSAIDs are lower than the NNTs for other analgesic drugs (e.g., opioids for mild to moderate pain). Data from other studies suggest a combined NNT of 3.1 for topical NSAIDs (Moore et al., 1998). The onset and duration of action of certain oral NSAIDs is shown in Table 8.3. There are a number of contraindications to the use of NSAIDs, including hypersensitivity to aspirin/NSAIDs, coagulation defects, active peptic ulcer disease (all NSAIDs), previous peptic ulcer disease (conventional NSAIDs), ischemic heart disease (coxibs), cerebrovascular disease (coxibs), peripheral

CHAPTER 8

Nonsteroidal anti-inﬂammatory drugs

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Other nonopioid drugs for breakthrough pain

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arterial disease (coxibs), and moderate to severe heart failure (all NSAIDs). In addition, there are a number of relative contraindications relating to the known adverse effects of NSAIDs (see later sections). Side effects are relatively common. The major side effects of conventional NSAIDs are hypersensitivity reactions (e.g., bronchospasm), gastrointestinal problems (e.g., peptic ulceration), renal problems (e.g., renal failure), and cardiovascular problems (e.g., congestive cardiac failure). Gastrointestinal problems are a major cause of morbidity and/or mortality. However, gastrointestinal problems may be reduced by prescribing proton pump inhibitors and addressing other risk factors (Dickman and Ellershaw, 2004). The major side effects of coxibs are cardiovascular problems (e.g., ischemic heart disease), but if used chronically (e.g., more than several months), the adverse gastrointestinal effects may also become problematic (Lebwohl and Neugut, 2007). In summary, the NSAID class of analgesics is useful in the management of acute pain and chronic painful conditions involving inﬂammation, although risks—especially in older patients—become appreciable. The use of NSAIDs for breakthrough pain has never been addressed in speciﬁc clinical trials, but episodic use, especially for the control of incident nociceptive pain, may be beneﬁcial alone or in combination with immediate-release or rapid-onset opioid analgesics.

Midazolam and other benzodiazapines Midazolam is a benzodiazepine indicated for anxiolysis, sedation, premedication for anesthesia, and induction of anesthesia (Reeves et al., 2000). Its mechanism of action involves binding to the GABAA receptor, thereby enhancing the inhibitory effect of GABA (Twycross et al., 2002). Table 8.3 Clinical features of speciﬁc nonsteroidal anti-inﬂammatory drugs Nonsteroidal antiinﬂammatory drug Ibuprofen

Onset of action (oral route) 15 to 25 min

Duration of action (oral route) 4 to 6 h

Diclofenac

30 min

8h

Ketorolac

30 min

5 to 6 h

Naproxen Meloxicam

30 to 60 min 90 min

Up to 12 h —

Celcoxib

45 to 60 min

4 to 8 h (single dose)

Comments Peak effect: 30 to 90 min Long-acting preparations available Long-acting preparations available Peak effect: 3 h Onset of action intravenous/ intramuscular route: 30 min — Given once a day Onset of action intramuscular route: 80 min Given once or twice a day

From Micromedex database; Twycross et al., 2002; reprinted with permission from Davies, 2006.

Ketamine Ketamine is a parenteral anesthetic agent and is approved for induction and maintenance of anesthesia (Reeves et al., 2000), but it is also used for treatment of difﬁcult-to-control pain (Fine, 1999). The analgesic effect of ketamine is thought to be related to blockade of the N-methyl-D-aspartate receptor (and reduction of central sensitization/“wind-up”), although it may be related to a number of other actions, including an effect on descending inhibitory pathways (Meller, 1996). Ketamine has been used effectively in subanesthetic doses in the management of breakthrough pain (Carr et al., 2004) and in the management of certain types of background pain (e.g., neuropathic pain) (Twycross et al., 2002). In general, ketamine is used in combination with opioids in the management of background pain. Carr et al. (2004) reported a small, double-blind, randomized, controlled, crossover trial of intranasal ketamine in the management of breakthrough pain. The intranasal ketamine was found to be effective with an onset of pain relief within 10 minutes, peak effect at 40 minutes, and duration of pain relief of at least 60 minutes. The intranasal application of ketamine was also found to be generally well tolerated; side effects included fatigue, dizziness, feeling of unreality, and change in taste. The literature contains a number of case reports, case series, and clinical trials of the use of ketamine in the management of cancer pain. As discussed earlier, ketamine is generally used in combination with opioids in the management of background pain. It has been reported that ketamine can restore opioid responsiveness and prevent the development of opioid tolerance. However, a re-

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Midazolam is highly effective for sedation and amnesia. It is used to sedate patients prior to diagnostic and therapeutic procedures (e.g., endoscopy, dressing changes). Its role in managing procedural pain has been endorsed in the European Association for Palliative Care expert consensus document on breakthrough pain (Mercadante et al., 2002). Apart from the use of benzodiazepines in combination with opioids in procedural pain, there is little evidence to support a wider role in the management of breakthrough pain. However, there has been a report of its use in the treatment of refractory incident pain secondary to bone metastases (del Rosario et al., 2001), and there is the potential for its use in the management of breakthrough pain secondary to muscle spasm (Twycross et al., 2002). Midazolam is available in parenteral and oral preparations in the United States. The parenteral preparation may be administered via enteral routes (buccal, rectal) as well as via parenteral routes (intravenous, subcutaneous), similar to lorazapam. Midazolam has the advantage of a short onset of action (intravenous—2 to 3 minutes; subcutaneous—5 to 10 minutes), but it has an intermediate duration of action (⬇4 hours) (Twycross et al., 2002), which can be problematic for very brief episodes or events where sedation and analgesia are required on a recurrent basis. Outside of highly circumscribed clinical situations involving invasive procedures or in palliative care settings, use of the benzodiazepines either alone or as an adjunctive agent cannot be recommended for the prevention or treatment of breakthrough pain.

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cent systematic review of the literature concluded that the evidence was “insufﬁcient to assess the beneﬁts and harms of ketamine” (Bell et al., 2003).

Nitrous oxide Nitrous oxide is an inhalational anesthetic used for maintenance of anesthesia and management of pain (most commonly in dental care). Its mechanism of action has not been completely elucidated; one hypothesis is that nitrous oxide causes the release of opioid peptides in the periaqueductal gray area of the midbrain, which leads to activation of descending noradrenergic pathways, which leads to modulation of pain impulses in the dorsal horn of the spinal cord (Entonox Reference Guide). Apart from its use in procedural pain, there is mixed evidence justifying the use of nitrous oxide in the management of breakthrough pain in palliative care and/or cancer pain settings. Findings from a small case series (Keating and Kundrat, 1996) and a small, double-blind, randomized, controlled, crossover trial (Parlow et al., 2005) support the use of nitrous oxide in the management of breakthrough pain. However, there is another small case series that does not support the use of nitrous oxide in the management of breakthrough pain (Enting et al., 2002). Nitrous oxide is co-administered with oxygen (50:50 mixture for analgesia): it comes in a portable gas cylinder with a breath-activated valve and may be used with either a facemask or a mouthpiece. It has a short onset of action (<1 minute), a quick time to peak effect (2 minutes), and a short duration of action (5 to 40 minutes: subjective measures–objective measures) (Entonox Reference Guide). Contraindications to the use of nitrous oxide include the presence of a pneumothorax—the nitrous oxide can diffuse into the pneumothorax, causing an increase in the volume/pressure of the pneumothorax. The side effects of nitrous oxide include sedation (7.6%), dizziness (10.3%), nausea (5.7%), excitation (3.7%), and “numbness” (0.3%) (Entonox Reference Guide). Nitrous oxide can interfere with vitamin B12, and chronic use may result in megaloblastic anemia and neurological problems (polyneuropathy, spinal cord degeneration) (Doran et al., 2004). In addition, there is the potential to develop tolerance to the drug; this problem may occur during acute administration of the drug (Ramsay et al., 2005). In summary, nitrous oxide is a well-proven anesthetic and analgesic, but a trial of nitrous oxide for the treatment of breakthrough pain should be limited to palliative care settings only where other agents have proved ineffective or are contraindicated. Dysphoric reactions may occur, so use under supervision of someone who can quickly turn off the ﬂow of the agent and calm the patient is important.

References Argoff CE, Backonja MM, Belgrade MJ, et al. Consensus guidelines: Treatment planning and options. Diabetic peripheral neuropathic pain. Mayo Clinic Proceedings. 2006;81(4 Suppl):S12–S25. Backonja M. Use of anticonvulsants for treatment of neuropathic pain. Neurology. 2002; 59:S14–S17.

Carr DB, Goudas LC, Denman WT, et al. Safety and efﬁcacy of intranasal ketamine for the treatment of breakthrough pain in patients with chronic pain: A randomized, double-blind, placebo-controlled, crossover study. Pain. 2004;108:17–27. Davies A. Cancer-Related Breakthrough Pain. Oxford, UK: Oxford University Press, 2006. del Rosario MA, Martin AS, Ortega JJ, Feria M. Temporary sedation with midazolam for control of severe incident pain. Journal of Pain and Symptom Management. 2001;21:439–442. Dickman A, Ellershaw J. NSAIDs: Gastroprotection or selective COX-2 inhibitor? Palliative Medicine. 2004;18:275–286. Donen N, Tweed WA, White D, Guttormson B, Enns J. Pre-hospital analgesia with Entonox. Canadian Anaesthetists’ Society Journal. 1982;29:275–279.

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Bruera E, MacDonald N. Intractable pain in patients with advanced head and neck tumors: A possible role of local infection. Cancer Treatment Reports. 1986;70:691–692.

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Bell R, Eccleston C, Kalso E. Ketamine as an adjuvant to opioids for cancer pain. Cochrane Database of Systematic Reviews. 2003;(1):CD003351.

Doran M, Rassam SS, Jones LM, Underhill S. Toxicity after inhalation of nitrous oxide for analgesia. British Medical Journal. 2004;328:1364–1365.

Eisenberg E, Berkey CS, Carr DB, Mosteller F, Chalmers TC. Efﬁcacy and safety of nonsteroidal antiinﬂammatory drugs for cancer pain: A meta-analysis. Journal of Clinical Oncology. 1994;12:2756–2765. Enting RH, Oldenmenger WH, van der Rijt CC, Koper P, Lieverse J, Sillevis SP. Nitrous oxide is not beneﬁcial for breakthrough cancer pain. Palliative Medicine. 2002;16:257–259. Fine PG. Low-dose ketamine in the management of opioid resistant terminal cancer pain. Journal of Pain and Symptom Management. 1999;17:296–300. Fine PG. Nerve blocks, herpes zoster, and postherpetic neuralgia. In Watson CPN, Gershon A (Eds.), Herpes Zoster and Postherpetic Neuralgia. Amsterdam: Elsevier Science BV, 2001. Fine PG, Bellamy C. Bisphosphonates for metastatic bone pain. Journal of Pain and Palliative Care Pharmacotherapy. 2005;19(2):61–63. Fishbain D, Berman K, Kajdasz DK. Duloxetine for neuropathic pain based on recent clinical trials. Current Pain and Headache Reports. 2006;10(3):199–204. Grond S, Radbruch L, Meuser T, Sabatowski R, Loick G, Lehmann KA. Assessment and treatment of neuropathic cancer pain. Pain. 1999;79:15–20. Keating HJ, Kundrat M. Patient-controlled analgesia with nitrous oxide in cancer pain. Journal of Pain and Symptom Management. 1996;11:126–130. Lebwohl B, Neugut AI. NSAIDs and COX-2 inhibitors may prevent colorectal cancer but increase gastrointestinal and cardiovascular harm. American College of Physicians Journal Club. 2007;147(1):16. Lussier D, Portenoy RK. Adjuvant analgesics in pain management. In Doyle D, Hanks G, Cherny N, Calman K (Eds.), Oxford Textbook of Palliative Medicine (3rd ed., pp. 349–378). Oxford: Oxford University Press, 2004. McNicol E, Strassels SA, Goudas L, Lau J, Carr DB. NSAIDS or paracetamol, alone or combined with opioids, for cancer pain. Cochrane Database of Systematic Reviews. 2005;(2):CD005180.

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Dworkin RH, Backonja M, Rowbotham MC, et al. Advances in neuropathic pain: Diagnosis, mechanisms, and treatment recommendations. Archives of Neurology. 2003;60:1524–1534.

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Meller ST. Ketamine: Relief from chronic pain through actions at the NMDA receptor? Pain. 1996;68:435–436. Mercadante S, Portenoy RK. Opioid poorly-responsive cancer pain. Part 3. Clinical strategies to improve opioid responsiveness. Journal of Pain and Symptom Management. 2001;21:338–354. Mercadante S, Radbruch L, Caraceni A, et al. Episodic (breakthrough) pain. Consensus conference of an Expert Working Group of the European Association for Palliative Care. Cancer. 2002;94:832–839. Moore RA, Tranmer MR, Carroll D, Wiffen PJ, McQuay HJ. Quantitative systematic review of topically applied non-steroidal anti-inﬂammatory drugs. British Medical Journal. 1998;316:333–338. Parlow JL, Milne B, Tod DA, Stewart GI, Grifﬁths JM, Dudgeon DJ. Self-administered nitrous oxide for the management of incident pain in terminally ill patients: A blinded case series. Palliative Medicine. 2005;19:3–8. Ramsay DS, Leroux BG, Rothen M, Prall CW, Fiset LO, Woods SC. Nitrous oxide analgesia in humans: Acute and chronic tolerance. Pain. 2005;114:19–28. Reeves JG, Glass PSA, Lubarsky DA. Nonbarbiturate intravenous anesthetics. In Miller RD (Ed.), Anesthesia (5th ed., pp. 228–271). New York: Churchill Livingstone, 2000. Rosenstock J, Tuchman M, LaMoreaux L. Pregabalin for the treatment of painful diabetic neuropathy. A double-blind placebo-controlled trial. Pain. 2004;110:628–638. Ross JR, Saunders Y, Edmonds PM, Patel S, Broadley K, Johnston SR. Systematic review of role of bisphosphonates on skeletal morbidity in metastatic cancer. British Medical Journal. 2003;327:469–472. Saarto T, Wiffen P. Antidepressants for neuropathic pain. Cochrane Database of Systematic Reviews. 2005;(3):CD005454. Terneus W. Pregabalin and duloxetine for the treatment of neuropathic pain disorders. Journal of Pain and Palliative Care Pharmacotherapy. 2007;21(1):79–84. Tremont-Lukats IW, Megeff C, Backonja MM. Anticonvulsants for neuropathic pain syndromes. Mechanism of action and place in therapy. Drugs. 2000;60(5):1029–1052. Twycross R, Wilcock A, Charlesworth S, Dickman A. Palliative Care Formulary (2nd ed.). Abingdon: Radcliffe Medical Press, 2002. Wiffen P, Collins S, McQuay H, Carroll D, Jadad A, Moore A. Anticonvulsant drugs for acute and chronic pain. Cochrane Database of Systematic Reviews. 2005a;(3): CD001133. Wiffen PJ, McQuay HJ, Edwards JE, Moore RA. Gabapentin for acute and chronic pain. Cochrane Database of Systematic Reviews. 2005b;(3):CD005452. Wiffen PJ, McQuay HJ, Moore RA. Carbamazepine for acute and chronic pain. Cochrane Database of Systematic Reviews. 2005c;(3):CD005451. Wong R, Wiffen PJ. Bisphosphonates for the relief of pain secondary to bone metastases. Cochrane Database of Systematic Reviews. 2002;(2):CD002068.

Chapter 9

A wide variety of nonpharmacologic interventions have been used to treat chronic pain syndromes (Doyle et al., 2004; Hadjistavropoulos and Fine, 2007). This chapter focuses on anesthetic interventions used to treat difﬁcult pain problems associated with breakthrough pain episodes. Anesthetic interventions are usually intended to be an adjuvant to systemic analgesic treatment. Indeed, these interventions have been proposed in a modiﬁcation of the World Health Organization analgesic ladder (Miguel, 2000; Fine, 2005). In the management of cancer pain, it has been estimated that between 5% and 15% of patients may beneﬁt from interventional therapies (Zech et al., 1995). There are no well-validated studies that specify the percentage of patients with chronic noncancer pain syndromes who might beneﬁt from interventional therapies, but they are commonly performed, again, with variable reported success (Bernstein et al., 2005).

General principles The usual indications for anesthetic and related techniques (i.e., injections, neuraxial drug delivery, or neurostimulation) include pain that is poorly responsive to systemic analgesics or the development of intolerable side effects to systemic analgesics. Thus these techniques may allow patients to experience better pain relief from current drug doses or may allow patients to reduce drug doses, thereby reducing drug side effects. A patient with a short life expectancy, and with limited time available for the safe titration of systemic analgesics, may also be considered for anesthetic techniques (Hicks and Simpson, 2004). Nerve blockade may be useful in patients with well-localized pain, and also in patients with pain with a neuropathic element. Similarly, neuraxial analgesic delivery may be useful in patients with pain from spinal, thoracoabdominal, pelvic, or lower extremity pain-producing disorders. Under most circumstances, alternative options should have been considered before an anesthetic intervention is undertaken (e.g., disease-modifying treatments, alternative systemic analgesics). Furthermore, when an anesthetic intervention is undertaken, initially the simplest and least invasive method should be undertaken. For example, a temporary local anesthetic blockade should be

97

Nonpharmacologic interventions

Nonpharmacologic interventions CHAPTER 9

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performed before a permanent neurolytic blockade or ablative procedure is performed in those situations where neurolysis is acceptable (e.g., pancreatic malignancy; medial branch rhizotomy for facet disease). As with any form of treatment, appropriate patient selection is necessary. The assessment process involves taking a history, performing an examination, and the utilization of relevant investigations. The history should include a detailed assessment of the pain, and the examination should include a full neurological assessment (Bruera and Neumann, 2003). Laboratory investigations will include a platelet count and a coagulation screen to identify potential bleeding problems. Radiological investigations may include a computed tomography (CT) scan or a magnetic resonance imaging (MRI) scan: these tests are necessary to identify the potential cause of the pain and potential problems relating to planned procedure (e.g., anatomical distortion or variance) (Erdine, 2005). Absolute contraindications to anesthetic interventions include patient refusal, noncorrectable coagulopathy, and localized infection at the proposed site of the anesthetic intervention. The assessment for and use of complex interventions such as neuraxial analgesia or dorsal column stimulation require a coordinated approach from a multidisciplinary pain management team, which will usually comprise pain medicine specialists, nurses, physical and/or occupational therapists, and psychologists. It requires appropriate resources to apply these techniques, including relevant support services (e.g., laboratory service, radiology services, operating suite with ﬂuoroscopic imaging). It also requires appropriate resources to monitor and provide follow-up on patients who have received these techniques. Furthermore, it is important that there be effective communication with, and support for, others involved in the patient’s care (e.g., primary care/specialist physicians, other health-care providers, case workers, third-party payers, etc.).

Peripheral procedures Local anesthetic injections are probably the most common interventions practiced in pain management. Examples of useful techniques include myofascial trigger point injections, sympathetic blocks (e.g., stellate ganglion block; lumbar sympathetic block), intercostal nerve blockade for rib pain, suprascapular nerve blockade for shoulder pain, plexus blockade (e.g., brachial plexus blockade for upper extremity pain, celiac plexus blockade for pancreatic cancer, or superior hypogastric blockade for pain from pelvic tumor), lateral femoral cutaneous nerve block for meralgia parasthetica, and sciatic/femoral nerve blockade for lower extremity pain. These procedures cause minimal patient discomfort and carry a low incidence of serious adverse effects when performed by a skilled, experienced expert. Local anesthetic nerve blockade can produce anesthesia/analgesia lasting up to 12 hours, although it has been observed that the analgesic effect may outlast the anesthetic effect by days or weeks (Boys et al., 1993). Corticosteroids may

Neuraxial drug delivery The epidural and intrathecal (subarachnoid) routes are the two main routes used to deliver neuraxial blockade (Erdine, 2005). The epidural route remains the preferred route of neuraxial analgesia for short-term therapy (Baker et al., 2004). However, there is growing evidence to suggest that opioids delivered by the intrathecal route may provide better analgesia, and may be even safer, than opioids delivered by the epidural route (Gestin et al., 1997; Dahm et al., 1998). As a result, the intrathecal route is being used increasingly and is being used exclusively in some treatment centers (Baker et al., 2004). In oncologic care, the epidural route should probably be avoided in patients with known epidural disease, because this may interfere with the positioning of the catheter and with the free ﬂow of the analgesic agents. In addition, the epidural route may not be suitable for long-term use because of the potential for development of local ﬁbrosis, which may also interfere with the ﬂow of the analgesic agents (Wagemans et al., 1997). Epidural opioids become absorbed into the systemic circulation via Batson’s plexus, and because they also need to be given in higher dosages than intrathecal opioids, epidural opioid delivery may be associated with greater side effects compared with intrathecal opioid delivery. Drug delivery is via a percutaneous catheter and external pump or via a totally implantable drug delivery system. Percutaneous catheters may or may not

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be combined with local anesthetics with the aim of providing additional and/or longer-lasting analgesia if inﬂammation is a contributing factor (Twycross, 1994). A modiﬁcation of the “single-shot” technique involves the placement of a catheter for the administration of repeated boluses, or continuous infusion, of local anesthetic (Aguilar et al., 1995; Fisher et al., 1996). To provide more prolonged analgesia, a temporary block using local anesthetic may be followed up by a more permanent block using a neurolytic agent. Neurolytic agents include alcohol (3% to 100%), phenol (5% to 15%), and glycerol. Neurolytic agents damage the nerves in different ways, but all have the potential to be reversible, thereby causing the pain to return after a period of time (weeks to months) (Williams, 2003). One complication of neurolytic blockade is the development of postneurolysis deafferentiation neuralgia (neuropathic pain). When life expectancy is more than a few months, nonchemical neurolytic blockade (e.g., radiofrequency ablation, cryoablation) is preferable to chemical neurolytic blockade (e.g., alcohol, phenol), as the incidence of neuropathic pain has been found to be reduced with these techniques (Erdine, 2005). It should be noted that a successful local anesthetic block does not guarantee a successful neurolytic block, because there is no guarantee that the neurolytic agent will be placed at precisely the same location as the local anesthetic or that the neurolytic agent will act physiologically in the same manner as the local anesthetic.

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be tunneled under the skin (to exit at a distant site): tunneled catheters are more robust and have a lower incidence of infection than nontunneled catheters (Arbit and Pannullo, 2003). Implantable delivery systems are reserved for longer-term intrathecal therapy (i.e., for patients with a prolonged life expectancy). Implantable delivery systems have a high initial cost but appear to be cost effective in the longer term (several months to years) (Swarm et al., 2004). Neuraxial analgesia is best established by a constant infusion (Baker et al., 2004), as adverse events frequently relate to bolus delivery of the analgesic agents, particularly when treatment is ﬁrst instituted. Large boluses have caused cardiorespiratory arrest (Piquet et al., 1998). The newer external pumps, and some implantable delivery systems, offer the ability to deliver low-dose, patient-controlled boluses of the analgesic agents, which may provide improved analgesia with less systemic side effects and may be applicable in the treatment of breakthrough pain. A variety of opioids have been used for neuraxial analgesia, although morphine has been the traditional opioid of choice (Hicks and Simpson, 2004). Morphine is relatively hydrophilic, which results in a relatively slower onset of action (epidural route) and longer duration of action compared with other opioids (Hicks and Simpson, 2004). Morphine is also more likely to spread in a cranial direction, which may extend the level of analgesia but also increases the risk of respiratory depression. Other opioids that have been used for neuraxial analgesia include hydromorphone, oxycodone, fentanyl, sufentanil, and methadone, but only preservative-free morphine is currently approved for this indication in the United States. Neuraxial delivery of opioids produces inadequate analgesia in 10% to 30% of patients (Malone, 1985). In these cases, the co-administration of a local anesthetic may provide additional analgesia (Du Pen et al., 1992). Indeed, there is a growing trend to use combination treatment from the outset. Opioids and local anesthetics may act synergistically, allowing lower doses of the individual drugs to be used, which may limit the side effects of the individual drugs. It should be noted that low-dose infusions of local anesthetics (e.g., bupivacaine, ropivacaine) can provide adequate analgesia without producing signiﬁcant sensory disturbance or motor impairment (Dahm et al., 2000). However, boluses of local anesthetics can produce unpleasant paraesthesia and symptomatic hypotension. Other analgesic agents may also be delivered via the neuraxial route, including clonidine, baclofen, midazolam, ketamine, and ziconotide (Swarm et al., 2004). Clonidine, an α2 adrenoreceptor agonist, is a useful adjunct to spinal opioids, particularly in patients with neuropathic pain (Eisenach et al., 1995). The early complications of these techniques include catheter misplacement, cerebrospinal ﬂuid leak, bleeding, and infection. The later complications of these techniques include catheter kinking, catheter displacement or catheter obstruction by ﬁbrosis (epidural catheters), or granuloma formation (intrathecal catheters). Rarely, spinal cord compression is caused by hematomas, abscesses, or granulomas (Cabbell et al., 1998). Other complications relate to the analgesic agents that are used. Long-term intrathecal opioid infusion can lead to tolerance or hyperalgesia (Osenbach and Harvey, 2001).

Figure 9.1 Physio-Med TPN 200 PP TENS machine. Reprinted with permission from Davies, 2006.

Nonpharmacologic interventions

Transcutaneous electrical nerve stimulation (TENS) is a potent form of nerve stimulation (Thompson, 1998). It acts by inhibiting transmission of pain impulses from the periphery to the central nervous system, as a result of stimulating peripheral sensory nerve ﬁbers (Bercovitch and Waller, 2004). Other mechanisms may also be relevant, including activation of descending inhibitory pathways and activation of the sympathetic nervous system (Bercovitch and Waller, 2004). A basic TENS machine consists of a small, battery-operated electrical-pulse generator and a set of electrodes (Fig. 9.1) (Bercovitch and Waller, 2004). Most machines have the ability to vary the intensity, frequency, pulse duration, and type of output (i.e., continuous pulses, bursts of pulses, modulation/variation of pulses). The optimal settings for obtaining pain relief vary from patient to patient and need to be determined by trial and error in each patient (Bercovitch and Waller, 2004). TENS is a well-established treatment of musculoskeletal pain syndromes. However, there is relatively little evidence to support its use in the treatment of cancer pain (Bercovitch and Waller, 2004). TENS has been used to treat background pain and episodes of breakthrough pain (Filshie and Thompson, 2000; Zeppetella and Ribeiro, 2003). TENS is not used as often as perhaps it might, partly because of doubts about effectiveness for pain disorders associated with advanced medical illness and the time and effort needed to ﬁnd the optimal electrode placement and generator settings (Thompson, 1998). TENS can be used to treat any localized pain of somatic or neuropathic origin, providing paresthesias can be generated in the region of the pain or within

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Neuromodulation

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the same or a closely related dermatome (Woolf and Thompson, 1994). It can be difﬁcult to predict the response to TENS; a therapeutic trial is the only way to determine whether TENS will be successful ( Johnson et al., 1991). Contraindications to TENS include skin inﬂammation, skin infection, and the presence of a cardiac pacemaker (Bercovitch and Waller, 2004). TENS should not be used over the anterior neck, as stimulation of the laryngeal nerves may lead to laryngospasm and stimulation of the carotid sinus may lead to hypotension. Serious adverse effects are rare. Local adverse effects include skin irritation, skin burns, and allergy (to electrode gel and/or tape) (Bercovitch and Waller, 2004).

Spinal cord stimulation The analgesic mechanism of spinal cord stimulation is not fully understood, but it is thought to work by activating endogenous inhibitory systems within the central nervous system (Swarm et al., 2004). Spinal cord stimulation involves implanting electrodes in the epidural space at the spinal level corresponding to the site of pain. The procedure is now performed percutaneously, and with the patient awake, in order to ensure the safe and correct placement of the electrodes (Stannard, 2003). Initially, a trial of spinal cord stimulation is undertaken using a temporary external system. Subsequently, if this proves successful, the temporary external system can be replaced by a fully implantable system. Although numerous studies document the efﬁcacy of spinal cord stimulation, there are few data on the effectiveness of spinal cord stimulation in reducing breakthrough pain associated with cancer and noncancer chronic pain conditions. Older case series provided mixed conclusions; Meglio et al. (1989) concluded that spinal cord stimulation was not useful for cancer pain, but the results were equivocal in a preceding series (Krainick and Thouden, 1974). The main complications of spinal cord stimulation are infection (<1%) and technical failures such as migration of electrodes and breakage of electrodes. In this author’s experience, most patients who beneﬁt from spinal cord stimulation still require intermittent analgesic therapy to treat breakthrough pain.

Neuroablation Neuroablation (neurolytic blockade) is deﬁned as the physical interruption or destruction of neurons and pathways conducting pain impulses. It can be performed chemically, thermally, or surgically. Over the past two decades, there has been a diminishing role for neurolytic blockade and an increasing role for neuraxial analgesic delivery. Nevertheless, there remains a limited role for its use in patients with well-localized intractable pain, and especially those with a relatively short life expectancy (Goh, 2005).

Peripheral neurolytic blockade See previous section.

Celiac plexus blockade Celiac plexus blockade is probably the most established and beneﬁcial of all the neurolytic procedures. It can be useful for visceral pain arising from the lower half of the stomach through the hepatobiliary system, the pancreas, and midtransverse colon (Swarm et al., 2004). Needle placement is performed using radiographic imaging such as ﬂuoroscopy or CT in sedated or anesthetized patients. Endoscopic ultrasound (EUS)–guided neurolytic celiac plexus blockade has recently been described (Arcidiacono and Rossi, 2004). A meta-analysis of relevant studies found that 89% of patients had good to excellent pain relief during the ﬁrst 2 weeks post-blockade, that ≈90% of patients had partial to complete pain relief at 3 months post-blockade, and that 70% to 90% of patients had partial to complete pain relief up until death (Eisenberg et al., 1995). Certain adverse effects are common after celiac plexus block. These include orthostatic hypotension (63%) and diarrhea (44%) (Swarm et al., 2004). These effects are usually transient, are generally mild in nature, and require little or no treatment. Other more serious, although uncommon, complications have also been reported. These include paraplegia (<1%), aortic dissection, generalized seizures, and circulatory arrest (Davies, 1993; Kaplan et al., 1995). Although post-neurolysis breakthrough pain has not been studied speciﬁcally, in this author’s experience, most patients continue to require intermittent opioid analgesics for breakthrough pain. This conclusion can be deduced from ﬁndings from a comparative trial reported by Wong (2004), wherein he reported beneﬁts from neurolytic celiac plexus block but continued high rates of opioid use for pain control.

Lumbar sympathetic blockade Lumbar sympathetic blockade can be useful for neuropathic and ischemic pain arising from the lower extremities and for visceral pain arising from lower abdominal and pelvic structures (Brevik et al., 1998).

Nonpharmacologic interventions CHAPTER 9

The sympathetic nervous system plays a role in the modulation of certain pain impulses (Swarm et al., 2004). Moreover, the sympathetic chain and ganglia are traversed by visceral nociceptive ﬁbers. Consequently, blockade of the sympathetic nervous system may be useful in certain types of pain (i.e., visceral pain, neuropathic pain). It has recently been suggested that neurolytic sympathetic blockade of the celiac plexus, lumbar plexus, or superior hypogastric plexus be considered earlier, rather than later, in the management of pain due to abdominal or pelvic cancers (de Oliveira et al., 2004). A diagnostic block using local anesthetic is sometimes used to establish the relative contribution of the sympathetic system to the etiology of the pain.

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Superior hypogastric blockade This type of blockade may be useful in patients with visceral pain from pelvic structures (Swarm et al., 2004). This is usually reserved for terminal illness, usually related to tumors.

Ganglion impar (ganglion of Walther) blockade This type of blockade may be useful in patients with perineal pain and/or rectal pain (Swarm et al., 2004). Beneﬁts with regard to breakthrough pain have not been reported following any of these techniques.

Neurolytic blockade of the central nervous system Intrathecal (subarachnoid) neurolysis The aim of intrathecal neurolysis is to disrupt the anterolateral spinothalamic tracts. These blocks can be effective for bilateral perineal pain (“saddle pain”) and for unilateral torso pain (Patt and Cousins, 1998).

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Cervical cordotomy The aim of cervical cordotomy is to disrupt the spinothalamic tracts just below the medulla oblongata. It is particularly helpful for unilateral pain from a mesothelioma (Kanpolat et al., 2002) or a Pancoast’s tumor (Ischia et al., 1985) that has failed to respond to other treatment. However, it may also be helpful for other unilateral pains involving the chest, upper extremity, pelvis, and lower extremity (Hassenbach and Cherny, 2004). A variety of other neurolytic procedures have been reported, although many of them are rarely used these days due to the increased safety and relative ease of intrathecal drug delivery (Hassenbach and Cherny, 2004; Swarm et al., 2004).

Other interventions Acupuncture Acupuncture is an ancient and time-tested therapeutic modality. It is a form of sensory stimulation that relies on Aδ nerve stimulation using percutaneous needles to produce analgesia via neuromodulation of pain pathways and numerous endogenous spinal and supraspinal analgesic mechanisms (Filshie and Thompson, 2004). Acupuncture has been shown to raise the pain threshold (Brockhaus and Elger, 1990), as well as to reduce experimentally induced pain (White, 1999) and acute pain (Kotani et al., 2001). It is regularly used to treat noncancer chronic pain and cancer pain, although there is a lack of good evidence to support its role in the treatment of cancer pain. One of the main reasons for the lack of good evidence is the difﬁculty of undertaking controlled and/or blinded trials of acupuncture (Filshie and Thompson, 2004).

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Acupuncture can provide acute pain relief as well as more prolonged pain relief (i.e., days to weeks) (Filshie and Thompson, 2004). It seems to be more helpful in treating the underlying pain state than in treating actual breakthrough pain episodes. Acupuncture is especially useful for pain of musculoskeletal origin (Baldry, 2004). A variety of techniques may be used involving different acupuncture points, different modes of stimulation (e.g., minimal stimulation, vigorous stimulation), different durations of stimulation, and variable course lengths. A typical course of acupuncture will involve weekly treatments for 6 weeks, followed by “topup” treatments every few weeks thereafter (Filshie and Thompson, 2004). Contraindications to acupuncture have been described in patients with advanced medical illness and include thrombocytopenia, neutropenia, lymphedema, local infection, and local tumor (Filshie, 2001). Furthermore, needling should not be performed near an unstable spine, because any muscle relaxation may worsen the spinal stability. Acupuncture has been shown to be safe in a number of large prospective studies, with the common adverse effects being post-treatment pain (≈1%), bleeding and/or bruising (≈3%), and somnolence (MacPherson et al., 2001; White et al., 2001).

A variety of other interventional techniques have been reported to be useful in treating pain secondary to bone disease, although most of them have not been subjected to rigorous scientiﬁc investigation. These include the following: (1) corticosteroid instillation (Rousseff and Simeonov, 2004), (2) alcohol instillation (Gangi et al., 1996), (3) phenol instillation (Gangi et al., 1996), (4) cryoablation (Callstrom et al., 2006), (5) radiofrequency ablation (Goetz et al., 2004), (6) laser ablation (Callstrom et al., 2006), (7) cementoplasty/vertebroplasty (Gangi et al., 2003) (this technique involves injecting methylmethacrylate cement into the affected bone), and (8) balloon kyphoplasty (Fourney et al., 2003) (this technique is similar to vertebroplasty but involves initially inﬂating a balloon within the affected bone to improve the alignment of the bone, and also to create a cavity for the cement within the bone).

Miscellaneous interventions for breakthrough pain episodes A variety of other nonpharmacological methods have also been reported to be useful in treating actual breakthrough pain episodes, although most of them have not been subjected to rigorous scientiﬁc investigation: (1) rubbing and/or massage (Fine and Busch, 1998; Swanwick et al., 2001), (2) application of heat (Fine and Busch, 1998; Swanwick et al., 2001), (3) application of cold (Fine and Busch, 1998; Petzke et al., 1999), (4) distraction techniques (Portenoy, 1997; Petzke et al., 1999), (5) relaxation techniques (Portenoy, 1997; Fine and Busch, 1998), and (6) hypnotherapy/hypnosis (Liossi, 2000; Wild and Espie, 2004). The noninvasive, low-risk, and relatively inexpensive nature of these interventions means that it is usually worth a therapeutic trial of these modalities. Furthermore, patients ﬁnd these types of treatment highly acceptable for man-

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aging their breakthrough pain, particularly as they have often used them for managing other types of pain (e.g., benign musculoskeletal pain). In summary, there are myriad nonpharmacologic techniques that are practiced commonly for the control of pain, but there is only anecdotal evidence for the reduction or relief of breakthrough pain per se. Clearly, this suggests that there is a need to evaluate breakthrough pain as an independent outcome variable when clinical trials are implemented. Methodology to discern breakthrough pain and quality-of-life improvements related to breakthrough pain reduction requires reﬁnement in clinical trials involving these various techniques.

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Chapter 10

Regardless of medical diagnosis, the decision to proceed with long-term opioid therapy requires serious initial consideration and reconsideration over time based on meeting speciﬁc therapeutic goals and minimizing potential harms. Effectiveness of therapy, which is a positive balance of therapeutic outcomes and adverse effects, must be continually reassessed and documented. Because immediaterelease and rapid-onset opioids are a mainstay for breakthrough pain and their use has the potential to create powerful positive conditioning for the brain’s “reward center,” it must be ascertained over time that the use of these agents is medically appropriate and beneﬁcial (Ballentyne and LaForge, 2007; Fields, 2007). Long-term management with opioids implies a life expectancy greater than weeks to months. Unfortunately, there is an absence of prospective studies that allow for accurate predictions of effectiveness in a given patient over such a period of time. Therefore, in such cases, clinicians who prescribe opioid analgesics for the treatment of chronic pain have an obligation to implement therapy according to accepted principles of prescribing and to minimize the risk of misuse, abuse, addiction, and diversion through individualized application of risk assessment and management strategies (Fine and Portenoy, 2007). This requires physicians to have the ability to evaluate for and recognize potential or ongoing problematic drug-related behaviors, part and parcel of a basic skills set in addiction medicine. This necessity is underscored by a documented increase in prescription drug abuse in recent years, especially among teens and young adults, and the strong call for “balance” by both pain specialists and those in the regulatory and law enforcement communities (Birnbaum et al., 2006; Katz et al., 2007). Clinicians must understand the regulations and laws that govern the use of controlled prescription drugs, assess and stratify risk in every case, and structure a prescription regimen that is consistent with the perceived risk of abuse or addiction.

Laws and regulations Uncertainty regarding regulatory issues and a fear of potential disciplinary action may give physicians pause when considering whether to prescribe long-term

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opioid therapy. Surveys have shown that physicians have a very real fear of disciplinary action for prescribing controlled substances, particularly if the patient has noncancer pain or a history of drug abuse. Even in populations with cancer pain or HIV-related pain, for which there is wide acceptance of opioid therapy, concerns about regulatory scrutiny are believed to be a signiﬁcant cause of undertreatment (Dahl et al., 2005). The framework of laws and regulations governing the use of opioids and other controlled substances has three tiers: (1) international laws and treaties, (2) federal laws and regulations, and (3) state laws and regulations. National governments are obligated to ensure the availability of opioid medications for legitimate medical and scientiﬁc purposes. International treaties have been designed to achieve a balance between ensuring the availability of controlled substances for medical purposes and preventing illegal diversion.

International regulation The International Narcotics Control Board was established in 1968 as an independent and quasi-judicial body empowered to implement the United Nations drug conventions. It attempts to ensure that adequate supplies are available for medical and scientiﬁc uses and that leakages from licit sources to illicit trafﬁc do not occur. To accomplish this, the board administers a system for estimating and fulﬁlling the legitimate need for opioids and monitoring international trade in drugs. It also monitors government control over the chemicals used in the illicit manufacture of drugs and assists governments in preventing diversion of these chemicals into illicit trafﬁc. Finally, the board also attempts to identify where weaknesses in the national and international control systems exist.

Federal regulation In the United States, two federal agencies, the Food and Drug Administration (FDA) and the Drug Enforcement Administration (DEA), work together to regulate drugs and limit diversion and abuse. Before a pain medication can become available to patients, the FDA must assess its efﬁcacy and safety, including its potential for abuse. If a product does not receive marketing approval (or an exemption) from the agency, it cannot be legally produced or prescribed. The Controlled Substances Act empowers the DEA to classify drugs into different schedules based on the risk of abuse and diversion, medical use, and safety. Controlled substance schedules range from I to V. Schedule I drugs (e.g., heroin, LSD, marijuana) have a high potential for abuse, a lack of accepted safety, and no current federally accepted medical use. Schedule II drugs (e.g., morphine, fentanyl, hydromorphone, levorphanol, methadone, oxycodone, oxymorphone, methylphenidate, dextroamphetamine, dronabinol) have a high potential for abuse, may produce severe psychological or physical dependence liability, and have current accepted medical uses. Drugs classiﬁed into Schedules III through V (e.g., hydrocodone [only available co-compounded with acetaminophen or NSAID], codeine, diazepam) represent substances considered to

Each state works independently as well as with the federal government to oversee the movement of controlled prescription drugs and minimize abuse and diversion. Each also has sole responsibility for maintaining standards of health-care practice through licensure of professionals. Law enforcement involvement occurs at the local and the state level through numerous agencies. Medical practice and licensure are governed through state medical boards, whereas law enforcement under the Department of Justice in each state oversees criminal activities that are deemed outside the bounds of medicine (Joranson et al., 2002b). Historically, the policies, laws, and regulations that govern the use of controlled prescription drugs in most states have been skewed toward enforcement and not patient care. The principle of balance found in international and federal law has not been central to the oversight efforts of the states (PPSG, 2006). During the past 5 years, however, many states have attempted to redress the major concerns and explicitly recognize the need to protect clinical practice while reducing opioid abuse and diversion. In the area of medical practice, for example, the Federation of State Medical Boards, a national organization, has drafted model policies for the medical use of controlled substances (“Model Policy for the Use of Controlled Substances for the Treatment of Pain”), which have now been adopted, at least in part, by almost half of the states. This model policy is used by state boards to judge the appropriateness of a therapy and should be considered by prescribers as the basic approach to the structuring and documentation of opioid therapy (Table 10.1) (FSMB, 2007). Although progress also has been made in establishing a dialogue with state regulatory and law enforcement communities about the evolving role of opioid analgesics in pain management, physicians continue to be concerned about investigation and potential sanctions. The number and complexity of the agencies that can initiate an investigation after a complaint, the variation in laws and regulations from jurisdiction to jurisdiction, the lack of certainty that local investigators follow the intentions of senior management in any agency, and the potential to be duped by those who would divert drugs into the illicit market combine to create, at very least, a perceived level of prescriber risk associated with prescribing controlled drugs. Anecdotal reports of physicians who have been investi-

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have progressively less abuse potential and relatively reduced psychological or physical dependence (Portenoy et al., 2005). The DEA enforces the Controlled Substances Act and the laws regulating the manufacture, distribution, dispensing, and record-keeping requirements for controlled substances. It also sets production quotas for controlled drugs, which are intended to accommodate all legitimate medical and scientiﬁc uses of scheduled drugs. According to the Controlled Substances Act, the use of a scheduled drug is legal as long as it is prescribed and dispensed in the usual course of professional practice and for a legitimate medical purpose (Gilson, 2002). This underscores the importance of documenting ongoing indications for and outcomes of ongoing opioid therapy.

Table 10.1 Key elements in the Model Policy for the Use of Controlled Substances for the Treatment of Pain of the Federation of State Medical Boards Guideline Evaluation of the patient

Treatment plan

Informed consent and agreement for treatment

Periodic review

Consultation

Medical records

Compliance with controlled substances laws and regulations

Comment History and examination must be documented. Pain history, comorbidities, and indication for opioid should be documented. Objectives used to determine success should be noted. Treatment should be adjusted over time to reﬂect changes; nonopioid therapies should be prescribed if indicated. Risks and beneﬁts should be discussed. Prescriptions given by one physician and pharmacy whenever possible. Consider written agreement if patient is at high risk of abuse; if used, agreement should outline patient responsibilities, including drug screening when requested, number and frequency of all prescription reﬁlls, and reasons for which drug may be discontinued. Continuation or modiﬁcation of therapy should depend on evaluation of progress toward treatment objectives; satisfactory response may be indicated by decreased pain, improved function, or better quality of life. Objective indicators of improvement should be monitored and use of history from family or other caregivers should be considered. If progress unsatisfactory, therapy should be reconsidered. There should be willingness to refer, particularly if patient is at risk for misuse, abuse, or diversion; consider consulting an expert if patient has a history of substance abuse or a comorbid psychiatric disorder that may require extra care. Accurate and complete medical records should include: • the medical history and physical examination; • diagnostic, therapeutic, and laboratory results; • evaluations and consultations; • treatment objectives; • discussion of risks and beneﬁts; • informed consent; • treatments; • medications (including date, type, dosage, and quantity prescribed); • instructions and agreements; and • periodic reviews. Both federal and state laws and regulations must be followed.

Risk assessment is key to the positioning of opioid therapy among the treatments that may be offered for breakthrough pain. If the decision is made to implement an opioid trial with the intention of continuing therapy, the treatment must include strategies to minimize the risk of misuse, abuse, and addiction. This is no less important than strategies to optimize drug administration to achieve the best balance between analgesia and side effects (Fine and Portenoy, 2007). The creation of an individualized plan to minimize risk and maintain an appropriate level of monitoring should be considered a part of the plan of care for all patients, a concept that has been termed “universal precautions” (Gourlay et al., 2005). As with universal precautions associated with infectious diseases, applying a set of criteria to every patient with chronic pain improves patient care, reduces stigma, and minimizes overall risk (Box 10.1). The initial assessment can be based on clinical ﬁndings or on the ﬁndings of a validated instrument designed to predict risk (Webster and Webster, 2005; Ives et al., 2006). The goal of the initial assessment is risk stratiﬁcation. Empirically, it is reasonable to stratify patients into lower and higher risk categories based on the assessed level of risk. Although this process cannot yet be guided by scientiﬁcally based principles, the clinical utility is clear. Decision making concerning the need for consultation or referral can be based on risk strata, and if opioid treatment proceeds, the therapy should be structured in a manner commensurate with the perceived risk. Proactive strategies should be adopted at the start of therapy to structure the therapy based on risk in a manner that minimizes the potential for aberrant drug-related behaviors and establishes appropriate monitoring (Box 10.2) (Fine and Portenoy, 2007). If the risk is perceived to be very low (e.g., the opioidnaïve elderly with no history of substance abuse and progressive pain from osteoarthritis), then minimal or no special strategies may be needed. If the risk is relatively high (e.g., the work-injured, depressed man with a history of binge drinking and a family history of alcoholism), then treatment might be initiated with many of the strategies in place.

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gated (a costly and highly stressful process, even if the outcome is favorable), disciplined by their licensing boards, or prosecuted by state authorities for alleged criminal activities further lead to a high level of concern and may produce a chilling effect that contributes to the undertreatment of pain (Gilson et al., 2004). To minimize risk, prescribers must follow laws and regulations when prescribing, and both prescribe and document in accordance with accepted medical practice, as depicted in the Model Guideline (Table 10.1). A clinician who recognizes the necessity of risk assessment and management is best able to maintain the controls necessary to prescribe in a manner consistent with federal and state requirements.

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Box 10.1 The 10 steps of universal precautions in pain medicine 1. Make a diagnosis with appropriate differential a. Identify treatable causes for pain and direct therapy to pain generator b. In absence of speciﬁc objective ﬁndings, treat symptoms c. Address any comorbid symptoms, including substance abuse and psychiatric illness 2. Psychological assessment including risk of addictive disorders a. Inquiry into personal and family history of substance abuse b. Perform patient-centered urine drug testing 3. Informed consent 4. Treatment agreement a. Expectations and obligations of patient and practitioner should be understood b. Forms basis of therapeutic trial 5. Pre- and post-intervention assessment of pain level and function 6. Appropriate trial of opioid therapy with or without adjunctive medication 7. Reassessment of pain score and level of function 8. Regularly assess the “Four A’s” of pain medicine (analgesia, activity, adverse effects, and aberrant behavior) 9. Periodically review pain diagnosis and comorbid conditions, including addictive disorders 10. Documentation Adapted from Gourlay et al., 2005.

Managing aberrant drug-related behavior As treatment proceeds, drug-related behaviors must be monitored. This can be performed by regular clinical assessment. This assessment can be supplemented by ancillary sources of information, such as drug screening, pill counts, interviews with family members (with patient approval in the case of adult patients), and prescription monitoring programs where available (Joranson et al., 2002a). The plan to acquire this type of information should be part of the plan when the patient is assessed as relatively high risk, and the speciﬁcs should be explained to the patient beforehand. Ongoing assessment of drug-related behaviors has been incorporated into a clinical tool developed for the purpose of monitoring and documenting the key outcomes associated with long-term opioid therapy. The Pain Assessment and Documentation Tool (PADT) assesses four types of outcomes: analgesia, activities of daily living, adverse events, and potential aberrant drug-related behavior (known by the mnemonic “the 4 As”). It provides a checklist of problematic behaviors and, if used repeatedly, provides a means of documenting changes in therapeutic adherence (Passik et al., 2004). If problematic behavior is identiﬁed, a detailed reassessment is needed. The purpose is to clarify the meaning of the behavior and to generate one or more potential diagnoses (Box 10.3). The plan should be based on the diagnosis. For

Reactive strategies • Written agreement that addresses speciﬁc behaviors and outlines consequences going forward • Discontinue rescue dose • Frequent visits and small quantities prescribed • Urine drug screen at baseline and expressed intention to request screens in the future • Requirement that only one pharmacy be used (with permission to contact) • Instruction to bring pill bottle to appointment (for count) • Instruction that there will be no early reﬁlls and no replacement of lost prescription without a police report documenting loss • Requirement for nonopioid therapies, including psychotherapy • Requirement that all other health-care providers be contacted • Required referral to addiction medicine specialist, with follow-up treatment for aberrant behaviors • Requirement that others (e.g., spouse) be allowed to give feedback to the physician • In states with electronic prescription reporting, intention to query the database on a regular basis going forward Adapted with permission, Fine and Portenoy, 2007.

example, in the extreme case of the patient who begins to grind and inject an oral formulation, the diagnosis of abuse is certain and that of addiction usually is clear. Subsequently, the abused pain therapy typically is suspended or greatly altered as the patient is referred to a specialist in addiction medicine for primary follow-up. If the nature of the behavior is uncertain and the assessment concludes that therapy can be continued, ample resources for assessing risk

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Proactive strategies • Written agreement after detailed consent discussion • Prescribe long-acting drug without “rescue dose” • Frequent visits and small quantities prescribed • Urine drug screen at baseline and expressed intention to request occasional screens in the future • Requirement that only one pharmacy be used (with permission to contact) • Instruction to bring pill bottle to appointment (for count) • Instruction that there will be no early reﬁlls and no replacement of lost prescription without a police report documenting loss • Requirement for nonopioid therapies, including psychotherapy • Requirement for all prior records and permission to contact all other health-care providers prior to prescribing • Required referral to addiction medicine specialist for all at-risk patients • Requirement that others (e.g., spouse) be allowed to give feedback to the physician • In states with electronic prescription reporting/tracking, intention to query the database initially and on a regular basis

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Box 10.2 Proactive and reactive strategies to minimize risk of abuse and enhance monitoring

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Box 10.3 Differential diagnosis of aberrant drug-related behavior Addiction: a primary, chronic, neurobiologic disease with genetic, psychosocial, and environmental factors; characterized by impaired control over drug use, compulsive use, continued used despite harm, and drug craving. Undertreated pain (often called “pseudoaddiction”): aberrant drug-related behaviors induced by desperation over unrelieved pain; may be driven by psychiatric disease or coexist with addiction. Other psychiatric disorder: Axis I disorder (e.g., anxiety disorders, major depression) Axis II disorder (e.g., personality disorders such as borderline personality, sociopathic personality) Encephalopathy (e.g., associated with medication toxicity) Other psychosocial/emotional issues (e.g., family discord, ﬁnancial worries, work-related discontent, “rebellion”) Recreational use (e.g., experimentation, pleasure, escape, peer pressure) Criminal intent (e.g., selling drugs, falsifying prescriptions to procure more drug)

118

Consensus Document: The American Academy of Pain Medicine, The American Pain Society, The American Society of Addiction Medicine, 2001.

and observing outcomes must be in place, as the diagnosis may become evident over time as the patient deals with a new structure for the therapy. The restructuring of therapy may involve the addition of one or more reactive strategies (see Box 10.2) (Fine and Portenoy, 2007). Like those imposed at the start of therapy, these are intended to minimize future risk of abuse, addiction, or diversion and increase the level of monitoring. Whenever problematic drug-related behaviors occur, the clinician has cause to decide about continuation of treatment and the possibility of referral. Pain treatment may be continued with opioids (using a different structure for prescribing) or continued without opioids, or the patient may be discharged from the practice. The decision to continue treatment with the opioid should be based on careful assessment of the severity and meaning of the problematic behavior. There should be an explicit plan to change or discontinue the current therapy (often called an “exit strategy”) unless (1) favorable outcomes (pain relief, improved function, and/or improved quality of life) are manifest, (2) there is a high likelihood that control over the therapy can be reacquired, and (3) restructuring allows better monitoring of drug-related behavior. Discharge from the practice may be warranted if the possibility of therapeutic progress has been severely undermined by mistrust or the assessment reveals that the patient lacks interest in treatments other than the opioid agent (Fine and Portenoy, 2007). When aberrant drug-related behavior of a signiﬁcant enough magnitude or frequency occurs, referral to a specialist in addiction medicine or an addiction program also should be considered. Addiction is a chronic disease like any other, and it is no more appropriate to neglect referral for this disorder once it

A formal written agreement between the patient and the physician at the start of opioid therapy is a common tool for deﬁning expectations and documenting informed consent. Although these agreements have been called “contracts,” they have no statutory force of law, and this term is not preferred because it suggests a legal rather than therapeutic relationship between the physician (or other prescriber) and the patient. Pain specialists differ in their views of this approach (Fishman and Kreis, 2002). On the positive side, these agreements can be used as educational tools that outline the clinician’s policy for providing controlled prescription drugs and describe the consequences of problematic drug-related behavior. They can reinforce the idea that opioid medications must be used responsibly and can also assure patients that medication will be prescribed as long as outcomes are positive and there is adherence to therapy. On the negative side, these agreements can contribute to the stigmatization of opioid therapy. If they are framed in a manner that the patient perceives as threatening, they may contribute to assessment difﬁculties as the patient withholds or skews information in an effort to meet expectations. If they give a clinician a false sense of security and thereby reduce the vigilance, monitoring, and use of appropriate proactive and reactive strategies that are essential to risk management, they could paradoxically increase risk. Finally, if the agreements implicitly hold a clinician to a certain level of clinical performance, they could ultimately be used adversely in a medicolegal dispute. Given these potential positives and negatives—and the lack of consensus about the role of this approach—each clinician must decide whether the use of an agreement is appropriate and likely to be beneﬁcial. Use of opioid agreements may be informed by a recent survey that identiﬁed the most common elements used by 39 university-afﬁliated pain management centers (Table 10.2). This work highlighted the necessity for careful consideration of prohibitions endorsed in order to help patients normalize, rather than restrict, their activities. For example, rather than prohibiting patients from driving while using opioids for breakthrough pain, an admonition against driving for the ﬁrst hour or two after a rapid-onset agent (transmucosal opioid) or

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is suspected than it is to neglect referral for any other complex, potentially lifethreatening disease. The clinician also might consider referral to a pain specialist or to a mental health care provider (other than an addiction specialist), depending on the needs identiﬁed. If therapy must be restructured, it is important that documentation be comprehensive and complete. The medical record should reﬂect the thoughtful reassessment, and the written plan of care should be explicit. It may be useful to provide the patient with a letter that clariﬁes the next steps, his or her obligations, and the consequences should problems recur.

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for 3 to 4 hours after an immediate-release agent (oral opioid) would be sensible. Likewise, rather than prohibiting pregnancy during treatment, the agreement may outline the prescriber’s concerns about pregnancy and require notiﬁcation should pregnancy occur or be anticipated, so that counseling and appropriate perinatal referral can be provided. In an effort to further clarify the type of language that may be most appropriate for these agreements, the American Academy of Pain Medicine developed a model approach (Box 10.4).

Table 10.2 Statement groups found most often in opioid agreements Statement category 1. Avoid improper use of controlled substances (includes overdosing, seeking medication elsewhere, selling medication, stopping medication abruptly) 2. Terms of disciplinary termination (medication abuse, missed appointments, contract violation, inappropriate behavior) 3. Limitations for replacing medication or changing prescriptions 4. Inform physician of relevant information (e.g., side effects, other medications, changes in condition) 5. Submit to random drug screens 6. Terms regarding appointments (missing appointment, follow-up, appearing without appointment) 7. Include additional health-care providers involved in care (e.g., primary care physician, physical therapist, psychologist) 8. Limits on drug reﬁlls (telephone allowances, only in person, call in advance, normal ofﬁce hours) 9. Education about side effects (including withdrawal) 10. Terms of nondisciplinary termination (e.g., no improvement, pregnancy, tolerance, toxicity) 11. Education on addiction risks and behaviors 12. Education on opioids and chronic pain 13. Health-care providers informed of prescription (e.g., primary care physician, pharmacist) 14. Pharmacy issues included (use of only one pharmacy, use of in-state pharmacy) 15. Goals (outline goals) 16. Additional risks discussed (e.g., other drug use, misuse, pregnancy) 17. Necessity of contract discussed (reasons why necessary, including federal guidelines and abuse) 18. Legal considerations discussed 19. Single prescriber for all opioid prescriptions 20. Dosing limitation (how much, interval between prescriptions, rescue dosing, as-needed use, dose escalation) Adapted with permission, Fishman et al., 1999.

Contracts (%) 95

92 85 74 69 62 59 56 56 51 49 49 46 44 38 38 36 33 33 31

Box 10.4 Sample opioid agreement SAMPLE FOR ADAPTATION AND REPRODUCTION ON PHYSICIAN LETTERHEAD, PLEASE CONSULT WITH YOUR ATTORNEY. Long-term controlled substances therapy for chronic pain The purpose of this agreement is to protect your access to controlled substances and to protect our ability to prescribe for you. The long-term use of such substances as opioids (narcotic analgesics, benzodiazepine tranquilizers, and barbiturate sedatives) is controversial because of uncertainty regarding the extent to which they provide long-term beneﬁt. There is also the risk of an addictive disorder developing or of relapse occurring in a person with a prior addiction. The extent of this risk is not certain. Because these drugs have potential for abuse or diversion, strict accountability is necessary when use is prolonged. For this reason the following policies are agreed to by you, the patient, as consideration for, and a condition of, the willingness of the physician whose signature appears below to consider the initial and/or continued prescription of controlled substances to treat your chronic pain. 1. All controlled substances must come from the physician whose signature appears below or, during his or her absence, by the covering physician, unless speciﬁc authorization is obtained for an exception. (Multiple sources can lead to untoward drug interactions or poor coordination of treatment.) 2. All controlled substances must be obtained at the same pharmacy, where possible. Should the need arise to change pharmacies, our ofﬁce must be informed. The pharmacy that you have selected is:_____________________ Phone:_______________ 3. You are expected to inform our ofﬁce of any new medications or medical conditions and of any adverse effects you experience from any of the medications that you take. 4. The prescribing physician has permission to discuss all diagnostic and treatment details with dispensing pharmacists or other professionals who provide your health care, for purposes of maintaining accountability. 5. You may not share, sell, or otherwise permit others to have access to these medications. 6. These drugs should not be stopped abruptly, as an abstinence syndrome will likely develop. 7. Unannounced urine or serum toxicology screens may be requested, and your cooperation is required. Presence of unauthorized substances may prompt referral for assessment for addictive disorder. 8. Prescriptions and bottles of these medications may be sought by other individuals with chemical dependency and should be closely safeguarded. It is expected that you will take the highest possible degree of care with your medication and prescription. They should not be left where others might see or otherwise have access to them. 9. Original containers of medications should be brought in to each ofﬁce visit. 10. Since the drugs may be hazardous or lethal to a person who is not tolerant to their effects, especially a child, you must keep them out of reach of such people. 11. Medications may not be replaced if they are lost, get wet, are destroyed, are left on an airplane, etc. If your medication has been stolen and you complete a police report regarding the theft, an exception may be made. 12. Early reﬁlls will generally not be given. 13. Prescriptions may be issued early if the physician or patient will be out of town when a reﬁll is due. These prescriptions will contain instructions to the pharmacist that they not be ﬁlled prior to the appropriate date. 14. If the responsible legal authorities have questions concerning your treatment, as might occur, for example, if you were obtaining medications at several pharmacies,

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Box 10.4 (Continued) 15. 16. 17. 18. 19.

all conﬁdentiality is waived and these authorities may be given full access to our records of controlled substance administration. It is understood that failure to adhere to these policies may result in cessation of therapy with controlled substance prescribing by this physician or referral for further specialty assessment. Renewals are contingent on keeping scheduled appointments. Please do not phone for prescriptions after hours or on weekends. It should be understood that any medical treatment is initially a trial and that continued prescription is contingent on evidence of beneﬁt. The risks and potential beneﬁts of these therapies are explained elsewhere (and you acknowledge that you have received such explanation). You afﬁrm that you have full right and power to sign and be bound by this agreement and that you have read, understand, and accept all of its terms.

______________________________________ Physician signature ______________________________________ Patient signature ______________________________________ Date ______________________________________ Patient name (printed) Adapted from the American Academy of Pain Medicine, Glenview, IL.

Conclusion In summary, risk management is an implicit part of all medical care, and of prescribing of controlled substances in particular. Optimal treatment of breakthrough pain requires skillful use of all available tools and methods in order to allow patients to maintain the most functional life they can. Physicians must become adept and skilled at integrating risk assessment and management techniques into their day-to-day practices in order to meet their professional responsibilities to their patients and to the public health and to protect their prescribing privileges.

References Ballentyne JC, LaForge KS. Opioid dependence and addiction during opioid treatment of chronic pain. Pain. 2007;129:235–255. Birnbaum HG, White AG, Reynolds SL, et al. Estimated costs of prescription opioid analgesic abuse in the United States in 2001: A societal perspective. Clinical Journal of Pain. 2006;22:667–676. Dahl JL. How to reduce fears of legal/regulatory scrutiny in managing pain in cancer patients. Journal of Supportive Oncology. 2005;3:384–388.

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Federation of State Medical Boards, Inc. (FSMB). Model Policy for the Use of Controlled Substances for the Treatment of Pain. 2007. Available at: http://www.fsmb.org/pdf/ 2004_grpol_Controlled_Substances.pdf. Accessed August 1, 2007. Fields HL. Should we be reluctant to prescribe opioids for chronic non-malignant pain? Pain. 2007;129(3):233–234. Fine PG, Portenoy RK. A Clinical Guide to Opioid Analgesia (2nd ed.). New York: Vendome, 2007. Fishman SM, Bandman T, Edwards A, et al. The opioid contract in the management of chronic pain. Journal of Pain and Symptom Management. 1999;18:27–37. Fishman SM, Kreis PG. The opioid contract. Clinical Journal of Pain. 2002;18:S70–S75. Gilson AM, Joranson DE. US policies relevant to the prescribing of opioid analgesics for the treatment of pain in patients with addictive disease. Clinical Journal of Pain. 2002;18:S91–S98. Gilson AM, Ryan KM, Joranson DE, Dahl JL. A reassessment of trends in the medical use and abuse of opioid analgesics and implications for diversion control: 1997–2002. Journal of Pain and Symptom Management. 2004;28:176–188. Gourlay DL, Heit HA, Almahrezi A. Universal precautions in pain medicine: A rational approach to the treatment of chronic pain. Pain Medicine. 2005;6:107–112. Ives TJ, Chelminski PR, Hammett-Stabler CA, et al. Predictors of opioid misuse in patients with chronic pain: A prospective cohort study. BMC Health Services Research. 2006;6:46. Joranson DE, Carrow GM, Ryan KM, et al. Pain management and prescription monitoring. Journal of Pain and Symptom Management. 2002;23:231–238. Joranson DE, Gilson AM, Dahl JL, Haddox JD. Pain management, controlled substances, and state medical board policy: A decade of change. Journal of Pain and Symptom Management. 2002;23:138–147. Katz NP, Adams EH, Benneyan JC, et al. Foundations of opioid risk management. Clinical Journal of Pain. 2007;23:103–118. Pain and Policy Studies Group (PPSG). Achieving balance in state pain policy: A progress report card. 2006. Available at: http://www.medsch.wisc.edu/painpolicy. Accessed August 1, 2007. Passik SD, Kirsh KL, Whitcomb L, et al. A new tool to assess and document pain outcomes in chronic pain patients receiving opioid therapy. Clinical Therapeutics. 2004;26:552–561. Portenoy RK, Payne R, Passik S. Acute and chronic pain. In Lowinson JH, Ruiz P, Millman RB (Eds.), Comprehensive Textbook of Substance Abuse (4th ed., pp. 863–903). Baltimore: Williams and Wilkins, 2005. Webster LR, Webster RM. Predicting aberrant behaviors in opioid-treated patients: A preliminary validation of the Opioid Risk Tool. Pain Medicine. 2005;6:432–442.

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A Abdominal pain, 4 Aberrant (drug-related) behavior, 116–19, 118f Acetaminophen, 15, 16f Active functional evaluation, 26 Acupuncture, 104–5 Addiction, 115–16, 116f. See also aberrant (drug-related) behavior; risk assessment deﬁnition, 118f Adjuvant analgesics, 37, 85 Agitation, 89. See also anxiety Alcohol instillation, 105 Alfentanil, 68 Alternative medicine and therapies, 26, 36, 36t, 40 American Academy of Pain Medicine, 120, 121f Amitriptyline, 88f Analgesics, 15, 37. See also speciﬁc types additional, 37, 85 basal, 1, 14f increasing frequency of, 40 onset of action, 43t oral transmucosal opioid analgesics, 55–71 fentanyl, 58–68, 59f, 60t, 61f, 62t–63t, 64f, 65f, 66f, 67f responsiveness to, 26, 52, 93 rotation of, 37, 40, 40f timing for, 39 World Health Organization guidelines, 90 Anesthesia induction, 92 Anticipatory analgesia, 86 Anticonvulsants, 37, 40, 89–90, 89t Antidepressant drugs, 37, 86t, 87–88, 88f Anxiety, 20, 21f, 88f, 89. See also nervousness Anxiolysis, 92 Application-site irritation, 65 Around-the-clock medication, 14f, 41, 52 nonopioid, 85 starting dose for, 41–42

Assessment, 25–32, 27f, 29f–31f, 32f, 116–19, 118f. See also reassessment; risk assessment Breakthrough Pain Questionnaire, 28–31, 29f–31f comorbid condition assessment, 116f Likert assessment scale, 28 pain documentation sheet, 3t, 31–32, 32f public safety vs. patients’ interests, 42 risk, 111–22, 114t, 116f, 117f, 118f, 120t, 121f–122f tools for, 28–32, 29f–31f difﬁculty in using, 28 Ataxia, 89 Atomization device, 81

B Background pain, 1, 14f. See also chronic pain; end-of-dose failure breakthrough dose vs. background dose for, 50–52, 51f, 66f multimodal management of, 36 poorly controlled, 14f, 31 Balloon kyphoplasty, 105 Basal analgesic, 1, 14f Benzodiazepines, 92–93 opioids in combination with, 93 Bisphosphonates, 90 Blood sugar control, 16f. See also diabetes Bone metastases, 15f Bone pain, nonopioid pharmacotherapy for, 90 Bowel function, 16f constipation, 16f, 20, 88f, 88t diarrhea, 88f Breakthrough pain (BTP). See also background pain; chronic pain; pain background pain vs., 50–52, 51f, 66f

Breakthrough Pain Questionnaire, 28–31, 29f–31f case histories, 15f–16f characteristics, 17t–18t classiﬁcation, 2, 13–14 complications, 20–21, 21f, 21t deﬁnition, 1–2 demographics, 4 etiology, 7, 8t clinical features vs., 19 European Association for Palliative Care, 93 general features of, 16 management strategies, 41–42 mixed, 8t more than one type of, 26 multimodal management of, 36 neuropathic, 8t, 14, 16f, 19, 37 treatment guidelines for peripheral, 86t patterns of, 14f, 25, 32f, 50–52, 51f, 66f circadian variation, 19–20 post-surgery, 8t prevalence, 1, 3, 3t, 5t–6t Breakthrough pain: Deﬁnition, prevalence and characteristics (Portenoy and Hagen), 1, 3 Breakthrough Pain Questionnaire, 28–31, 29f–31f Bronchopulmonary route, 41, 43t, 76t, 81–82 BTP. See breakthrough pain Buprenorphine, 58f, 68–69 Bupropion (Wellbutrin), 86t

C CAM. See complementary and alternative medicine Cancer chronic pain from, 2–4, 3t, 5t–6t, 62t–63t circadian variation vs. pain intensity, 19–20

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Index

INDEX

126

Cancer (continued) -related BTP, 93 mood disorders vs., 20–21, 21f OTFC and FBT for, 61–71 -related neuropathic pain disorders, 89t stages of, 7 Capsaicin, 86t Carbamazepine, 86t, 89, 89t Celecoxib, 92t Celexa. See citalopram Cementoplasty/vertebroplasty, 105 Chemotherapy, BTP from, 8t Chronic pain. See also background pain from cancer, 2–4, 3t, 5t–6t, 62t–63t noncancer, 4–7, 6t Circadian variation, 19–20 Citalopram (Celexa), 86t Co-analgesics, 37, 85 Cognitive impairment, 20, 88t, 89 difﬁculty in using assessment tools, 28 Cold application, 36, 105 Comorbid condition assessment, 116f Complementary and alternative medicine (CAM) and therapies, 26, 36, 36t, 40 Complex regional pain syndrome, 7 Concomitant disease, 116f BTP from, 8t Constipation, 16f, 20, 88f, 88t Controlled-release oxycodone, 86t Controlled substances, 111–22, 114t, 116f, 117f, 118f, 120t, 121f–122f model policy for, 114t sample agreement form, 121f–122f Corticosteroids, 40 instillation of, 105 Cost effectiveness, 9, 20–21, 21t, 53 Coughing, 17t Cryoablation, 105

D Deep vein thrombosis, 20 Delirium, 19–20 Dental caries, 65 Depression, 20, 21f

antidepressants, 37, 86t, 87–80, 88f Desipramine, 87, 88f Diabetes, 16f neuropathy, 89t Diagnosis, 116f, 118f Diamorphine, 58f Diarrhea, 88f Diclofenac, 92t Differential diagnosis, 118f Dilantin. See phenytoin Distraction techniques, 36, 105 Dizziness, 42, 62t, 88f Documentation, 116f pain documentation sheet, 3t, 31–32, 32f Dolophine. See methadone Doxepin, 88f Drowsiness, 88f Drugs. See also medication; side-effect; speciﬁc medications accidental overdosing, 40 antidepressant, 37, 86t, 87–80, 88f Food and Drug Administration approval, 89 neuraxial drug delivery, 99–100 nonsteroidal anti-inﬂammatory, 40, 91–92, 92t OraVescent Drug Delivery Technology, 59f risk assessment, aberrant drug-related behavior, 116–19, 118f urine drug screen, 117f Dry mouth, 65, 88t, 89 Duloxetine, 16f, 86t, 88

E Effexor. See venlafaxine, extended release (Effexor) End-of-dose failure, 2, 3t, 13, 16f, 19, 39–40, 40f. See also rescue dose European Association for Palliative Care, 93 Ewing’s sarcoma, 15

F FBT. See fentanyl buccal tablet FDA. See Food and Drug Administration Fentanyl, 56, 59t, 60t. See also fentanyl buccal tablet; morphine; oral transmucosal fentanyl citrate

pharmacokinetic proﬁle, 60–61, 60t sublingual absorption of, 58f transdermal patch, 40, 40f, 51f, 63t transmucosal route for, 58–68, 59f, 60t, 61f, 62t–63t, 64f, 65f, 66f, 67f Fentanyl buccal tablet (FBT), 15f, 59f, 60t absorption of, 58–60, 59f clinical data, 61–68, 64f, 66f, 67f OTFC vs. FBT, 61f titration protocol, 66f, 67f modiﬁed-release, 56 opioid-tolerant patients, 67f pharmacokinetic proﬁle, 60t Fentora. See fentanyl buccal tablet (FBT) Fibromyalgia, 7 Food and Drug Administration (FDA) approval, 89 “Four A’s” of pain medicine, 116f Functional capacities (patients’), 20, 26 analgesics timed for, 39 assessment of, 116f environmental modiﬁcation for, 38 evaluation of, 26

G Gabapentin, 15, 86t, 89, 89t Gomez-Batiste, X., 3t

H Hagen, N. A., 1, 3 Headache, 7, 62t, 89 Heat application, 36, 105 Herpetic neuralgia, 89t History of patient, 25–26 with analgesics, 26, 52, 93 HIV-associated neuropathy, 89t Home setting (palliative care) patients, 5t, 15 environmental modiﬁcation for, 38 European Association for Palliative Care, 93 Hospice patients, 5t environmental modiﬁcation for, 38 Likert assessment scale used by, 28 Hospital patients, 5t, 6t costs vs. BTP, 21, 21t

I

M

IASP. See International Association for the Study of Pain Ibuprofen, 92t Imaging studies, 25 Imipramine, 87, 88f Immediate-release opioids, 39, 61f Immediate-release oral morphine sulphate (MSIR), 61f. See also morphine Incident pain, 3t, 13, 15f, 19, 20, 37–39, 38f, 39f Informed consent, 116f Inhalation (bronchopulmonary) route, 41, 43t, 76t, 81–82 Injections, patients’ dislike for, 43t, 44 Insomnia, 88f Intensity of pain, 14f, 20, 21f, 26 circadian variation vs., 19–20 FBT vs., 64f severe vs. moderate vs. slight, 18t Intermittent pain, 14f International Association for the Study of Pain (IASP), 4 Intramuscular route, 43t, 76t, 78 Intranasal route, 41, 76t, 79–81, 81f, 93 Intrapulmonary route, 41, 43t, 76t, 81–82 Intravenous route, 41, 43t, 76t, 78

MAD atomization device, 81f Management strategies, 3 5–44. See also speciﬁc medications breakthrough medication, 41–42 incident pain, 37–39, 38f, 39f multimodal, 36 nonpharmacological interventions, 36, 36t, 97–106 pain management vs. pain measurement, 28 pharmacological treatment, 35–36, 36t, 41–44, 43t spontaneous pain, 13, 15f, 19, 21, 37 surgical stabilization/orthotic devices, 38, 38f MAOIs. See monoamine oxidase inhibitors Massage, 36, 105 Medical records, 114t Medication, 35–36, 36t, 41–44, 43t. See also drugs; speciﬁc medication; speciﬁc type of pain acceptability of, 43–44, 43f accidental overdosing, 40 adherence to, 42–43 around-the-clock, 14f, 41, 52 nonopioid, 85 starting dose for, 41–42 effect/side-effect proﬁle, 37, 40 “Four A’s” of, 116f peak effect of, 39, 41, 92t prescription of, 42 Meloxicam, 92t Methadone (Dolophine), 40, 49t, 58f, 69–70, 86t Methylphenidate, 37 Midazolam, 92–93 Mixed breakthrough pain, 8t, 14 Mobility, decreased, 20–21, 21f Monoamine oxidase inhibitors (MAOIs), 88 Mood disorders, 20–21, 21f Morphine, 41, 49t, 58f, 70. See also fentanyl; oral transmucosal opioid analgesics immediate-release oral morphine sulphate, 61f plasma concentration of, 50f

J Joint stiffness, 20

K Ketamine, 93–94 Ketorolac, 92t Kyphoplasty, balloon, 105

L Lamotrigine, 86t, 89t Laser ablation, 105 Laws, controlled substance, 111–15, 114t. See also controlled substances

Movement-related pain. See incident pain MSIR. See immediate-release oral morphine sulphate Multidimensional measurement scales, 26–28, 27f Muscle wasting, 20

INDEX

Lidocaine, 86t Likert assessment scale, 28 Lorazepam, 93 Low back pain, 4, 15f, 17t

N Naproxen, 92t Nasal route, 41, 43t, 76t, 79–81, 81f, 93 Nausea, 20, 42, 62t, 88f, 89. See also vomiting Nervousness, 88f. See also anxiety Neuraxial drug delivery, 99–100 Neuroablation, 102–4 Neurological examination, 26. See also neuropathic breakthrough pain; neuropathy Neuromodulation, 101–2, 101f Neuropathic breakthrough pain, 8t, 14, 16f, 19, 37 treatment guidelines for peripheral, 86t Neuropathy, 7 nonopioid pharmacotherapy for, 86–90, 88f, 89t post-herpetic neuralgia, 89t trigeminal neuralgia, 89t Nitrous oxide, 94 NNH. See number needed to harm NNT. See number needed to treat Nociceptive breakthrough pain, 8t, 13, 19 Nonopioid pharmacotherapy anticonvulsants, 37, 40, 89–90, 89t antidepressants, 37, 86t, 87–80, 88f benzodiazepines, 92–93 bisphosphonates, 90 bone pain management, 90 ketamine, 93–94 midazolam, 92–93 neuropathic pain management, 86–90, 88f, 89t nitrous oxide, 94 nonsteroidal antiinﬂammatory drugs, 40, 91–92, 92t role of, 85–86 Nonpharmacological interventions, 36, 36t, 97–106 acupuncture, 104–5

127

Hydrocodone, 16f, 39 Hydromorphone, 39, 41, 49t, 58f, 69 Hypnotherapy/hypnosis, 105

INDEX

128

Nonpharmacological interventions (continued) alcohol instillation, 105 balloon kyphoplasty, 105 cementoplasty/vertebroplast y, 105 cold application, 36, 105 corticosteroid instillation, 105 cryoablation, 105 distraction techniques, 36, 105 general principles, 97–98 heat application, 36, 105 hypnotherapy/hypnosis, 105 laser ablation, 105 massage, 105 neuraxial drug delivery, 99–100 neuroablation, 102–4 neuromodulation, 101–2, 101f peripheral procedures, 98–99 phenol instillation, 105 radiofrequency ablation, 105 relaxation techniques, 105 Nonsteroidal antiinﬂammatory drugs (NSAIDS), 40, 91–92, 92t Nonvolitional pain, 2, 13 Norepinephrine serotonin reuptake inhibitors (NSRIs), 88 Nortriptyline, 87, 88f NSAIDs. See nonsteroidal anti-inﬂammatory drugs NSRIs. See norepinephrine serotonin reuptake inhibitors Number needed to harm (NNH), 87, 89, 90 Number needed to treat (NNT), 87, 89, 90

O Onset of action (analgesia), 43t Onset of pain, 18t, 25 Opioid-responsive pain, 26, 52, 93 Opioid therapy. See also oral opioids; oral transmucosal opioid analgesics dose increase, 38 immediate-release, 39, 61f oral, 48t, 47–53, 49t, 50f, 51f patient’s responses to/ concerns about, 26, 52, 93 risk assessment, 111–22, 114t, 116f, 117f, 118f, 120t, 121f–122f rotation of, 37, 40, 40f

routes for administering, 41 short-acting, 37 Opioid therapy agreement, 117f, 119–22, 120t, 121f–122f sample, 121f–122f Opioid-tolerant patients, 67f Oral mucosa, 55–56. See also oral route Oral opioids, 48t, 47–53, 49–52, 49t, 50f, 51f. See also opioid therapy; oral transmucosal opioid analgesics acceptability to patient, 52–53 background dose vs. breakthrough dose, 50–52, 51f, 66f combination products, 48t cost effectiveness of, 53 drug considerations, 49–52, 51f pharmacokinetics vs. breakthrough pain pattern, 52 plasma concentration of morphine sulfate, 50f route considerations, 47–49 Oral route, 41–42, 43t. See also oral opioids; routes of medication administration Oral transmucosal fentanyl citrate (OTFC), 39, 41 absorption of, 58, 58f, 59f clinical data, 61–68, 62t–63t, 65f, 66f, 67f MSIR vs. OTFC, 61f OTFC vs. FBT, 61f titration protocol, 66f, 67f dry mouth from, 65 opioid-tolerant patients, 67f pharmacokinetic proﬁle, 60–61 Oral transmucosal opioid analgesics, 55–71. See also morphine; oral opioids alfentanil, 68 buprenorphine, 58f, 68–69 fentanyl, 58–68, 59f, 60t, 61f, 62t–63t, 64f, 65f, 66f, 67f hydromorphone, 69 methadone, 40, 49t, 58f, 69–70, 86t oxycodone, 70 sufentanil, 70–71 OraVescent Drug Delivery Technology, 59f Orthostatic hypotension, 88t Orthotic devices, 38, 39f OTFC. See oral transmucosal fentanyl citrate

Outcome measurement, 26–28, 27f Overdosing, 40 Oxcarbazepine, 89t Oxycodone, 15f, 39, 49t, 58f, 70, 86t controlled release, 86t Oxymorphone, 39, 49t

P Pain. See also breakthrough pain; chronic pain; site of pain American Academy of Pain Medicine, 120, 121f background, 1, 14f, 31, 36, 50–52, 51f, 66f cancer-related, 2–4, 3t, 5t–6t, 7, 19–20, 61–71, 62t–63t, 89t, 93 mood disorders vs., 20–21, 21f end-of-dose failure, 2, 3t, 13, 16f, 19, 39–40, 40f exacerbating vs. relieving factors, 26 function capacities vs., 116f incident, 3t, 13, 15f, 19, 20, 37–39, 38f, 39f management vs. measurement, 28 mixed breakthrough, 8t, 14 nonvolitional, 2, 13 opioid-responsive, 26, 52, 93 paroxysmal, 3t post-stroke, 89t precipitants of, 3t, 32f procedural, 2, 13 quality of, 25 radiation of, 25, 26 spontaneous, 13, 15f, 19, 21, 37 temporal patterns of, 14f, 19–20, 25, 32f, 50–52, 51f, 66f circadian variation, 19–20 transitory, 31 visceral, 13, 19 Pain documentation sheet, 3t, 31–32, 32f Pain measurement scales, 26–28, 27f Palliative care patients, 5t, 15 environmental modiﬁcation for, 38 European Association for Palliative Care, 93 Palpation, 26 Paroxetine (Paxil), 86t Paroxysmal pain, 3t Patient history, 25–26 with analgesics, 26, 52, 93

Q Quality of life, 9, 20–21, 21f, 25–26 after therapeutic intervention, 27, 27f Quality of pain, 25. See also pain

R Radiation of pain, 25, 26 Radiation therapy, BTP from, 8t Radiofrequency ablation, 105 Radiotherapy, 15 Reactive vs. proactive strategies (drug abuse risk), 117f Reassessment procedure, 26–28, 27f, 116f. See also assessment; risk assessment recommendations for opioid rotation, 37, 40, 40f

S Salivary-gland dysfunction, 56 Sedation risks, 42, 88t, 89 Selective norepinephrine serotonin reuptake inhibitors (NSRIs), 88 Senna preparation, 16f. See also bowel function Sexual dysfunction, 88t

SIADH. See syndrome of inappropriate antidiuretic hormone Side-effect, 37, 42. See also drugs; speciﬁc medication; speciﬁc side-effect dental caries, 65 dosage increase vs., 40 dry mouth, 65, 88t, 89 gabapentin, 89 intranasal route vs., 80 respiratory depression, 65 tricyclic antidepressants, 88f Site of pain, 25, 32f abdominal, 4 complex regional pain syndrome, 7 ﬁbromyalgia, 7 headache, 7, 62t, 89 low back, 4, 15f, 17t neuropathies, 7 neuropathy, 7, 86–90, 88f, 89t pelvic, 4, 7 Sleep disorders, 20–21, 42, 62t Sling, 38, 39f Social and societal complications, 20–21, 21f Somatic pain, 13, 19 Somnolence, 42, 62t Spontaneous pain, 13, 15f, 19, 21, 37 Steroid. See also routes of medication administration cortico-, 40, 105 injection, 15 nonsteroidal antiinﬂammatory drugs, 40, 91–92, 92t Stigmatization, 20 Stroke, pain from post-, 89t Subcutaneous route, 41, 43t, 76t, 78–79 Sublingual route, 43t Sufentanil, 70–71 Supplemental medication, 41–44, 43t Surgery BTP from, 8t stabilization of tissues, 38, 38f Symptoms, 116f Syndrome of inappropriate antidiuretic hormone (SIADH), 89

T Tachycardia, 88t TCAs. See tricyclic antidepressants Temporal patterns of pain, 14f, 25, 32f

INDEX

Rectal route of administration, 43t, 76t, 77, 93 Regulatory issues (opioid therapy), 111–15, 114t Relaxation techniques, 36, 105 Relieving factors, 36t. See also management strategies Renal cell carcinoma, 15f Rescue dose, 14f, 40f, 41–44, 43t, 86. See also end-of-dose failure discontinuation of, 117f Respiratory depression, 42, 65 Responsiveness to analgesics, 26, 52, 93 Risk assessment, 111–22, 114t, 116f, 117f, 118f, 120t, 121f–122f. See also assessment; reassessment procedure aberrant drug-related behavior, 116–19, 118f opioid therapy, 111–22, 114t, 116f, 117f, 118f, 120t, 121f–122f agreement form, 117f, 119–22, 120t, 121f–122f sedation, 42, 88t, 89 structuring therapy to reduce risk, 115–16, 116f Routes of medication administration, 41. See also speciﬁc medications inhalation (bronchopulmonary), 41, 43t, 76t, 81–82 muscular, 76t, 78 nasal, 76t, 79–81 neuraxial drug delivery, 99–100 oral transmucosal opioids, 56–57, 58f patient’s acceptability toward, 43t rectal, 43t, 76t, 77, 93 subcutaneous, 41, 43t, 76t, 78–79 sublingual route, 43t transdermal, 40, 40f, 51f, 63t, 79 venous, 76t, 78

129

Paxil. See paroxetine Peak effect, 39, 41, 92t Pelvic pain, 4, 7 Pharmacological treatment, 35–36, 36t, 41–44, 43t. See also speciﬁc medications Pharmacy, 117f Phenol instillation, 105 Phenytoin (Dilantin), 86t, 89t Physical exam, 25–26. See also history of patient Pneumonia, 20 Polysling, 38, 39f Portenoy, R. K., 1, 3 Post-herpetic neuralgia, 89t Precipitating event, 3t, 32f Pregabalin, 86t, 89, 89t Pregnancy, 120 Prescription, 42, 117f. See also risk assessment Pressure sores, 20 Proactive vs. reactive strategies (drug abuse risk), 117f Procedural pain, 2, 13 Prostheses, 38 Psychological assessment, 116f. See also assessment Psychological complications, 20–21, 21f, 26 Psychotherapy, 117f Public safety, side effects of opioids vs., 42 Pulmonary, intra-, route of administration, 41, 43t, 76t, 81–82

INDEX

130

Temporal patterns of pain (continued) breakthrough dose vs. background dose, 50–52, 51f, 66f circadian variation, 19–20 TENS. See transcutaneous nerve stimulation Topamax. See topiramate Topiramate (Topamax), 86f Tramadol, 15, 86t Transcutaneous nerve stimulation (TENS), 36 Transdermal fentanyl patch, 40, 40f, 63t background, vs. breakthrough oral morphine, 51f Transdermal route of administration, 40, 40f, 51f, 63t, 79

Transitory pains, 31 Treatment agreement, 116f Tricyclic antidepressants (TCAs), 37, 86t, 87–80, 88f Trigeminal neuralgia, 89t

U Uncontrolled background pain, 14f, 31 Urinary retention, 88t Urine drug screen, 117f

V Venlafaxine, extended release (Effexor), 86t Vertebroplasty, 105 Visceral pain, 13, 19 Vision impairment, 88t, 89

Volitional pain, 2, 13, 20 Vomiting, 42, 62t, 89. See also nausea

W Wellbutrin. See bupropion WHO analgesic guidelines. See World Health Organization analgesic guidelines Work status, 20 World Health Organization (WHO) analgesic guidelines, 90

Z Zeppetella, G., 3t, 32f