Treating Alcohol and Drug Abuse An Evidence Based Review Edited by M. Berglund, S. Thelander, E. Jonsson
Treating Alcohol and Drug Abuse. Edited by M. Berglund, S. Thelander, E. Jonsson Copyright c 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 3-527-30682-X
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Treating Alcohol and Drug Abuse An Evidence Based Review
Edited by Mats Berglund, Sten Thelander, Egon Jonsson
Editors Prof. Dr. Mats Berglund University Hospital MAS Alcohol and Drug Clinic S-20502 Malmö Sweden Dr. Sten Thelander Project Manager, SBU Box 5650 S-11486 Stockholm Sweden Prof. Dr. Egon Jonsson Executive Director, SBU Box 5650 S-11486 Stockholm Sweden
This book was carefully produced. Nevertheless, editors, authors and publisher do not warrant the information contained therein to be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate. Library of Congress Card No.: applied for A catalogue record for this book is available from the British Library. Bibliographic information published by Die Deutsche Bibliothek Die Deutsche Bibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data is available in the Internet at http://dnb.ddb.de. c 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim All rights reserved (including those of translation in other languages). No part of this book may be reproduced in any form – nor transmitted or translated into a machine language without written permission from the publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law. Printed in the Federal Republic of Germany. Printed on acid-free paper.
Composition Hagedorn Kommunikation, Viernheim Printing betz-druck GmbH, Darmstadt Bookbinding Litges & Dopf Buchbinderei GmbH, Heppenheim Cover Design Grafik Design Schulz, Fußgönheim ISBN
3-527-30682-X
Evidence Preface
Preface (Background and Methodology) Evidence Based Medicine and the Swedish Council on Technology Assessment in Health Care
Like many other governments in the early 1980s, the government of Sweden faced an accelerating number of emerging technologies and medical innovations that were being incorporated into its health care system. The consequent (and alarming) increase in the cost of health care became an urgent concern. This situation led in 1987 to the founding of the Swedish Council on Technology Assessment in Health Care (the official acronym is SBU). As its name implies, SBU assesses the technologies and methods used in providing health services. These assessments are systematic evaluations that summarize the medical and scientific literature from around the world. Leading experts, mostly from Sweden but also from other countries, are involved in conducting and reviewing the SBU assessment projects. While striving to keep the needs of the patient (the whole patient) at the center of health care planning, each assessment project investigates not only the medical aspects of a treatment option, but also its economic, social, and ethical aspects. Assessment projects aim to identify the most effective and, if possible, the most cost-effective interventions. They also aim to identify the technologies already in use that are not adequately supported by scientific evidence. Assessment findings can be used by clinicians, administrators, and policy makers to assure the most appropriate allocation of the limited resources available to health care. A Project Group comprising 13 investigators, including a statistician, was selected to assess the wealth of scientific literature on the treatment of alcohol and drug problems. The Group performed the initial, integrated literature search with guidance from a specially trained librarian. A checklist for rating quality was developed, based on already available instruments. Meta-analytic techniques were optional, but were applied where possible. In most areas it was possible to draw conclusions based solely on randomized controlled trials (RCTs). Based on the completed reviews and guided by comments from several external reviewers, the Chair of the Project Group and SBU staff members wrote an Executive Summary. The SBU Board of Directors and the SBU Scientific Advisory Committee approved the Summary and Conclusions.
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Preface
The scope of the SBU review was extremely comprehensive, covering all clinically relevant RCTs in the fields of alcohol and narcotics. Because of the large number of studies, the detailed type of analysis often found in a Cochrane review of a small and narrowly defined area was not possible.
Quality Assessment
Many methods for assessing the quality of studies have been described, ranging from a few basic aspects to elaborate scales with weighting of the individual items. The purpose of quality rating is to identify sources of bias, which could endanger the results of the study. In many cases, aspects of external validity or generalizability are also included in the quality assessment. The empirical value of quality assessment remains uncertain. Some, but not all, studies have found larger effects when randomization was unreliable, blinding was not accomplished, or noncompleters were unaccounted for. Our checklist was developed on the basis of already available checklists, and included items related to both internal and external validity. Each item could score from 1 to 3, with 3 representing the highest quality. A scoring manual was also developed. The maximum score possible was 30 for individual studies and 33 for multicenter studies. The summary score was primarily used as a qualitative measure, and was never used to exclude studies or to give them different weights in the meta-analyses. Because of time constraints, not all studies were read by two independent readers. This is a potential source of bias. In an attempt to reduce this risk, studies selected via a random sample were read by each member of the Project Group, and a consensus was reached concerning ratings of the different items. Most large and new studies were read by several members of the Project Group.
Meta-analytic Procedures
The use of formal meta-analytic procedures was optional, but was to a considerable extent related to the quantity or quality of studies in the areas reviewed. Meta-analyses were performed in the chapters on psychosocial treatment of alcohol dependence and drug dependence and in those on medication for drug dependence, and on some treatments in the chapter on medication for alcohol dependence. Metaanalyses were not performed in the other chapters. We decided to use the standardized mean difference effect sizes as the general outcome measure throughout the entire report, with very few exceptions. The Hedges correction was used (Hedges and Olkin, 1985) to adjust for small sample size bias. The correction factor is 1–[3/(4n–9)], where n equals the total number of participants. Although no strict clinical interpretation of effect sizes is agreed upon, many apply the convention that 0.2 is a small but relevant effect, 0.5 a moderate effect, and 0.8 a large effect.
Preface
For categorical data we first calculated the odds ratio and then transformed it to d according to Shadish and Haddock (1994). Intention-to-treat analysis (ITT) was applied when the primary outcome was calculated. We defined intention-to-treat as all patients randomized. If intention-totreat results were not available, an attempt was made to recalculate the figures (presented in the individual study section). If an ITT analysis was not possible, we used the results of the completers analysis. Outcome variables as similar as possible were used in the separate chapters of the analysis. The outcomes could vary among the chapters and also for different analyses within a chapter. The main variables were the abstinence rate and the number of abstinence days in the alcohol section. Some analyses used the rate of return to heavy drinking and number of heavy drinking days. In the chapters on drug dependence, two outcome variables were used concurrently. Those variables were abuse and retention rate in treatment programs. In most studies, especially the older studies on alcohol, no primary outcome variable was defined. Generally, the choice of outcome variables was made as similar as possible for the different studies in the separate analyses. In most of the studies that used pharmacological treatment, the outcome was defined as that at the end of the treatment period. Analysis was generally performed without attempts to standardize the duration of treatment. The psychosocial treatment studies usually used outcome after a follow-up period. The period was chosen to be as constant as possible for the different studies in the separate analyses. Aggregated effect sizes were computed with the Comprehensive Meta-analysis Software Program (Borenstein et al., 1998). The different meta-analytic calculations were tested for heterogeneity using the same program. If the studies were homogenous, a fixed model was used. If, however, heterogeneity was present, a search for moderator effects was initially performed. If no obvious moderator could be identified, the results of a random-effects model were presented in addition to those from the fixed-effects model. The moderators were tested for significances using the same meta-analytic program. Publication bias is always a reason for concern. The simple, but not completely reliable, funnel-plot methodology was used in the meta-analyses of psychosocial interventions for drug dependence. No signs of publication bias were evident in the opiate studies, and a slight tendency was found in the cocaine studies.
English Edition
The English language edition of the report presented here includes papers that were published after the Project Group had completed their literature search for the Swedish edition. Most of the chapters include the new papers as an addendum. In the chapter on pharmacotherapy of alcohol dependence, however, the new papers have been integrated in the text. The meta-analytic methodology has been refined and developed (Borenstein et al., 1998). Some inadequate calculations
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of effect sizes in the original Swedish version have been corrected. Because of the lack of evidence for cost-effectiveness of particular interventions, a section on economic aspects that appeared in the Swedish version has been excluded in the English edition.
References
Borenstein M, Rothstein H. Comprehensive Meta Analysis. A Computer Program for Systematic Reviews. Biostatä, Englewood, 1998. Hedges LV, Olkin I. Statistical methods for meta-analysis. Orlando, Fl., Academic Press, 1985. Shadish WR, Haddock KC. Combining estimates of effect size. In: Cooper H, & Hedges EV (Eds): The handbook of research synthesis. New York, Russel Sage Foundations pp. 26-281, 1994.
Treating Foreword
Treating Alcohol and Drug Abuse – An Evidence Based Review Foreword by Henry R. Kranzler, M. D. It is a challenge to provide a suitable introduction for a work as ambitious as that undertaken here by The Swedish Council on Technology Assessment in Health Care (SBU). The Council and the contributors to this volume are to be commended for their diligence, hard work, and courage in bringing to fruition an effort of this magnitude. The numerous scientific reviewers of the work also deserve credit for their important contribution. For much of its history, the field of alcohol and drug abuse treatment has been steeped in lore and tradition. Empirical research has not been seen as a necessary basis for clinical practice in this area. During the past decade, however, interest in evidence-based practice in medicine generally and the increasing “medicalization” of substance abuse treatment have led to a greater emphasis on the scientific method to generate practice guidelines for the diagnosis and treatment of addictive disorders. Most notably, the randomized clinical trial has become the agreed-upon standard in substance abuse treatment research. In large measure, however, evidence-based treatments for substance use disorders have lagged behind the treatment of other disorders, including psychiatric disorders such as schizophrenia and mood disorders. The current volume, which is comprehensive and detailed, should help to narrow this gap. The volume, consisting of 10 chapters, covers a full range of topics in alcohol and drug abuse treatment. It begins with a review of interventions for hazardous drinking. The pharmacological treatment of alcohol withdrawal is covered next. Separate chapters on the psychosocial and pharmacological treatment of alcoholism follow. A chapter on the long-term course of alcohol and drug dependence provides the transition to four chapters on the treatment of drug dependence. As is true for alcohol dependence, there is a separate chapter on psychosocial treatments for drug dependence. Three chapters on the pharmacological treatment of drug dependence (i.e., treatment of opioid withdrawal, treatment of opioid dependence and treatment of cocaine dependence) follow. A final chapter reviews the literature on substance abuse during pregnancy and the neonatal period. Three appendices provide a list of the contributors and scientific reviewers, the criteria used to rate the quality of the articles reviewed and guidelines employed to estimate effect size.
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Foreword
This volume is an English translation of the work that was originally published in Swedish. Not all reviewers of the Swedish version of this magnum opus agree that the volume is as important a contribution as I believe it to be. Poikolainen (2002) criticized the Swedish version of this work as containing errors that cast doubt on the validity of the main findings. Although many of the problems attributed to the Swedish version of the review have been corrected in the English translation, the impact on the main findings of those corrections was not great, arguing against the criticism leveled by Poikolainen. I believe that this volume should be required reading for anyone who seeks to be knowledgeable in the treatment of alcohol and drug dependence. Although the summary and conclusions can be read rather easily, it is clear that the overview provided by that brief section serves only to orient the reader. The full measure of this work is in the detailed information that is contained in the 10 chapters that follow.
Reference
Poikolainen, K. A nice try that fails: The Swedish Council on Technology Assessment in Health Care (SBU) evaluation of the effect of treatment of alcohol and drug problems: The epidemiologist’s view. Alcohol & Alcoholism 37:416–418, 2002.
Contents
Contents Preface V Foreword IX 1
1.1 1.2 1.3 1.3.1 1.3.2 1.3.3 1.3.4 1.3.5 1.4 1.4.1 1.4.2 1.4.3 1.4.4 1.4.5 1.5 1.5.1 1.5.2 1.6 1.6.1 1.7 1.8 1.9
Intervention against Hazardous Alcohol Consumption – Secondary Prevention of Alcohol Problems 1 Introduction 1 Aim 2 Methods 2
Selection of Studies, Inclusion and Exclusion Criteria 2 Search Strategy 2 Outcome Measures 3 Rating Scientific Quality 3 Analyzing the Results 3 Results 4 Literature Search 4 Previous Reviews and Meta-Analysis 4 Randomized and Controlled Studies 5 Studies with Positive Outcome (Measures) Presented in Order of Quality 16 Studies without Significant Effects, Presented in Order of Quality 23 Analysis of the Overall Results of the Reviewed Studies 26 Studies with a Positive Outcome 26 Studies which Showed No Effects 36 Important Aspects of Brief Intervention 36 Analysis of Special Groups 36 Problems with Dropout in Studies 37 Problems with Implementation 37 Summary 38 Glossary 38 References 39
Treating Alcohol and Drug Abuse. Edited by M. Berglund, S. Thelander, E. Jonsson Copyright c 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 3-527-30682-X
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2 2.1 2.1.1 2.1.2 2.1.3 2.1.4 2.1.5 2.1.6 2.1.7 2.1.8 2.2 2.2.1 2.2.2 2.2.3 2.3 2.3.1
2.3.2 2.4 2.5 2.5.1 2.5.2 2.5.3 2.5.4 2.5.5 2.5.6 2.5.7 2.6 2.6.1 2.7 2.8 2.9 2.10 2.11 2.12 2.13 2.14
3 3.1 3.2 3.2.1 3.2.2 3.2.3
Psychosocial Treatment for Alcohol Dependence 43
Introduction 43 Earlier Reviews 43 Assessing the Effects of Different Methods 43 Methodological Deficiencies and Problems 45 Treatment Methods 45 Treatment Effects 47 Questions Addressed 48 Intensity and Aftercare 49 Subgroups of Alcohol Dependence 49 Method and Material 50 Search Strategies 50 Result Protocol 50 Meta-analysis 51 Results 51 Does psychosocial treatment have any effect? Comparisons with no treatment 51 Are some methods superior to others? 54 Motivational Methodology 54 Methods Specifically Aimed at Changing the Drinking Problem Itself 56 Cognitive Behavioral Therapy (CBT) 56 Broad Spectrum Treatment with CBT Focus 57 CRA Treatment – Community Reinforcement Approach 59 Self-control Training 61 Cue Exposure 62 Other 63 Twelve-Step Treatment 63 Methods Aimed at the Factors Behind Alcohol Dependence 65 Dynamically Oriented Treatments 65 Standard Treatment 67 Marital Therapies and Interventions Focused on Family Members 69 Studies Showing Matching Results 70 Comparing the Intensity of Treatment and Aftercare 73 Subgroups of Alcohol-Dependent Patients 75 Therapist Factors 78 Gender-related Effects 79 Renewed Literature Search 82 References 178 Pharmacotherapy for Alcohol Withdrawal Syndrome 189
Introduction 189 Methods 190 Selection Criteria 190 Diagnostic Criteria and Outcome Measures 190 Search Strategy 190
Contents
3.2.4 3.3 3.3.1 3.3.1.1 3.3.1.2 3.3.1.3 3.3.1.4 3.3.1.5 3.3.1.6 3.3.1.7 3.3.1.8 3.3.1.9 3.3.2 3.3.2.1 3.3.2.2 3.3.2.3 3.3.2.4 3.3.2.5 3.3.2.6 3.4 3.5
4 4.1 4.2 4.2.1 4.2.2 4.2.3 4.3 4.3.1 4.3.2 4.4 4.5 4.6 4.6.1 4.6.2 4.6.3 4.6.4 4.6.5 4.6.6 4.6.7 4.6.8 4.6.9 4.7
Results 191 Included Studies 191 Treatment of Alcohol Withdrawal 191 Benzodiazepines 191 Chlormethiazole and Anti-Epileptics 204 Imidazoline Agonists 214 Beta-Receptor Antagonists 220 Nitrous Oxide 221 Thiamine 221 Psychological Treatment 228 Other Treatment 228 Meta-analyses and Reviews 229 Treatment of Delirium Tremens 229 Barbiturates 229 Benzodiazepines 234 Chlormethiazole 234 Imidazoline Agonists 234 Other Treatment 235 Meta-analyses 235 Discussion 235 Summary 239 References 240 Pharmacotherapy for Alcohol Dependence 247
Introduction 247 Methods 248 Search Strategies 248 Complementary Search 248 Unpublished Studies 249 Analytical Principles 249 Categorization 249 Target Group and Treatment Goals 249 Overview of Tables 250 Overview of Included Studies 252 Results 252 Aversive Agents 252 Antipsychotic Drugs 260 Dopamine Agonists 260 SSRI Agents 261 Other Agents with Effect on the 5-HT System 268 Acamprosate 268 Naltrexone and Nalmefene 269 Other Agents 289 Lithium 289 Comorbidity 294
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4.7.1 4.8 4.8.1 4.8.2 4.8.3 4.8.4 4.9
5 5.1 5.2 5.2.1 5.2.2 5.2.3 5.3 5.4 5.4.1 5.5 5.6 5.7
6 6.1 6.2 6.2.1 6.2.1.1 6.2.1.2 6.2.1.3 6.2.2 6.2.3 6.2.4 6.3 6.3.1 6.3.2 6.3.3 6.4 6.4.1 6.4.2 6.4.3 6.4.4 6.4.5 6.4.6 6.5
Anti-Depressive Treatment and Psychiatric Comorbidity (Depression) 294 Discussion 295 Acamprosate and Naltrexone 295 Aversive Agents 295 Other Agents 302 Treatment of Comorbid Conditions 302 Conclusions 302 Reference 303 The Long-Term Course in Alcohol and Drug Dependence 313
Introduction 313 Methods 314 Search Strategies 314 Inclusion Criteria 314 Search Results 314 Epidemiological Studies 315 Longitudinal Clinical Trials 317 Long-Term Course in Alcohol Dependence 317 Long-Term Course in Heroin Dependence 319 Alcohol and Drug Abuse as a Chronic Condition 321 Conclusions 322 References 323 Psychosocial Treatment for Drug Dependence 325
Introduction 325 Psychosocial Methods – a Review 326 Supportive Treatment Methods 326 Institutional Treatment 327 Structure-Enhancing Interventions 328 Other Supportive Intervention and Treatment Methods 328 Re-educative Methods 329 More Extensive Psychotherapy 331 Reconstructive Therapy 333 Research Considerations 335 Observational Studies 335 Questions 335 Theoretical Approach 335 Methods 336 Search Strategies 336 Representativity 336 Publication Bias 337 Quality Rating 338 Classifying and Synthesizing the Material 338 Data Analysis 339 Results 340
Contents
6.5.1 6.5.1.1 6.5.1.2 6.5.1.3 6.5.2 6.5.2.1 6.5.2.2 6.5.2.3 6.5.3 6.5.3.1 6.5.3.2 6.5.3.3 6.5.4 6.5.4.1 6.5.4.2 6.5.4.3 6.5.4.4 6.5.5 6.5.5.1 6.5.5.2 6.5.6 6.5.6.1 6.5.6.2 6.5.6.3 6.5.6.4 6.5.7 6.5.7.1 6.5.7.2 6.6
7 7.1 7.2 7.3 7.3.1 7.3.1.1 7.3.1.2 7.3.1.3 7.3.1.4 7.3.1.5 7.3.2
Meta-analysis of Treatment for Opiate Dependence 340 Reduction of Heroin Abuse 341 Retention in Opiate Studies 344 Conclusions 344 Meta-analysis of Interventions in Cocaine Dependence 344 Reduction of Cocaine Abuse 345 Retention in Cocaine Studies 350 Conclusions 351 Limitations in Interpreting the Results of Meta-analyses 351 Combination Therapy with Antidepressants and Cognitive Therapy in Cocaine Dependence 351 Meta-analysis of Interventions in Cannabis Dependence 354 Conclusions 354 Randomized Studies of Institutional Treatment 355 Meta-analysis of Institutional Treatment with Opiate Abuse as Outcome Measure 355 Meta-analysis of Institutional Treatment with Reduced Opiate and Cocaine Abuse as Outcome Measure 355 Retention in Institutional Treatment 358 Conclusion 359 Structure-enhancing Interventions 359 Treating Mentally Ill and Homeless Abusers 362 Conclusions 363 Before-and-After Changes in Treatment 363 Studies of Opiate Abuse 363 Studies of Cocaine Abuse 363 Studies of Institutional Treatment 368 Conclusions 368 Effects on Factors other than Abuse 369 Treatment Focus 369 Limitations of Randomized Treatment Studies 369 Appendix 369 References 404 Pharmacotherapy for Opioid Withdrawal 415
Background 415 Principles of Withdrawal Treatment 416 Non-Rapid 417 Adrenergic Agonists Clonidine (unless otherwise stated) versus 417 Placebo 417 Methadone 417 Bubrenorphine 418 Doxepin 418 Other Adrenergic Agonists 418 Opioid Agonists Methadone versus 420
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7.3.2.1 7.3.2.2 7.3.2.3 7.3.2.4 7.3.2.5 7.4 7.4.1 7.4.1.1 7.4.1.2 7.4.1.3 7.4.2 7.4.2.1 7.5 7.5.1 7.5.2 7.5.3 7.6 7.7 7.8 7.8.1 7.8.1.1 7.8.1.2 7.8.1.3 7.8.2 7.8.3 7.8.4 7.8.5
8 8.1 8.2 8.2.1 8.2.2 8.2.3 8.2.4 8.2.4.1 8.2.4.2 8.3 8.3.1
Placebo 420 Bubrenorphine 420 Propoxyphene 420 Chlordiazepoxide 420 Summary (Non-Rapid) 421 Rapid 438 Adrenergic Agonist + Opioid Antagonists Clonidine versus Clonidine + naltrexone/naloxone versus 438 Placebo 438 Buprenorphine 438 Methadone 438 Partial opioid agonist + opioid antagonist + adrenergic agonist 439 Summary (Rapid) 439 Ultra-Rapid (Adrenergic agonist) + opioid antagonist under anesthesia, or under different levels of sedation 448 Naloxone versus Placebo 449 (Clonidine) + Naloxone/Naltrexone under Light Sedation versus Deep Sedation 448 Summary (Ultra-Rapid) 448 Reviews 449 Conclusion 452 Reference 453 Appendix 455 Non-Rapid 455 Adrenergic Agonists 455 Opioid agonists 458 Dopamine agonists 458 Rapid Adrenergic agonist + opioid antagonists 458 Ultra-Rapid (Adrenergic agonists) + opioid antagonists under anesthesia 460 Reviews 462 Conclusion 462 Appendix References 463 Pharmacotherapy for Opioid Dependence 465
Background 465 Agonists 467 Agonists (Including Partial) Versus Control 467 Agonists versus Other Agonists 469 Agonists versus Antagonists 472 Agonists versus the Same Agonists 472 Distribution Studies 472 Dose Level Studies 473 Antagonists 498 Antagonists versus Control 498
Contents
8.3.2 8.3.2.1 8.4 8.4.1 8.5 8.6 8.7 8.7.1 8.7.2 8.7.3 8.7.4 8.8 8.8.1 8.8.1.1 8.8.1.2 8.8.1.3 8.8.2 8.8.2.1 8.8.2.2 8.8.2.3 8.8.2.4
9 9.1 9.2 9.2.1 9.2.1.1 9.2.1.2 9.2.1.3 9.2.1.4 9.2.2 9.2.3 9.2.4 9.3 9.3.1 9.3.2 9.4 9.4.1 9.4.2 9.4.3 9.4.4 9.5 9.6
Antagonists versus the Same Antagonists 499 Distribution Studies 499 Adjunctive Treatment with Antidepressants for Depressive Disorders 506 Antidepressants versus Control 506 Meta-Analysis 506 Reviews 512 Conclusion 512 Agonists, Including Partial 512 Antagonists 513 Antidepressants 513 Other Illegal Drugs 513 References 514 Appendix 519 Agonists 519 Agonists (Including Partial) versus Control 519 Agonists versus Other Agonists 519 Agonists versus the Same Agonists 519 Antagonists 526 Antagonists versus Control 526 Antagonists versus the Same Antagonists 528 Meta-Analysis 528 Conclusion 529 Appendix References 530 Pharmacotherapy for Cocaine Dependence 533
Background and Pharmacological Principles 533 Long-term Pharmacotherapy in Cocaine Dependence 535 Antidepressants 535 Tricyclic antidepressants 535 SSRI 536 Other antidepressants 536 Meta-analysis 537 Dopamine Agonists 538 Other Dopamine Agonists 538 Antiepileptics 539 Withdrawal Treatment in Cocaine Dependence 541 Dopamine Agonist 541 Partial Serotonin Agonist 541 Interaction Studies 554 Antidepressants 554 Dopamine Agonists 554 Antiepileptics 554 Partial Opioid Agonist 554 Review Articles 554 Long-term Pharmacotherapy in Methamphetamine Dependence 554
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9.6.1 9.6.1.1 9.7 9.7.1 9.7.2 9.7.3 9.7.4
9.8 9.8.1 9.8.1.1 9.8.1.2 9.8.1.3 9.8.1.4 9.8.1.5 9.8.1.6 9.8.1.7 9.8.1.8 9.8.1.9
10 10.1 10.1.1 10.2 10.3
10.4 10.5 10.5.1 10.5.2 10.5.3 10.5.4 10.5.5 10.5.6 10.6 10.7 10.8
Antidepressants 555 Tricyclic Antidepressants 555 Conclusions 555 Long-term Pharmacological Treatment in Cocaine Dependence 555 Withdrawal Treatment in Cocaine Dependence 558 Interactions 558 Long-term Pharmacological Treatment in Methamphetamine Dependence 558 References 559 Appendix 562 Long-term Pharmacotherapy in Cocaine Dependence 563 Antidepressants 563 Dopamine Agonists 563 Antiepileptics 563 Disulfiram 563 Neuroleptics 570 Serotonin Antagonists 570 Opioid Antagonist 570 Stimulants 570 b-Blockers 570 Appendix References 571 Pregnancy, Neonatal Period, and Substance Abuse 573
Introduction 573 Aim 573 Search Strategy and Methods 574 Incidence and Prevalence of Alcohol and Drug Use in Pregnant Women 574 Treatment Research – Alcohol and Pregnancy 575 Narcotics and Pregnancy 576 Cannabis and Pregnancy 577 Amphetamine, Other Central Stimulants, and Pregnancy 577 Cocaine and Pregnancy 577 Opiates and Pregnancy 578 Benzodiazepines and Pregnancy 578 Other Narcotics and Pregnancy 578 Studies of the Treatment of Drug Abuse in Pregnancy 578 Staff Training 579 Summary 579 References 581
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Appendix
Appendix Appendix Appendix Appendix
1. 2. 3. 4.
Project Group Authors and Scientific Reviewers 583 Quality Checklist 585 Guidelines for Estimating Effect Size 586 Glossary 587
Conclusions by SBU 595 SBU Summary 599 Index 611
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Intervention against Hazardous Alcohol Consumption – Secondary Prevention of Alcohol Problems Mikko Salaspuro
1.1
Introduction
Secondary prevention of alcohol problems covers the methods used for early detection and treatment of people with excessive alcohol consumption. The methods aim at preventing the development of alcohol dependence and alcohol-related diseases and injuries. Problem drinking is detected either in primary care or at a hospital by means of screening methods including questionnaires and laboratory tests. Preventive methods are referred to as brief interventions. Brief intervention is based on knowledge about alcohol being a major social and health problem, which reinforces the need to develop new strategies for primary and secondary prevention. Early detection of risk drinking is of central importance to the intervention. When an alcohol problem is detected, the patient receives information about the harmful effects which alcohol abuse or high alcohol consumption may cause. This is followed by a motivational discussion to reduce alcohol consumption. Brief intervention may also involve written advice and followup visits. Table 1.1 presents the framework of brief intervention (FRAMES) as described by Bien et al. [8].
Table 1.1. Content of brief interventions, FRAMES. Feedback of personal risk or impairment Feedback and information about alcohol is given in relation to the patient’s problems and symptoms. Emphasis on personal responsibility The patient’s decision to reduce the drinking should for change be his/her own. Clear advice to change The decision to reduce or quit drinking should be supported. A menu of alternative change options Alternative strategies to reduce drinking are created. Therapeutic empathy as a counseling The interventions are carried out in a warm, style reflective, empathetic, and understanding manner. Enhancement of client self-efficacy or Self-trust and optimism concerning success is optimism encouraged.
Treating Alcohol and Drug Abuse. Edited by M. Berglund, S. Thelander, E. Jonsson Copyright c 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 3-527-30682-X
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1 Intervention against Hazardous Alcohol Consumption – Secondary Prevention of Alcohol Problems
1.2
Aim
The aim of this systematic review of the literature is to review all published, randomized controlled trials (RCTs) as a basis for drawing conclusions about the effect of brief (minimal) interventions on alcohol consumption and alcohol-related problems.
1.3
Methods 1.3.1
Selection of Studies, Inclusion and Exclusion Criteria
The randomized controlled studies available in the field were systematically reviewed. Some studies included not only people with hazardous consumption levels but also alcohol-dependent individuals. However, the studies that analyzed alcohol dependence exclusively have been excluded. Also excluded were studies undertaken within the framework of substance abuse services or those where participants were recruited by advertising. Furthermore, this review excluded studies which compared brief intervention with more intensive treatment, and studies where the intervention extended beyond what is usual for a brief intervention. No requirements were established concerning the minimally acceptable followup time or the type of staff that performed the intervention. 1.3.2
Search Strategy
The search of the literature for this chapter was limited to MEDLINE from 1966 through 2000, but has been updated more recently to include some of the most important new studies or reviews on the topic. The following search terms were used in combination (number of identified publications are given in parentheses): ● Heavy drinking and intervention (36); – and advice (11) ● Brief intervention and alcohol (52) ● Counseling and alcohol and controlled study (2) ● Intervention and problem drinking (47); – and controlled drinking (5); – and problem drinker (10); – and alcohol consumption and controlled trial (17); – and alcohol and general practitioner (14) ● Intervention and problem drinkers (62) ● Advice and alcohol consumption (91) ● Early intervention and alcohol (104); – and controlled study (2) ● General practitioner intervention (9) ● Alcohol and intervention and controlled trial (44) ● Alcoholism and intervention and controlled trial (19).
1.3 Methods
Bibliographies from the studies found and from previously published meta-analyses, literature reviews, and dissertations were also reviewed [3, 7, 12, 20, 23, 33, 34, 35, 42, 46, 47]. 1.3.3
Outcome Measures
The most important outcome measures applied in the studies were changes in (a) alcohol consumption and (b) alcohol-related problems. Other outcome measures were: changes in laboratory values (GGT, AST, blood alcohol level, MCV), number of sick days, hospital in-patient days, physical or mental illness. 1.3.4
Rating Scientific Quality
The following were considered in rating the quality of the selected articles: randomization, blinding, patient recruitment and selection, criteria for diagnosis and selection, type of control treatment, dropout analysis and documentation on outcome estimates, outcome measures, multicenter studies, delivery of treatment, reporting of the total treatment situation, and statistical methods. 1.3.5
Analyzing the Results
The percentage of individuals in the intervention and control groups who reduced their alcohol consumption to a moderate or more risk-free level was calculated in all studies where this was possible. This information was used to estimate the relative risk reduction (RRR), the absolute risk reduction (ARR), and the number needed to treat (NNT), i.e., the number of heavy drinkers who would need brief intervention to enable each one to reduce his/her alcohol consumption to a more riskfree level [38]. Furthermore, the 95% confidence interval for each NNT was calculated [38].
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1.4
Results 1.4.1
Literature Search
The search of the database and bibliographies in previously published meta-analyses, reviews, and dissertations identified 478 articles. Of these, 27 studies fulfilled the inclusion criteria established by the group. The studies which were excluded usually focused on comparisons between different forms of therapy for alcohol dependence (as discussed above). The absence of a control group or lack of randomization were other reasons for excluding a study. 1.4.2
Previous Reviews and Meta-Analysis
Six systematic and several less comprehensive literature reviews addressed studies of brief interventions [7, 8, 12, 20, 21, 23, 29, 30, 33–35, 42, 46, 47]. The second edition of Hester and Miller’s book on the treatment of alcoholism [20] is based on a systematic evaluation of the literature. Only randomized and case-control studies were included. The review covered 211 studies of which 149 (69%) reported a significant outcome. Twenty-three studies from 1977 to 1992 which addressed brief interventions are included in the review. The analysis by the authors found stronger support for a good outcome from brief intervention than from any other form of treatment. However, Hester and Miller also included studies that compared brief intervention with more intensive forms of treatment, studies that had been performed outside of the standard health care organization, and studies where advertising had been used to recruit problem drinkers. Furthermore, some studies included in the present review were missing in Hester and Miller’s book. Kahan et al. used almost the same inclusion criteria as those used in this review. Eleven studies fulfilled these criteria, but the search strategy failed to identify all randomized studies [23]. The authors concluded that the studies supported the effectiveness of brief intervention. However, they stated that further studies were needed to investigate the effects of brief intervention on morbidity and mortality. Furthermore, uncertainty remained concerning the most suitable patients for intervention, the optimum intensity of intervention, and the most effective components of the brief intervention. Further studies were also found to be necessary to develop strategies to effectively motivate health care staff to use the method. In 1997, Wilk et al. published a meta-analysis of randomized controlled studies of brief intervention in heavy drinkers [47]. Their analysis included 12 randomized studies that fulfilled the inclusion criteria. The quality of the articles was comparable to equivalent studies in other research areas. The authors concluded that heavy drinkers who were subjected to minimal intervention were twice as likely to reduce their alcohol consumption to a more moderate level 6 to 12 months after the intervention compared to the control group which was not exposed to an intervention.
1.4 Results
The outcome was independent of patient gender, intervention intensity, and type of organization. The authors concluded that brief intervention is an inexpensive and effective preventive method for treating heavy drinkers of alcohol who are identified through the health services. A review by Ashenden included studies investigating the effect from different intervention methods on lifestyle changes [7]. The review also included studies which, in addition to alcohol consumption, also addressed patients’ smoking, diet, and exercise habits. In this review, the effect on alcohol consumption was analyzed in only six studies, of which one was nonrandomized. The authors concluded that further studies are needed before any conclusions can be drawn concerning the most effective interventions and the magnitude of the effect. Poikolainen performed a meta-analysis of primary care studies in which he compared brief intervention (5–20 min) to a more extensive intervention (repeated followup visits) [33]. Seven studies were included in the analysis. The outcome measure was a quantitative change in alcohol intake. The brief intervention showed no confirmed effects in either men or women. The more intensive intervention led to a significant reduction in alcohol consumption in women but not in men. Because of the differences in design between the different studies it was not possible to claim that the demonstrated difference in alcohol consumption would apply more generally. The author(s) concluded that further studies are needed to investigate why some interventions yield better results than others. Moyer et al. included two types of studies in their meta-analytic review [27]: studies comparing brief interventions with control conditions in nontreatment-seeking samples (n=34) and those comparing brief interventions with extended treatment in treatment-seeking samples. In studies of the first type, small to medium aggregate effect sizes favoring brief interventions emerged across different followup points. In contrast to this SBU review, the meta-analysis by Moyer et al. also included one study on alcoholics with gastrointestinal disease and five studies (one thesis) that had not been detected in the present literature search or accepted in the final review. Furthermore, Moyer’s review included, as separate entities, nine studies from the collaborative WHO project, which the present review includes as a single entity [45]. On the other hand, Moyer’s review failed to identify nine RCTs on brief intervention that have been included in this report. Nevertheless, the conclusions of these two reviews are largely the same. 1.4.3
Randomized and Controlled Studies
Table 1.2 (see page 6–15) shows characteristic features of the selected 27 randomized controlled studies addressing secondary prevention (brief) in heavy alcohol consumption and alcohol problems, including the number of patients, inclusion and exclusion criteria, type of intervention, followup time, quality rating, main outcome measures, and positive or negative effect. In these 27 studies, 9965 patients (approximately 8000 men and 2000 women) were randomized to intervention or brief intervention groups, brief information groups, investigation groups, or
5
6
1 Intervention against Hazardous Alcohol Consumption – Secondary Prevention of Alcohol Problems Table 1.2. Randomized and controlled studies addressing secondary prevention of alcohol problems. Article, year, care setting
Population, gender, mean age
Inclusion criteria
Exclusion criteria
Anderson and Scott [3] 1992 Primary care
N=154 men 7 community health centers, 44 years
>350 g of alcohol/w
>1050 g of alcohol/w, previous counseling
Antti-Poika et al. [4] 1988 Hospital
N=120 men Trauma patients in the surgical unit, 38 years
MAST ≥7
Severe head injuries
Chick et al. [8] 1985 Hospital
N=156 men Different medical units, 18–65 years
>50 dr/w, alcohol problems
Homeless, demented, severe illness, previous referral to psychiatrist
Córdoba et al. [9] 1998 Primary care
N=229 men 33 community health centers, 37 years
>36 dr (8 g)/w or >10 dr/day during 1 month
Previous advice to reduce, chronic illness
Cushman et al. [10] 1998 Primary care
N=641 636 men, 5 women, 58 years
≥3 dr/day during 6 months, diastolic RR 80–99
Alcohol dependence, drug addiction, severe illness
Elvy et al. [12] 1988 Hospital
N=263 168 men, 32 women Surgical units, 29 years
CAST questionnaire ≥3
Alcoholics, home outside the district
Fleming et al. [13] 1997 64 family practitioners in 17 community health centers Primary care
N=774 482 men 292 women 59.4% = 18–40 years 41.6% = 41–65 years
Men >168 g, Women >132 g/w
<18 or >65 years, previous problems with alcohol, >50 dr/w
Legend see page 14.
1.4 Results
7
Intervention
Followup period and %
Quality score
Outcome measure
Effect +/–
Control vs brief counseling (10 min) + laboratory tests + book
12 months (65%)
31/33
Alcohol consumption: ↓ IV 45%, C 27%, difference: –65 g/w, p<0.05
+
Control vs brief counseling + book + repeat at 1–3 times
6 months (74%)
24/30
Alcohol consumption: ↓↑ IV –58%, C +11%, IV –505 g/w, C +73 g/w, p<0.05 Difference: 578 g Improvement: IV 45%, C 20%
+
Control vs intervention (60 min) + book
12 months (83%)
27/30
Alcohol consumption: ↓ IV –296 g, C –272 g, difference: –24 g Improvement: IV 52%, C 34% GGT ↓
+
Brief counseling (5 min) vs intervention (15 min) + book + 1.54 followup visits
12 months (45%)
27/33
Alcohol consumption: ↓ IV –67.3%, C –44%, <21 doses/w: IV 46%, C 24%
+
Control vs cognitive behavior therapy with the goal: ≤ 2dr/ day or 50% reduction of alcohol consumption
3, 6, 12, 18, 24 months, (86%, 84%, 80%, 64%)
33/33
Alcohol consumption: ↓ IV –202 g, C –78 g, p<0.01, GGT: ↓ IV >C, p<0.05
+
Control vs brief intervention with the aim to make the patient accept a referral to an alcohol counselor
12 and 18 months (74% and 61%)
27/33
IV vs C: fewer alcohol problems, longer time from last drink
+
Control (30 min interview + book with general health information) vs 2 brief counseling sessions (15 min) + book
12 months (93%)
32/33
Alcohol consumption: ↓ IV 40%; C 18%, moderation: IV 63%; C 32% men: IV –97 g/w, C –61 g/w, women: IV –85 g/w, C –30 g/w, Days in hospital ↓
+
(Table continues on next page)
8
1 Intervention against Hazardous Alcohol Consumption – Secondary Prevention of Alcohol Problems Table 1.2. (cont.) Article, year, care setting
Population, gender, mean age
Inclusion criteria
Exclusion criteria
Fleming et al. [14] 1999 Primary care
N=158 105 men, 53 women, all over 65 years of age
Men >132 g/w, or >4 dr >2x/3 month, women >96 g/w, or >3 dr x >2/3 month + >2 CAGE positive answers
Alcoholics, previous counseling, suicidal thoughts, under 65 years of age
Gentiello et al. [16] 1999 Hospital
N=762 579 men 183 women trauma patients, 35–37 years
Elevated blood alcohol, SMAST >1–3, elevated GGT
<18 years, mental illness, homeless, severe head injury, <24 hours in hospital
Heather et al. [18] 1987 16 general practitioners Primary care
N=104 78 men 26 women, 36 years
Men >35 dr/w, women >20 dr/w, or alcohol problems
Alcoholism, severe mental illness, liver disease
Israel et al. [21] 1996 42 general practitioners Primary care
N=105
One positive response in a trauma questionnaire
Alcoholism, GGT >200, mental illness, AA, drug addiction
Kristenson et al. [23] 1983 Department of preventive medicine Hospital
N=473 men, 48–50 years
GGT >1.40 mkat/l
Hypertension, hyperlipidemia, diabetes
Lang et al. [24] 1995 14 companybased physicians Primary care
N=129 95% men, 43 years
RR >140/90 and GGT 1.5 x upper limit for normal level
Severe illness, non-alcohol cause of GGT
Legend see page 14.
age not reported
1.4 Results
Intervention
Followup period and %
Quality score
Control (book with general health education) vs 2 interventions (10–15 min) + book
12 months (92.4%), financial compensation to physician and patient
32/33
Control (assistance on demand) vs intervention (30 min) + letter 1 month later, information about AA
6 months (73–76%) 12 months (53–54%)
Control (extensive interview regarding alcohol consumption and problems) vs brief counseling vs interactive DRAMS intervention
9
Outcome measure
Effect +/–
Alcohol consumption:
+
29/30
Alcohol consumption (12 months): IV –21.6 dr, C –2.3 dr, reduction of new injuries 47%, in-hospital stay 48%
+
6 months (88%)
25/33
Alcohol consumption IV –20%; BC –17%; C –16%
–
Brief counseling vs cognitive intervention with laboratory tests (45 min + 6 x 20 min) performed by a nurse
12 months (70%)
28/33
Alcohol consumption: IV –70%, –319 g/w C –46%, –191 g/w psychosocial problems ↓ –85%, GGT ↓ –32%
+
Control vs brief counseling + repeated followup visits with laboratory tests
48 months (88%)
23/33
Sick leave: IV +22%, C + 110%, p <0.05
+
Control vs brief counseling with information about GGT after 1, 3, 6, and 18 months
12 and 24 months (90%, 78%)
29/33
Alcohol consumption: IV –238 g/w, C: –131 g/w, p = 0.09 GGT ↓ 34% in both
–
↓ IV 36%; ↓ C 1.9%
(Table continues on next page)
10
1 Intervention against Hazardous Alcohol Consumption – Secondary Prevention of Alcohol Problems Table 1.2. (cont.) Article, year, care setting
Population, gender, mean age
Inclusion criteria
Exclusion criteria
McIntosch et al. [26] 1997 12 general practitioners Primary care
N=159 83 men, 76 women, 31 years
≥5 dr/day during 1 month
Not mentioned
Maheswaran et al. [25] 1992 Primary care
N=47 men Hypertension clinic, 45 years
>20 dr/w
Diastolic blood pressure >105, diabetes, previous advice
Nilssen [27] 1991 Primary care
N=338 290 men, 48 women, 41–42 years
GGT >50 men, >45 women, alcohol for 2–3 days/w, one bottle of wine 1–2 times/month
Alcoholism, liver disease, mental illness, GGT >200
Ochene et al. [28] 1999 Primary care
N=530 343 men, 187 women, 44 years
Men >12 dr/w or >5 dr/d/month Women >9 dr/w or >4 dr/d/month
Alcoholism, pregnancy, mental illness, no telephone, drug addiction
Persson and Magnusson [29] 1989 Hospital
N=78 61 men, 17 women age ?
A >200 g/w men, >150 g/w women, GGT >0.6 mkat/l
Alcoholism, abuse of prescription drugs or narcotics
Richmond et al. [33] 1995 119 general practitioners Primary care
N=378 216 men, 162 women, 38 years
Alcohol >35 dr/w men, >21 dr/w women
Alcoholism, pregnancy, mental illness, previous treatment or advice
Legend see page 14.
1.4 Results
11
Intervention
Followup period and %
Quality score
Outcome measure
Effect +/–
No real C, advice by personal doctor (5 min) vs brief intervention by doctor vs brief intervention by nurse
3, 6, 12 months (99%, 93%, 90%)
26/30
Alcohol advice –40% men, –30% women, IV/physician –55% men, –56% women IV/nurse –46% men, –26% women, ns
–
Control vs brief counseling (10–15 min) + repeated followup visits
8w (87%)
28/30
Alcohol consumption: IV –50%, C 0%
+
Control vs brief counseling vs intervention + book + repeated followup visits
12 months (95%)
27/30
GGT: IV –16%, BC –22%, C +9% Alcohol consumption: double in C vs both IV groups
+
Control (book and health education) vs specific education of physician (2.5 hours) + IV (5–10 min) + followup visit
6 months (91%)
32/33
Alcohol consumption: IV –5.8 dr/w C –3.4 dr/w
+
Control vs brief counseling + >5 repeated followup visits with laboratory tests
24 months (68%)
24/30
Sick leave: IV –44%, C +80%
+
Control vs investigation (5 min) vs intervention (10–15 min) + 4 followup visits
6 and 12 months (69%)
32/33
Alcohol consumption: IV –25%, C –21%
–
(Table continues on next page)
12
1 Intervention against Hazardous Alcohol Consumption – Secondary Prevention of Alcohol Problems Table 1.2. (cont.) Article, year, care setting
Population, gender, mean age
Inclusion criteria
Exclusion criteria
Romelsjö et al. [34] 1989 14 general practitioners in 5 community health centers Primary care
N=83 70 men, 13 women, 44–48 years
A >30 g/d women, >40 g/d men, hangover, loss of control, CAGE ≥3, elevated GGT
Alcoholism, drug addiction, mental or severe illness, alcohol not cause of GGT
Scott and Anderson [36] 1990 8 community health centers Primary care
N=72 women 44–47 years
≥21 dr (210 g)/w
>70 dr/w, previous advice
Senft and Polen [37] 1997 3 community health centers Primary care
N=516 359 men, 197 women, 42–43 years
AUDIT 8–21
<21 years, pregnancy
Seppä [38] 1992 Primary care
N=178 140 men, 38 women, 47–54 years
Elevated MCV + Malmö-MAST 2 plus answers, elevated GGT
Alcohol not the cause of elevated MCV
Suokas [40] 1992 1 community health center Primary care
N=247 men, 40 years
GGT >60
Alcohol not the cause of elevated GGT
Tomson et al. [41] 1998 Primary care
N=222, 22–54 years
GGT >0.89 mkat/l, CAGE 2 +, men >280 g/w, women >210 g/w
Non-alcohol cause of elevated GGT, alcoholism
Legend see page 14.
1.4 Results
13
Intervention
Followup period and %
Quality score
Outcome measure
Effect +/–
Brief counseling vs intervention with laboratory tests and repeated followup visits
12 months (87%)
23/33
GGT: IV –17%, C –6%, Alcohol: IV –19%, C –0.4%, Alcohol problems: IV –10%, C –9%
–
Control vs brief counseling (10 min)
12 months (69%)
31/33
Alcohol consumption: IV –27%, C –26%
–
Brief counseling (30 s) vs intervention (15 min) + written advice
6 and 12 months (84%, 80%)
31/33
Reduction of alcohol consumption: IV 19% >C, during 6 months p=0.04, 12% during 12 months p=0.13
+
Control vs brief counseling + repeated followup visits with laboratory tests
12 months (52%)
18/30
IV and C no change in MCV
–
Brief counseling vs intervention with repeated followup visits with laboratory tests vs separate reference group (RE)
12 and 24 months (80%, 75%)
28/331 or 26/332
GGT: IV and C Significant reduction RE: significant increase
–1/+2
Control (discussion about GGT with a physician) vs 3 interventions by a nurse
24 months (C 37%, IV 30%)
19/30
IV: Lowering of GGT, C: Increase of GGT
+
(Table continues on next page)
14
1 Intervention against Hazardous Alcohol Consumption – Secondary Prevention of Alcohol Problems Table 1.2. (cont.) Article, year, care setting
Population, gender, mean age
Inclusion criteria
Exclusion criteria
Wallace et al. [42] 1988 47 community health centers Primary care
N=909 649 men, 272 women, 41–45 years
≥35 dr/w men, ≥20 dr/w women + CAGE ≥2 positive
Alcohol consumption
Severe physical illness, GGT >150
WHO study [45] 1996 Multicenter and multinational Primary care
N=1559 1260 men, 299 women, 36 years
answers
Alcohol consumption >50 g/day men, >32 g/day women
Alcoholism, liver disease
IV = brief intervention group, C = control group, dr = drinks, w = week, ↓ = down, ↑ = up, BC = brief counseling group, RE = reference group. 1 ) comparison between brief counseling and intervention. 2 ) comparison between intervention and the reference group.
1.4 Results
Intervention
Followup period and %
Quality score
Outcome measure
Effect +/–
Control vs brief counseling with a book and diary + 1–4 followup visits
12 months (85%)
32/33
Alcohol consumption: IV –45%, C –27%, decreased share of patients with large consumption and lowering of GGT
+
Control vs brief counseling (5 min) vs intervention (15 min) + instruction book
9 months (75%)
32/33
Alcohol consumption in men: IV –21%, BC –27%, C –7%, in women significant decrease in IV, BC, and C
+
15
16
1 Intervention against Hazardous Alcohol Consumption – Secondary Prevention of Alcohol Problems
control groups. The samples in most of the studies were representative of the general population, but some studies also included patients from health care centers, hospital units, or outpatient clinics. The number of participants in the different studies varies from 47 to 1559. Fifteen studies included individuals who during the past week had consumed more than 132–500 g alcohol. One study included patients who had consumed three drinks per day during the past 6 months and had a diastolic blood pressure from 80 to 99 mm Hg. Another study included patients with RR >140/90 and a GGT level 1.5 times higher than the normal level. Other inclusion criteria were an elevated GGT or MCV level, positive AUDIT (points 8–21), Cage (≥2 or ≥3), MAST (positive answers ≥2 or ≥7), SMAST (positive answers 1–3), or CAST (positive answers ≥3) questionnaire. One study included patients based only on a positive response in a trauma questionnaire. Most studies excluded alcohol-dependent individuals. Other exclusion criteria were, for instance, previous treatment of alcohol problems, previous advice to reduce alcohol consumption, previous referral to psychiatric treatment, liver disease, severe mental illness, dementia, severe brain damage, homelessness, residence outside of the district, abuse of prescription drugs or narcotics, and abnormal laboratory results not caused by alcohol or pregnancy. The brief intervention varied from short information (5 min) or counseling (10–15 min) up to 60 min of intervention. In one study, the intervention was given in the form of cognitive therapy which was repeated every second month for 1 year (45 min followed by six 20 min sessions). In another study, cognitive behavioral therapy was used, given as 6 sessions during the first 3 months and at least 3 sessions during the next 3 months. The aim of this therapy was to cut alcohol intake in half – or fewer than two drinks per day. Furthermore, the intervention could also include laboratory tests, written instructions, and repeated followup visits (1–6 times). Mainly, the intervention consisted of a motivational discussion about the risks of heavy consumption with advice to reduce alcohol consumption to a level associated with a low risk and few problems. The followup time was usually 12 months; in one study it was 8 weeks, in three studies 6 months, in five studies 24 months, and in one study it was 48 months. Furthermore, two new long-term follow-up studies were added more recently to this review. They report results from either 10 year or 10–16 year follow-up. The quality of the studies was generally moderate or good. Scientific quality in the studies was rated on a scale where the maximum number of points was 30 or 33. The quality rating varied from 18 to 33. 1.4.4
Studies with Positive Outcome (Measures) Presented in Order of Quality (see Table 1.3)
A somewhat more extensive intervention than the usual brief intervention was used in an extensive multicenter study in ambulatory care services for veterans in the United States. The material consisted of 636 men and 5 women with slightly elevated diastolic blood pressure who had been having three or more drinks per day
1.4 Results
for the past 6 months [11]. The intervention was a brief form of cognitive behavioral therapy and was given on six occasions during the 3 subsequent months. The aim was to cut alcohol intake in half or limit alcohol consumption to a maximum of two drinks per day. The strength of this study was that the control group did not receive any advice to reduce their alcohol consumption (Tables 1.2 and 1.4). The followup time varied from 3 to 24 months. During followup, alcohol consumption decreased significantly more in the intervention group. During the first 6 months, alcohol consumption decreased from 432 g/week to 230 g/week in the intervention group and from 445 g/week to 377 g/week in the control group. The reduced level of consumption remained the same after 24 months. In the intervention group, alcohol intake decreased more than 50% during the first 6 months in nearly 50% of the participants. The corresponding number in the control group was 23%. The reduction of the GGT level was significantly greater in the intervention group than in the control group. The effect of the reduced alcohol intake on blood pressure was insignificant. A study from the United States (Wisconsin) investigated the prevalence of problem drinking among 17695 patients in primary care [14]. From this total, 2450 patients were found to have a high alcohol consumption. Of these, 482 men and 292 women were randomized to the control or brief intervention group (Tables 1.2 and 1.4). The patients in the control group were given a general health examination, and their alcohol habits were also discussed. The intervention included two brief counseling sessions (15 min) and an instruction book containing advice, education, and information about a contract to reduce alcohol consumption. Followup was 12 months, and dropout was 7%. Compared to the control group, a significant reduction was found among both men and women in the intervention group as regards the weekly volume of alcohol intake, the number of drinking periods, intoxication episodes, and sick days. The authors concluded that intervention by a family practitioner reduces both alcohol consumption and the use of health services among individuals with excessive alcohol consumption. An economic analysis based on this study showed that the cost savings were approximately 6 times greater (a consequence of less emergency care and inpatient care, and lower rates of crime and traffic injuries) than the costs for the brief intervention [16]. A study conducted at 47 health care centers in Great Britain used a questionnaire to identify patients with a high alcohol consumption [45]. In total, 649 men and 272 women were randomly distributed to a control and an intervention group (Tables 1.2 and 1.4). The patients in the control group received no information about the risks of their alcohol intake. The brief intervention consisted of brief standardized counseling about alcohol-related risk and risk-free drinking and an instruction book. The men were advised not to drink more than 18 drinks (one drink equals one bottle of beer, one glass of wine, or 4 cl of distilled spirits), and the women no more than eight drinks per week. Furthermore, the patients were given a drinking diary and were scheduled for a followup visit (one to four times). The followup time was 12 months, and 85% of the patients participated in the followup. The intervention group showed a significant reduction in alcohol con-
17
18
1 Intervention against Hazardous Alcohol Consumption – Secondary Prevention of Alcohol Problems
sumption. The authors concluded that if the brief intervention became a routine with general practitioners in England, alcohol consumption would be reduced to a moderate level in 250 000 men and 67 500 women each year. A study from the United States (Massachusetts) randomized four physician offices, staffed by 46 physicians, to special intervention or standard treatment [31]. Two hundred fifty-six patients whose consumption exceeded the threshold value were given standard treatment (control) and 274 patients were given specific intervention (Tables 1.2 and 1.4). The control group, however, received an informational brochure about healthy living. When needed, the physicians also intervened against the patients’ possible alcohol problems. The physicians who belonged to the intervention group participated in a 2-hour patient- and alcohol-oriented educational program. The program included two group sessions with supervision and roleplay. The intervention (5 to 10 min) aimed at focusing on the number of drinks per week, intoxicating drinking, and on followup visits. The followup time was 6 months and 91% of the patients were followed up. A significant reduction in the number of drinks per week could be noted in the intervention group compared to the control group. An elegant study from the United States (Seattle) investigated 2524 trauma patients [17]. Of these, 1153 (46%) met the inclusion criteria for problem drinking. Out of this group, 366 were randomized to an intervention group and 396 to a control group (Tables 1.2 and 1.4). The followup time was 6 and 12 months, and the percentage followed up was 74% and 53%, respectively. After 12 months, the intervention group showed a significant reduction in alcohol consumption. The reduction was most obvious in patients with mild or moderate alcohol problems. Alcohol consumption in the intervention group declined along with a simultaneous, significant reduction in injuries requiring treatment in an emergency department and a 50% reduction in injuries normally requiring hospitalization. The authors concluded that there should be a routine attempt to detect and intervene against alcohol problems in emergency departments. WHO performed a large study in Australia, Kenya, Mexico, Norway, England, and Russia [48]. Hospital units, outpatient clinics, community health centers, and an institution for health examinations were called “functional units” (Tables 1.2 and 1.4). In total, 1260 men and 299 women whose alcohol consumption exceeded the threshold value were randomized to three groups: a control group, a brief counseling (5 min) group which received information about reasonable limits for drinking, and an intervention group (15 min) which received an illustrated instruction book addressing problem drinking and advantages of moderate drinking or abstinence. The mean followup time was 9 months, and the followup rate was 75%. After 9 months, the men in both the intervention groups reduced both their alcohol consumption and drinking intensity significantly more than the men in the control group. Among the women, a significant reduction in alcohol consumption could be noted in all three groups. A brief intervention was as effective as a longer one. The authors concluded that brief interventions are effective methods in certain health care organizations and cultures and, if sufficiently used in primary care, could improve secondary prevention of alcohol-related problems.
1.4 Results
A 9-month and 10-year followup was carried out in the cohort of 554 (nondependent) hazardous and harmful drinkers recruited into the Australian arm of the Phase II World Health Organization collaborative project (described above) [49]. The effectiveness of these forms of intervention, ranging from 5 to 60 min duration, was compared with a no-treatment control condition. The results provided further evidence for the short-term effectiveness of alcohol-related brief interventions. In comparison to controls, subjects offered intervention reported significantly lower consumption and less unsafe drinking at 9-month followup. However, analysis at 10 years failed to find any differences in outcomes between intervention and control groups in median consumption, mean reduction in consumption from baseline to followup, mortality, and ICD-10 diagnoses of alcohol dependence or harmful alcohol use. A new study by Fleming et al. indicates that the brief intervention is effective even in elderly problem drinkers [15]. Among 6073 patients above 65 years of age, 656 individuals with a high alcohol consumption were identified. Of these, 105 men and 53 women were randomized to the control or brief intervention group (Tables 1.2 and 1.4). The control patients were given a book with general health information. The intervention consisted of two brief counseling sessions (15 min) and an instruction book which contained advice, education, a contract on reducing alcohol consumption, and a drinking diary. The followup time was 12 months and the followup rate was 92%. Both physicians and patients received financial compensation for their participation in the study. The intervention group reduced weekly alcohol consumption by 34% and intoxicating drinking by 74% compared to the control group. The number of individuals who drank above the threshold value declined significantly in the intervention group compared to the control group. All differences were significant. A study which included only men was performed in Great Britain (Oxford) [4]. In this study, 154 men were randomized to two groups: a control group and a group which received brief counseling and an instruction book and on whom laboratory tests were taken (Tables 1.2 and 1.4). The followup time was 12 months and the followup rate was 65%. The intervention group showed a significant reduction in alcohol consumption compared to the control group. However, the differences in changes of laboratory tests were not significant. A study in three health centers in Oregon Kaiser Permanente randomized 516 individuals to a group which received brief information (30 s) from general practitioners followed by a 15 min motivating session with a health counselor and to a control group which received only the brief information (Tables 1.2 and 1.4) [40]. After 6 and 12 months of followup, the intervention group showed a significant reduction in the number of standard drinks during the past 3 months and in the number of drinking days per week compared to the control group. The authors concluded that within a primary care setting, a brief, occasional, and motivating intervention could achieve a significant reduction in alcohol consumption. However, it was proposed that new studies are needed to investigate whether and how the effects of the brief intervention can be enhanced and maintained.
19
20
1 Intervention against Hazardous Alcohol Consumption – Secondary Prevention of Alcohol Problems
A British study investigated the effects of brief intervention in patients with concurrent hypertension (Tables 1.2 and 1.4) [27]. The study was performed in primary care in a specialized blood pressure clinic. Forty-seven men with hypertension (diastolic blood pressure 90–105) who drank above the threshold value (>20 drinks/week) were randomized to 2 groups: a control group and a group which was given brief counseling (10 to 15 min), respectively, with repeated followup visits. The followup period was 8 weeks and the followup rate was 87%. Alcohol consumption was halved in the brief intervention group, but was not affected in the control group. The reduction in alcohol intake showed a significant association with a reduction in liver enzyme values. Diastolic blood pressure also decreased in the intervention group. The authors concluded that brief intervention is an active treatment form for patients with hypertension and excessive alcohol consumption. In a study from Norway (Tromsö), a general health examination was performed in which 21 000 men and women answered 5 questions concerning alcohol consumption [30]. Their GGT levels were also analyzed. From these, 290 middle-aged men and 48 women with an elevated GGT level and excessive alcohol consumption were selected and randomized to a control group and two intervention groups (Tables 1.2 and 1.4). The strength of the study lies in the fact that the control group was not given any information about screening results or GGT level. In the brief intervention (10–15 min), the following were provided: information about possible causes behind the elevated GGT level, advice to check on possible causes of the abnormal laboratory value, and an instruction book which described the effect of alcohol consumption on GGT levels. The “lengthy” intervention was aimed at decreasing alcohol consumption, and therefore information was given about different methods of achieving this. In addition, the subjects were given a diary to monitor alcohol consumption, and GGT levels were measured on repeated followup visits. The followup period was 12 months, and dropout was only 5%. The lowering of the GGT level was significant in both intervention groups in comparison with the control group. The level decreased in the intervention group by 16% and in the brief counseling group by 22%, but increased by 9% in the control group. A significant reduction in self-reported alcohol consumption was observed in both intervention groups. After 12 months, the subjects in the control group consumed twice as much alcohol as those in the two intervention groups. No significant differences in alcohol consumption or GGT level were found between the 2 intervention groups. The authors conclude that simple interventions may achieve important changes in drinking habits during the early phase of hazardous alcohol consumption. A study from Scotland (Edinburgh), which involved both inpatients who were heavy drinkers and inpatients with alcohol dependence, randomized 156 men to a control group and an intervention group (Tables 1.2 and 1.4) [9]. The control group received standard treatment and no information about the purpose of the screening instrument. In the 60-min intervention, a nurse informed the patient about the risks of high alcohol intake and gave the patient an instruction book. The aim was to reduce alcohol intake or to achieve complete abstinence. The followup period was 12 months and the followup rate was 83%. Alcohol consumption decreased signif-
1.4 Results
icantly in both groups. Furthermore, the intervention group showed a significant reduction in alcohol-related problems and GGT levels compared to the control group. The authors concluded that a systematic survey of alcohol consumption and problems in combination with an intervention should become routine in all patient investigations. A multicenter study by Israel et al. (involving 42 primary care physicians in Canada) questioned 15 686 patients about trauma experienced during the past 5 years [22]. The patients who answered positively to two or more of the trauma questions were given a questionnaire which surveyed their alcohol consumption (Tables 1.2 and 1.4). One hundred and five patients (18% women) who drank above a threshold value were randomized either to brief counseling or to an intervention group. The patients who were included in the counseling group were recommended to reduce their alcohol consumption and were given written advice aimed at achieving either abstinence or an acceptable level of consumption. The intervention was carried out by a nurse, who gave a standardized counseling lasting for 30 min. The goal was to achieve either abstinence or risk-free drinking. The participants were recommended to avoid alcohol in the evening and to keep a diary about their use of alcohol. During the 20-min followup visits, which were repeated every second month for one year, information was given about possible changes in the GGT level, and the strategy for reaching the treatment goal was repeated. The followup period was 12 months and the dropout rate was 30%. The patients in the intervention group reduced their alcohol consumption by 70%. Psychosocial problems decreased by 85%, the GGT level by 34%, and medical visits by 34%. All differences in relation to the control group were significant. The patients in the group given brief counseling reduced their alcohol consumption by 46%, while the changes of other outcome measures were not significant. The authors concluded that the cognitive intervention with repeated followup visits was more effective than counseling alone in reducing alcohol-related objective problems in trauma patients. In a Spanish multicenter study, 229 male primary care patients whose drinking exceeded the threshold value were randomized to a group which was given brief counseling (5 min) and to a group which also received the counseling plus an instruction book and an average of 1.5 followup visits (Tables 1.2 and 1.4) [10]. The followup period was 12 months, but the followup rate was only 45%. In the intervention group, 67% of the high consumers achieved a moderate consumption level. In the control group, the corresponding figure was 44%. The difference is statistically significant. Elvy et al. carried out an intervention study in hospitals in New Zealand aimed at examining the effects of a specific type of consultation on the patient’s alcohol problems (Tables 1.2 and 1.4) [13]. The CAST questionnaire (Canterbury Alcoholism Screening Test) was used to screen for alcohol problems among patients in two surgical units. In total, 200 patients (168 men and 32 women) who fulfilled the inclusion criteria were randomized to a control and an intervention group, respectively. The intervention was performed by a psychologist and was aimed at encouraging the patient to accept a referral to an alcohol counselor. The patients who accepted the referral met with the consulting physician within 24 h. Followup was done after
21
22
1 Intervention against Hazardous Alcohol Consumption – Secondary Prevention of Alcohol Problems
12 and 18 months among 74% and 61%, respectively, of the randomized patients. After 12 months a significant improvement could be demonstrated in the consultation group compared to the control group with respect to the number of self-reported alcohol problems, personal satisfaction, and working capacity. However, the differences between intervention and control groups decreased in the 18-month followup. The authors assumed that the followup visit after 12 months might have functioned as a brief intervention in the control group. The authors recommend that this type of consultation become standard hospital routine. A study by Antti-Poika et al. was performed in Finland (Helsinki University Hospital) [5]. One hundred and twenty male accident patients who answered positively to 7 or more MAST questions were randomized to a control group and a brief intervention group, respectively (Tables 1.2 and 1.4). This study may have included even alcohol-dependent individuals. The patients in the control group were given routine surgical or orthopedic treatment. The intervention group received a brief motivational counseling aimed at making the patient abstinent during a certain time period or to reduce his/her alcohol consumption to a more risk-free level. Furthermore, these patients were given an instruction book, and the intervention was repeated 1 to 3 times at followup visits. The followup time was 6 months and dropout was 24%. The intervention group reduced its alcohol consumption significantly compared to the control group which increased its alcohol intake by 73g per week. A significant reduction in alcohol consumption associated with a normalization of the GGT level could also be observed in the intervention group compared to the patients in the control group. According to the authors, this type of intervention ought to become standard routine in treating patients with alcohol-related accidents. An equivalent study involving hospital patients was performed by Persson and Magnuson [32]. This study randomized 61 men and 17 women to a control group and an intervention group (Tables 1.2 and 1.4). The intervention consisted of brief counseling, plus 5 or more followup visits with laboratory tests. Followup was 24 months, and the followup rate was 68%. During 2 years after the intervention, absenteeism due to illness decreased in the intervention group by 44% compared to 21% in the control group, a significant difference. The first pseudo-randomized brief intervention study was performed by Kristenson et al. [25]. This study was included as part of a general health examination which was performed by the department of preventive medicine in Malmö, Sweden (Tables 1.2 and 1.4). Of the 11 643 middle-aged men examined, 473 with an elevated GGT level were assigned (based on birth date) to two groups; either a control group or a group which was given brief counseling with repeated followup visits and laboratory tests every 3 months initially and less frequently after normalization of the GGT level. The followup period was 48 months and dropout 24%. Sick leave increased by 22% in the intervention group and 110% in the control group, which was a significant difference. Furthermore, the intervention group had 60% fewer hospital inpatient days, which was significantly less than in the control group. The authors concluded that intervention programs are effective for preventing the consequences of excessive alcohol consumption. Long-term followup of mortality for 10 to 16 years (median, 13 years) showed that 124 of 978 men had died (12.7%) [24].
1.4 Results
In 59 men (48%), death was alcohol-related. In the intervention group 10.4% and in the control group 13.9% men had died, and the difference was statistically significant. However, the difference between the groups in total mortality was not significant. The authors conclude that long-term intervention in urban males with alcohol-induced GGT increases may be beneficial in terms of survival. A study by Thomson et al., which was part of a general health survey of 2338 individuals in Stockholm, randomized 222 patients with elevated GGT levels to an intervention group and a control group (Tables 1.2 and 1.4) [44]. The patients in the intervention group met with a nurse 3 times during one year. The discussion focused on life style and alcohol consumption. A followup of the GGT levels was used to motivate the patients to reduce their drinking. The control group met with a general practitioner, who informed them that the elevated GGT level was probably caused by excessive alcohol consumption, but no advice was given on how they should reduce this. After 24 months the GGT level decreased significantly in the intervention group, while it increased in the control group. Dropout was as high as 70% in the intervention group and 67% in the control group, which makes interpretation of the results difficult. 1.4.5
Studies without Significant Effects, Presented in Order of Quality (Table 1.5)
A multicenter study conducted in Australia (Sydney) was unable to demonstrate any effect from brief intervention [36]. The patients who drank above the threshold value were recruited by 119 general practitioners in 40 community health centers (Tables 1.2 and 1.5). Two hundred and sixteen men and 152 women were randomized to four groups: (1) control group, (2) investigation only, (3) brief counseling (5 min), and (4) intervention (10–15 min) with four followup visits. The followup period was 6 and 12 months, and the followup rate was 69%. Alcohol consumption decreased by approximately one fourth in all groups. No differences in the change of GGT levels or MAST points were observed. The authors concluded that brief interventions were not shown to be effective in reducing alcohol consumption or alcohol-related problems. They also discussed weaknesses of the study and recommended new guidelines for further studies with brief intervention in primary health care. A study from Great Britain (Oxford) randomized 72 women who drank more than the threshold value to a control group and a group which was given brief counseling (10 min) and an instruction book and on whom laboratory tests were taken (Tables 1.2 and 1.5) [39]. Followup was 12 months and the followup rate was 69%. In these women, alcohol consumption decreased by approximately one fourth in both the intervention and the control groups. The authors suggest that general practitioners should routinely ask their patients about alcohol consumption and advise those at higher risk. A possible reason why no effect was found from brief intervention may have been that the control group received indirect intervention from the general practitioners. Perhaps the diagnostic interview already had an impact on the women.
23
24
1 Intervention against Hazardous Alcohol Consumption – Secondary Prevention of Alcohol Problems
In a multicenter study from Australia (Sydney), McIntosh et al. compared the outcome of three brief intervention methods on alcohol consumption in patients who went to family practitioners (Tables 1.2 and 1.5) [28]. The study randomized 83 men and 76 women whose drinking exceeded the threshold value into three groups: the first group members received advice (5 min) from their own physicians, the second group received brief intervention (2 x 30 min) by a physician, and the third group received brief intervention (2 x 30 min) by a nurse. Followup took place after 3, 6, and 12 months and included 99%, 93%, and 90% of the subjects respectively. A significant reduction in alcohol consumption (47% in men, 37% in women) was noted for the entire study group, but the differences between intervention and control were not significant. At the beginning of the study, 15% of the men and 22% of the women were problem free. The corresponding figures 12 months after the different interventions were 39% in the men and 53% in the women. The authors conclude that basic advice from a physician can motivate patients to reduce their alcohol consumption and that intervention by a nurse is as effective as the equivalent intervention by a physician. A primary care study performed in France (Paris) differs somewhat from other intervention studies [26]. This study was included because its aim was to reduce the alcohol consumption of patients with hypertension using a special form of brief intervention. In the study, 14 company-based physicians were randomized to an intervention and a control group (Tables 1.2 and 1.5). The physicians in the intervention group were educated in a new way of working with patients with hypertension who were heavy consumers of alcohol. One hundred and twenty-nine patients (95% men) with blood pressure above 140/90 and a GGT level 1.5 times the reference value were included in the study. The specially trained company-based physicians treated 67 patients. The 62 patients in the control group were treated by their own physicians in the usual manner, which could include different measures against excessive and harmful alcohol consumption. The patients in the intervention group were called to the clinic after 1, 3, 6, and 18 months, and their GGT levels were checked each time. The subjects were encouraged to find a level of alcohol consumption which would reduce their GGT levels to normal values. Blood pressure, which was measured in both groups at the outset and after 12 and 24 months, was not the focus of this study. The followup periods were 12 and 24 months and the followup rates were 90% and 78%, respectively. Alcohol consumption decreased by 238 g per week in the intervention group and by 131 g per week in the control group. The difference was not significant, which may have been because of the limited number of patients. However, a significant reduction in systolic blood pressure was found in the intervention group compared to the control group after both 12 and 24 months. No difference between the groups could be noted in the diastolic blood pressure or in the GGT levels. In Finland, Suokas conducted a randomized brief intervention study in a midsized city [43]. This study was part of a general health survey including middle-aged men (Tables 1.2 and 1.5). In 3844 men examined, 247 with an elevated GGT level were randomized to two groups: one group was given brief counseling (10–15 min) by a physician and the other was exposed to a longer intervention with an instruc-
1.4 Results
tion book and repeated followup visits with a nurse. Another 200 persons, with the same alcohol consumption as in the two intervention groups, were included to monitor changes in the GGT levels of individuals who received information that their liver values were normal. However, they did not receive any information about the risks of their excessive alcohol consumption. This reference group was not randomly recruited. The followup periods were 12 and 24 months and the followup rates were 80% and 75%, respectively. A significant reduction was found in the GGT levels in both intervention groups, while the reference group had a significant increase in the GGT level. Alcohol consumption and GGT level did not differ between the two intervention groups. A study by Heather et al. at eight community health centers in Scotland recruited patients whose drinking exceeded the threshold value (Tables 1.2 and 1.5) [19]. The study randomized 78 men and 26 women to three groups: (i) a control group which involved an interview on alcohol consumption and alcohol-related problems and brief advice, (ii) a group which was given an interactive DRAMS program (DRAMS = drinking reasonably and moderately with self-control scheme), and (iii) a group to which a physician gave short advice. DRAMS included a four-page instruction from a physician, a followup form to fill in results from laboratory tests (blood alcohol, GGT, MCV), a diary for noting alcohol intake, and an instruction book for controlled drinking. The followup time was 6 months and dropout was 12%. No differences in alcohol consumption were found between the three groups, but in the material as a whole a significant reduction could be noted in alcohol consumption and the GGT level, while physical condition improved. The authors conclude that their results can be used in planning future brief intervention studies. Romelsjö et al. identified heavy drinkers of alcohol and people with alcohol problems via a general health examination, which was performed in five community health centers in Stockholm (Tables 1.2 and 1.5) [37]. The study randomized 70 men and 13 women who fulfilled the inclusion criteria to two groups: either to brief counseling by their own physician about reducing their alcohol consumption or to a group which in addition received laboratory tests and were scheduled for repeated followup visits. The followup period was 12 months and the followup rate was 87%. Alcohol consumption, GGT levels, and the number of alcohol problems decreased more in the intervention group than in the brief counseling group, but the differences were not significant. A study by Seppä randomized 140 men and 38 women with an elevated MCV level to a control group and to a group which was given brief counseling and repeated followup visits and laboratory tests (Tables 1.2 and 1.5) [41]. The followup period was 12 months and dropout was as high as 48%. No significant differences in MCV levels could be noted between the two groups. More recently, Aalto et al. recruited 296 male early-phase heavy drinkers who had consulted a general practitioner for various reasons [1]. Those in the control group (n=88) were informed of the risks of drinking after screening and were advised at the subsequent feedback session about 2 weeks later to reduce their drinking. Two other groups (n=109 or 99) were offered, in addition, either seven or three brief intervention sessions, respectively. No statistically significant differences were
25
26
1 Intervention against Hazardous Alcohol Consumption – Secondary Prevention of Alcohol Problems
found between the study groups, either in self-reported alcohol consumption or in laboratory markers. However, all groups significantly reduced their alcohol consumption in 25–53% of the subjects, and this was associated with a significant decrease in the MCV value. The quality of the study was high and followup was 36 months. The dropout rates were 39% and 30% in the two intervention groups and 24% in the control group.
1.5
Analysis of the Overall Results of the Reviewed Studies
The quality in 25 out of 27 studies was high, good, or moderate, and was acceptable in 2. In the 25 studies, the quality rating varied from 33 of 33 possible to 23 of 33 or from 29 of 30 possible to 24 of 30 (Table 1.2). Seven of the studies had been performed in large patient groups, from 516 to 1559 subjects (total = 5691). It may be noted that the quality of the articles was comparable to that in equivalent studies in other areas of research. A meta-analysis of the studies was not judged to be meaningful, since inclusion criteria, intervention methods, and outcome measures were too heterogeneous. However, relative and absolute risk reductions were calculated in the individual studies when possible. Based on these figures, NNT (Number Needed to Treat) was also calculated. NNT is the number of heavy drinkers or persons with an alcohol problem who should receive brief intervention in order that one individual reduces his/her alcohol consumption to a more risk-free level. This information is given in Table 1.3,where the individual studies are listed in the order of their quality. 1.5.1
Studies with a Positive Outcome
In 18 out of 25 randomized controlled studies – of at least moderate quality – brief intervention had a significant positive effect (Tables 1.2 and 1.4). These 18 studies included 7812 individuals (6198 men and 1614 women) from general health care. Six of the studies which were carried out in primary health care and one study which was carried out in hospitals included a particularly large number of patients and were of high quality. In the seven studies, the intervention varied from brief counseling to a form of cognitive therapy in 6–9 sessions during 1 year [11, 48]. In 2 of these 7 studies, the significant difference in reduction of alcohol consumption could be confirmed by a significant difference in the reduction of the gamma GGT level [11, 45]. Furthermore, 2 of these studies showed a significant reduction in the number of hospital days and 1 study showed a significant reduction in the incidence of new injuries and the need for hospital care [14, 17]. In 12 of the studies mentioned above it was possible to calculate the relative risk reduction (RRR), the absolute risk reduction (ARR), and the number (NNT) of persons needed to receive an intervention in order that one individual reduces his/her alcohol consumption during 6 to 24 months to a more risk-free level (Table 1.3) (see
1.5 Analysis of the Overall Results of the Reviewed Studies
page 28-29). The results from the 6 other primary care-based studies also show positive effects (Table 1.4) (see page 30-33) [10, 25, 27, 30, 40, 44]. In one of these, a significant reduction in sick leave during 48 months in comparison with the control group could be shown [25]. The study by Maheswaran et al. showed a correlation between the reduction in alcohol consumption and a significant reduction in the GGT level and blood pressure [27]. Two more recent studies have addressed the long-term effects of brief interventions. One of these showed a decreased alcohol-related mortality after 10–16 years of the intervention. The long-term (10 years) effects of brief intervention, however, were negative in the other study. Six studies, which showed positive effects on alcohol consumption, were performed in hospital patients (Table 1.4). Further significant findings in these studies were: a reduction in the GGT level and fewer alcohol-related problems in one study, and reduction of psychosocial problems and physician visits in another study. Fewer alcohol problems, greater personal well-being, and better working capacity were shown in one study [13]. A reduction in sick leave and a reduction in new injuries and the need for hospital care could be documented in two studies (Table 1.4) [17, 31]. It can also be noted that in 8 of the 17 studies which showed a reduction in alcohol consumption, other positive effects could also be demonstrated. In most cases, these additional positive effects indicate a significant reduction in the negative effects caused by alcohol.
27
28
1 Intervention against Hazardous Alcohol Consumption – Secondary Prevention of Alcohol Problems Table 1.3. Relative (RRR) and absolute (ARR) risk reduction. Number (NNT) of problem drinkers who would need to have a brief intervention for one person to reduce his/her alcohol consumption to a more risk-free level. Article
Followup period
Type of intervention
Intervention group Number with reduced alcohol consumption/ total number (Intervention %)
Cushman et al. [10] 6 months 12 months 24 months
Extensive intervention
141/320 (44) 141/320 (44) 118/320 (37)
Fleming et al. [13]
12 months
2 brief counseling sessions + book
100/160 (63)
Wallace et al. [42]
12 months
Brief counseling + book + followup
201/448 (45)
Ochene et al. [28]
6 months
Education of the physician followed by intervention
102/274 (37)
WHO study [45]
6 months 6 months
One brief counseling Brief intervention + book
111/496 (22) 104/576 (18)
Fleming et al. [14] (>65 years)
12 months
2 interventions (10–15 min) + book
11/78 (29)
Richmond et al. [33] 12 months
Brief and extensive intervention
34/136 (25)
Anderson et al. [3]
12 months
Brief counseling + book + lab test
14/80 (18)
Scott et al. [36]
12 months
Brief counseling + book + lab tests
9/33 (27)
Chick et al. [8]
12 months
Intervention (60 min) + book
34/69 (49)
Antti-Poika et al. [4] 6 months
Intervention + book + followup visit
22/49 (45)
Heather et al. [18]
Brief or extensive intervention
9/59 (15)
6 months
RRR = Int % – Cont % / Int % ARR = Int % – Cont % NNT = 1 / ARR CI = Confidence interval for ARR.
1.5 Analysis of the Overall Results of the Reviewed Studies
29
Control group Number with reduced alcohol consumption/ total number (Control %)
Relative risk reduction RRR (%)
Absolute risk reduction ARR ± CI (%)
Number (NNT) of heavy drinkers needed to have brief intervention for one to reach a more risk-free level
Confidence interval (CI)
74/321 (23) 83/321 (26) 67/321 (21)
48 41 43
21±7 18±7 16±7
5 6 6
4–7 4–9 4–11
57/176 (32)
49
31±10
3
2–5
122/459 (27)
40
18±6
6
4–8
66/256 (26)
30
11±8
9
5–33
59/486 (12) 59/486 (12)
45 44
10±5 6±4
10 17
7–20 10–50
0/67 (0)
100
29
3
1–13
13/61 (21)
16
4±13
25
6–
4/74 (5)
72
13±10
8
4–33
10/39 (26)
4
1±
100
–
20/64 (31)
37
18±16
6
3–50
8/40 (20)
56
25±19
4
2–17
3/32 (9)
40
6±14
17
5–
30
1 Intervention against Hazardous Alcohol Consumption – Secondary Prevention of Alcohol Problems T 1able 1.4. Characteristics of the studies with a positive outcome presented in order of quality. Article
Characteristics
Intervention/comparison
Cushman et al. [10] Primary care
Large database N=641 High quality 33/33
C (no advice about alcoholism) vs a brief form of cognitive therapy for 6–9 months or several sessions for 1 year
Fleming et al. [13] Primary care
Large database N=774 High quality 32/33
C (general health examination) vs 2 brief counseling sessions + instruction book
Wallace et al. [42] Primary care
Large database N=909 High quality 32/33
C (no info) vs 1 brief counseling + instruction book + drinking diary + 1–4 followup visits
Ochene et al. [28] Primary care
Large database N=530 High quality 32/33
C (general health examination) vs education of the physician (2.5 hours) + IV (5–10 min) + followup visit
Gentiello et al. [16] Hospital
Large database N=762 High quality 29/30
C (routine treatment) vs intervention (30 min) + letter 1 month later
WHO study [45] Primary care
Large database N=1559 High quality 32/33
Control vs brief counseling (5 min) vs 1 brief intervention (15 min) + instruction book
Fleming et al. [14] All >65 years Primary care
Adequate database N=158 High quality 32/33
C (general health examination) vs 2 interventions (10 + 15 min) + instruction book
Anderson & Scott [3] Primary care
Adequate database N=154 High quality 31/33
Control vs 1 brief counseling (10 min) + laboratory tests + instruction book
Senft & Polen [37] Primary care
Large database N=516 High quality 31/33
C vs 1 brief advice (30 s) + motivational guidance (15 min) + written information
C = control; IV = intervention.
1.5 Analysis of the Overall Results of the Reviewed Studies
Outcome measure: Changes in alcohol consumption
Outcome measure: Changes in GGT
Outcome measure: Other changes
Significant difference in reduction of alcohol consumption and hazardous drinking
Significant difference in reduction of GGT level
Non-significant difference in reduction of blood pressure
Significant difference in reduction of alcohol consumption, periods of drinking, and drinking until intoxicated
Not analyzed
Significant reduction in number of days in hospital
Significant difference in reduction of alcohol consumption and number of patients with high consumption
Significant difference in number of individuals with reduction of GGT level
Significant difference in reduction of the alcohol consumption
Not analyzed
Significant difference in reduction of alcohol consumption
Not analyzed
Significant difference in reduction of alcohol consumption and intensity of drinking, difference between brief counseling and IV not significant
Not analyzed
Significant difference in reduction of alcohol consumption
Not analyzed
Significant difference in reduction of alcohol consumption
No significant changes
Significant difference in reduction of alcohol consumption
Not analyzed
Significant reduction in number of new injuries and medical care
(Table continues on next page)
31
32
1 Intervention against Hazardous Alcohol Consumption – Secondary Prevention of Alcohol Problems Table 1.4. (cont.) Article
Characteristics
Intervention/comparison
Maheswaran et al. [25] Primary care
Small database N=47 High quality 28/30 Patients with hypertension
Control vs brief counseling + repeated followup visits
Nilssen et al. [27] Primary care
Large database N=338 Good quality 27/30
C (no advice) vs brief IV (10–15 min) + instruction book vs long IV + diary + followup visit
Chick et al. [8] Hospital
Sufficient database N=156 Good quality 27/30
C (standard treatment) vs intervention (60 min) + instruction book
Israel et al. [21] Hospital
Sufficient database N=105 Good quality 28/33
Brief advice vs intervention (30 min) by nurse + 6 followup visits (20 min)
Córdoba et al. [9] Primary care
Large database N=229 Good quality 27/33
Brief advice (5 min) vs intervention (15 min) + instruction book + followup visit
Elvy et al. [12] Hospital
Large database N=263 Good quality 27/33
C (standard treatment) vs brief IV with intention to make the patient accept a referral to an alcohol counselor
Antti-Poika et al. [4] Hospital
Sufficient database N=120 Moderate quality 24/30
C (standard treatment) vs brief advice + instruction book + 1–3 followup visits
Persson et al. [29] Hospital
Small database N=78 Moderate quality 24/30
C (standard treatment) vs brief advice + >5 followup visits with laboratory tests
Kristenson et al. [23] Primary care
Large database N=473 Moderate quality 23/33
Control vs brief counseling + repeated followup visits with laboratory tests
Tomson et al. [41] Primary care
Sufficient database N=222 Acceptable quality 19/39
Control vs 3 interventions by a nurse
C = control; IV = intervention.
1.5 Analysis of the Overall Results of the Reviewed Studies
Outcome measure: Changes in alcohol consumption
Outcome measure: Changes in GGT
Outcome measure: Other changes
Significant reduction (50%) in intervention group, not in control group
Significant reduction (21%) in intervention group only
Significant reduction in AST (18%) and RR in intervention group only
Significant reduction in 2 of the IV groups, no difference between the IV groups
Significant reduction in the IV groups, not significant increase in the control group
Significant difference in reduction of alcohol consumption
Significant difference in reduction of the GGT level
Fewer alcohol-related problems in the intervention group
Significantly greater reduction of alcohol consumption in the intervention group
Significant reduction in the intervention group but not in the brief advice group
Significant reduction of psychosocial problems and medical visits in IV but not in brief advice groups
Significant reduction in alcohol consumption, significant difference between the groups
Not analyzed
Significantly longer time until the first drink in the intervention group
Not analyzed
In the intervention group: fewer alcohol problems, greater personal happiness, and better working capacity
Significantly greater reduction in the intervention group
Significant reduction in the intervention group
Significant improvement in the intervention group in comparison with controls
Reduction in the intervention group
Reduction in the intervention group
Significant reduction in sick leave in the intervention group, increase in the control group
Not analyzed
Significant reduction in both groups, but no difference between groups
Significant reduction of sick leave and fewer days in hospital in comparison with control group
Not analyzed
Reduction in intervention group, increase in control group
33
34
1 Intervention against Hazardous Alcohol Consumption – Secondary Prevention of Alcohol Problems Table 1.5. Characteristics of the studies which did not show any significant effects. Article
Characteristics
Intervention/comparison
Richmond et al. [33]
Large database N=378 High quality 32/33
Control (investigation only) vs brief advice (5 min) vs brief intervention (10–15 min) + 4 followup visits
Scott & Andersson [36]
Moderate database N=72 women High quality 31/33
Control vs brief advice (10 min) + laboratory tests + instruction book
McIntosh et al. [26]
Large database N=159 Good quality 26/30
Advice (5 min) by physician vs intervention by physician (2 x 30 min) vs intervention by nurse (2 x 30 min)
Lang et al. [24] Patients with hypertension
Moderate database N=129 Good quality 29/33
Control vs followup of the GGT level with motivation to reduce alcohol consumption
Suokas [40]
Large database N=247 Good quality 28/33
Brief counseling (5 min) by physician vs intervention with followup visits (2–3) and laboratory tests
Heather et al. [18]
Moderate database N=104 Moderate quality 25/33
Control (extensive interview) vs brief advice by physician vs DRAMS intervention
Romelsjö et al. [34]
Moderate database N=83 Moderate quality 23/33
Brief counseling by physician vs intervention with laboratory tests and repeated followup visits
Seppä [38]
Large database N=300 Acceptable quality 18/30
Control vs brief advice + repeated followup visits with laboratory tests
↓ = down, ↑ = up.
1.5 Analysis of the Overall Results of the Reviewed Studies
Outcome measure: Changes in alcohol consumption
Outcome measure: Changes in GGT
Outcome measure: Other changes
21–25% reduction in all 3 groups, no differences among groups
Not significant reduction in all groups
MAST points: no differences
Intervention: ↓ 27% Control: ↓ 26%
No significant changes
Significant reduction in dependence scale in both groups
26–56% reduction in all groups, no differences among groups
Not analyzed
14% problem-free in the beginning and 45% after 12 months in all 3 groups
Reduction in both groups, no differences among groups
Reduction in both groups, no significant differences between the groups
Greater reduction in RR in the intervention group
Both groups: no significant changes
Significant reduction in both groups, no difference between the groups
No significant differences in alcohol problems or number of sick days
Significant reduction in all groups, no differences among groups
Significant reduction in all groups, no difference between the groups
Improved physical condition in all groups
Reduction in both groups, no differences among groups
Reduction in both, no significant differences between the groups
No change in the MCV level
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1 Intervention against Hazardous Alcohol Consumption – Secondary Prevention of Alcohol Problems
1.5.2
Studies which Showed No Effects
The 8 studies which reported no effects involved a significantly smaller number (n=1472) of individuals (Table 1.5) (see page 34–35). This increases the probability of not detecting actual differences among the compared groups. In 3 of the negative studies there was no real control group, but a brief counseling by a physician was actually compared with more intense forms of intervention [28, 37, 43]. In 4 other studies with a negative outcome (measure), alcohol consumption decreased in all groups, and in 2 groups a significant reduction in the GGT level was noted, while no significant differences could be shown between the different intervention groups [19, 26, 36, 39]. Other effects which were observed in the 4 studies were a significant reduction in the dependence scale in both groups, improved physical condition in all 3 groups, and a greater reduction in the blood pressure in the intervention group (Table 1.5) [19, 26, 39]. The quality of the last, negative study was lower but acceptable. Only the change in MCV level was used as an outcome measure [41].
1.6
Important Aspects of Brief Intervention 1.6.1
Analyses of Special Groups
It would be interesting to compare the effectiveness of brief intervention in different subcategories such as women and hospitalized patients. It would also be of value to study differences between the effects of brief and more intensive interventions. However, it is well known that the risk of false positive and false negative effects increases significantly if subgroups of patients are analyzed retrospectively. The effectiveness of brief intervention in women can best be judged based on the results from the largest and best studies. The study by Cushman et al. included only 5 women [11]. In the study by Fleming et al., the greatest reduction in alcohol consumption, nearly 50%, could be attributed to the women in the intervention group (n=148) [14]. After 12 months, 22% of the women drank more than the threshold value for hazardous alcohol consumption in the intervention group as compared with 49% in the control group. The difference was statistically significant. The study by Wallace et al. included 272 women, and here alcohol consumption decreased significantly and approximately as much in men as in women [45]. In the WHO study, the 299 women significantly reduced their alcohol consumption both in the intervention group and in the control group, but the differences between the groups were not significant [48]. The same results were also achieved in the study by Scott and Anderson which included only women (n=72) [39]. Based on this limited material, it can be assumed that brief intervention has the same effect on women and men.
1.7 Problems with Dropout in Studies
In 8 studies, brief counseling given by a physician was compared to a more intense form of intervention [19, 22, 28, 30, 36, 37, 43, 48]. In 7 of these studies, no difference in effect between the 2 types of intervention was found. In one study it was found that cognitive intervention with repeated followup visits and laboratory tests was significantly more effective than brief counseling [22]. Thus, the optimal extension of a brief intervention still seems to be unclear.
1.7
Problems with Dropout in Studies
Edwards and Rollnick have pointed to the problems with dropout – when the estimates of effect are based only on those who could be interviewed during followup examinations [12]. It is argued that this complicates the interpretation and generalizability of information from the brief intervention studies. The brief intervention studies published to date indicate that the positive results are achieved in studies which have been performed in the most suitable populations [12]. This is in agreement with our findings. The populations in the studies presented in this review usually consist of middle-aged heavy drinkers and problem drinkers (Table 1.2) who have been identified in primary health care and have been willing to accept the intervention. The only exception to this was the study by Elvy et al., which included younger heavy drinkers (mean age 29 years) [13]. In other studies, the mean age varies from 30 to 65 years (usually above 40 years). Another problem is that the persons who dropped out during the followup time probably differed significantly from those who stayed in the study. For example, in the study by Suokas, those who could not be followed up drank significantly more, had more problems with alcohol, and smoked to a greater extent than the rest [43].
1.8
Problems with Implementation
Though the effects of brief intervention have been shown in many randomized controlled studies, the method has only been used to a limited extent. The difficulties of incorporating brief intervention with the routines of primary care and motivating health care employees to perform new activities are obvious. After a single day of education followed by some supervision, 35 physicians and nurses identified only 45 suitable cases for brief intervention during 6 months [6]. The authors conclude that it is possible to educate health care staff in using brief intervention. However, better screening methods are needed for the early detection of problem drinkers. It is also possible that certain physicians and nurses may be reluctant to address alcohol problems. A recently published study from the United States found that 2.5 h of education for physicians in using brief intervention in association with a continuous support doubles the activity of the physicians in this area [2].
37
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1 Intervention against Hazardous Alcohol Consumption – Secondary Prevention of Alcohol Problems
In a randomized controlled study from 1991, Goldberg et al. showed that it is possible to enhance both screening and brief intervention [18]. In this study, the screening was made as part of the normal patient admission routine. By means of a two-item screening form, the nurses succeeded in estimating the alcohol habits in 90% of their 1328 patients during 4 months. Of these patients, 36% had a hazardous level of alcohol consumption, and approximately 30% of these accepted a referral to an alcohol counselor. This is a good result as compared to the patients treated in the standard way by their physician. Of these, 20% were given a referral to alcohol counseling. The authors conclude that the number of patients given adequate alcohol counseling increases in routine use of screening for hazardous alcohol consumption.
1.9
Summary
Detection and treatment of early alcohol problems is potentially of great importance. Different short-term interventions were studied in 25 randomized studies involving over 9000 patients. Most of the studies were conducted in the Nordic and English-speaking countries. The interventions were delivered mainly in primary health care and were carried out by physicians or nurses. However, the design of optimal treatment remains unclear. More extensive interventions have not consistently resulted in greater treatment benefits. It is also uncertain whether the measures yield effects after more than 2 years or if the intervention must then be repeated. There are also difficulties in transferring the research results to routine health care. In most of the studies, a significant effect of a brief intervention on alcohol intake has been shown in followups for up to 2 years. The treatment effect is of the same magnitude as that achieved with many common medical treatments for chronic conditions.
Glossary
GGT ASAT ALAT MCV
An enzyme produced in the liver, often in greater amounts due to high alcohol consumption but sometimes for other reasons. An enzyme produced in the liver, sometimes in greater amounts in patients with high alcohol consumption. An enzyme produced in the liver, sometimes in greater amounts in patients with high alcohol consumption. The volume of the red blood cells. At times increased because of high alcohol consumption.
References
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1 Kolumnentitel
2
Psychosocial Treatment for Alcohol Dependence Sven Andréasson, Agneta Öjehagen
2.1
Introduction 2.1.1
Earlier Reviews
Numerous reviews on the effects of treatment for alcohol problems have been published since the 1940s [11, 37, 50, 55, 56, 68, 69, 91, 113, 117, 132, 137, 175]. The need for reviews has increased as treatment research has expanded and become increasingly difficult to overview. The current literature is extensive. A MEDLINE search of studies published from 1966 through 1999 on the treatment of alcohol problems yielded 22 870 studies. Limiting the search to randomized controlled trials (RCTs) yielded 722 studies. However, many of these studies focus exclusively on pharmacology, secondary prevention, or adolescents. 2.1.2
Assessing the Effects of Different Methods
The most extensive literature reviews are the Holder et al. study from 1991 and the further elaboration and expansion of this material by Miller et al. in 1995 [69, 117]. The latter analysis attempts to rank all treatment methods that have been studied in controlled trials. The rank is determined mainly quantitatively according to the number of studies where a particular method was found to yield better or poorer results than an alternative treatment. The magnitude of the effect was not calculated. Instead, it was estimated whether, and how well, an effect from a method could be demonstrated on a 4-grade scale. The strongest evidence is considered to exist if a method shows an effect in relation to (1) no treatment, or (2) better/equal effect than another method which has shown an effect in relation to no treatment, or (3) if adding a particular method to another method yields a better result than without this addition. If one method is compared to another, but a control group is lacking according to the alternatives mentioned above, the evidence is judged to be less Treating Alcohol and Drug Abuse. Edited by M. Berglund, S. Thelander, E. Jonsson Copyright c 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 3-527-30682-X
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strong. Results are based on changes in drinking habits and/or other measurements, during some period of the followup. Furthermore, particular value is attributed to methods that show results in at least two studies. Also, an attempt is made to adjust for the variations in study quality. The final result, the cumulative evidence score (CES), is an index value where the number of studies indicating effect is weighed together with the effect grade and quality scores. The CES score does not control for study size or the level of severity in the study population. Similar reasoning is used to assess the effects of psychological methods in general (including treatment for substance abuse). A distinction is made whether an effect has been demonstrated in comparison to no treatment or has yielded a specific effect, i.e., in relation to competing methods. In the latter case, one controls for factors common to all treatment, e.g., attention and expectation effects [30]. Furthermore, an emphasis is placed on replication in at least two studies performed by other researchers. Interpretation can be difficult, for example, when Miller et al. gives higher scores for studies where the control groups are not provided with any treatment, while comparisons between two established methods that show the same results are not given any score [117]. Although none of the studies is superior in relation to the others, this does not mean that they are lacking in effects. Furthermore, comparability problems arise when a specific treatment is compared to “standard treatment” since the information about standard treatment is often deficient compared to specific treatments that are well documented and supported by theory. Furthermore, the interest and commitment among those providing treatment according to a specific, often new, methodology may be higher than among those providing traditional treatment. Ideally, the effects of every method should be assessed using the same type of comparisons. A design using a control group which is not treated or placed on a waiting list is more difficult to apply to patients with moderate/severe alcohol problems. Miller’s scoring system therefore favors studies of patients with milder forms of alcohol problems [117]. This illustrates the difficulties in finding an appropriate placebo therapy within the area of psychosocial treatment. Hence, when a method appears to be superior it may be a function of what it was compared with. In an attempt to manage this problem (“level the field”), Finney et al. performed a new analysis of the original material from Holder [55, 69], attempting to evaluate both effect and study design. Furthermore, it considered several statistical factors such as number of tests performed, one- or two-tailed tests, and categorical or continuous data. An interesting finding is that Miller et al. ranking of studies changes only marginally in the analysis by Finney et al. [55, 117]. The only meta-analysis of treatment for alcohol problems (excluding brief intervention) so far was done by Vito Agosti [1, 2]. However, here the aim was not to identify which methods yield the best results. The Agosti analysis, which consists of two parts, aims instead to answer the questions of whether treatment for alcohol problems (regardless of method) leads to the patients reaching total abstinence and whether treatment leads to reduced alcohol consumption. The first question is
2.1 Introduction
answered negatively, the second affirmatively. However, the value of this analysis, certainly as regards an issue of central importance, is diminished by the limited sample of studies and by the meta-analysis technique (see discussion below on meta-analysis). 2.1.3
Methodological Deficiencies and Problems
The quality in the treatment literature has gradually improved. Five basic requirements should be made on alcohol treatment studies. First, the intervention itself should be described; e.g., the duration of treatment, the intensity of treatment (e.g., number of sessions per week), and the type of care setting (outpatient, inpatient) where treatment is given. Second, the patients studied should be described, e.g., demographic data, data reflecting the patients’ degree of alcohol dependence, their social situation, other substance use problems, prevalence of mental disorders/personality disorders, and their motivation to change. Third, the delivery of the treatment should be described, e.g., the competence of the caregivers, methods of quality assurance (manual-based treatment, videotaped sessions, supervision, followup) and the percentage of planned sessions that were actually carried out. Fourth, a presentation of results should contain data that enables the reader to estimate the magnitude of the effect (e.g., median values and standard deviations). It is desirable to show results concerning the drinking behavior itself (rates for total sobriety and rates of reduced consumption) and improvements in the life situation in a broad context (social situation, quality of life). Fifth, data should be provided which enables the reader to estimate a quality score of the study. Included here are the above-mentioned data on methods for randomization, principles for patient selection, diagnostic method, description of the control treatment and statistical method (e.g., number of performed tests, selection of one- or two-tailed tests, etc.) [118]. Nevertheless, many randomized studies that are published in the alcohol treatment field are deficient in some aspects, limiting their scientific value. When conducting literature reviews, these deficiencies lead to problems in interpretation, mainly due to poor comparability. 2.1.4
Treatment Methods
The methods used to treat alcohol problems can be divided into those directed mainly at 1. motivation to change 2. changing the problem behavior itself 3. methods that focus on factors behind drinking problems 4. general supportive counseling 5. treatment focusing on partners or family.
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Most treatment studies evaluate the effects of different methods that yield an (initial) change of drinking habits. Also, many studies address treatment or prevention of relapse. However, the literature is more limited concerning methods for motivating people to change and maintaining the changes achieved. 1.
Motivational methods These are methods that discuss perceived advantages and disadvantages of alcohol consumption, short-term and long-term consequences, risk situations for problem drinking and alternatives to alcohol. This type of counseling largely leaves the individual to deal with change on his/her own.
2.
Methods aimed specifically at changing drinking behavior These methods aim at identifying risk situations for problem drinking, finding strategies to deal with these situations, training aimed at changing problem drinking, and coping with internal and external stress factors of significance for problem drinking (these methods include variants of cognitive behavioral therapy methods, and 12-step treatment). These often involve active change efforts that focus on drinking behavior.
3.
Methods focusing on factors behind drinking problems These methods target substance abuse in relation to underlying factors. The methods involve dynamic-oriented treatment that include the patient’s life history to help understand the drinking problem, although treatment focuses on current problems, and interactional therapies directed at interpersonal problems which are presumed to increase the tendency to use alcohol. These methods do not directly focus on training to change the problem drinking itself.
4.
General supportive counseling These programs usually do not outline a focused strategy in relation to the problem behavior. A common theme is supportive counseling combined with social work interventions. Disulfiram treatment is also included in some cases. Increasingly, the focus is on circumstances surrounding problem drinking, including causes and consequences. The literature may describe these programs as “standard treatment”. Combinations of different measures are specified to a greater or lesser extent. These programs are usually not described as clearly as programs with methods specifically targeted at changing drinking behavior. The different supportive measures are described in varying detail and differ in their degree of structure.
5.
Treatment focused on partners and family This treatment approach consists of programs that involve the problem drinker and his/her partner together and programs aimed at partners or family members only.
2.1 Introduction
Section 2.3 (Results) presents an assessment of effects based on the method categories 1 to 5, where categories 1 to 3 and usually category 5 are called specific methods, i.e., theory-based and where the methodology is well described, while category 4 is reported as standard treatment. To a varying degree, treatment of alcohol problems can be combined with interventions on other life problems. These include counseling and interventions concerning employment, economy, relationships, health, and general support to prevent drinking. Psychosocial treatment is regularly included as a component in pharmacological treatment for alcohol dependence. Modern drugs reducing the desire to drink; mainly naltrexone and acamprosate (see Chapter 4) are usually combined with psychosocial treatment, e.g., cognitive behavioral therapy (CBT). Treatment research has been aimed at finding effective treatments and at developing guidelines to differentiate treatments considering variations in the problem profiles of drinkers, so-called matching. In some randomized studies, differential effects have been identified in secondary analyses, when effects were found in subgroups of patients with certain characteristics. Other studies have primarily investigated different matching hypotheses. Matching studies are presented separately in this report. 2.1.5
Treatment Effects
When discussing treatment effects, authors are usually referring to the effect of different treatment methods. However, the entire treatment context is of importance. Important components in addition to the method itself include the patients’ characteristics, the competence of the therapist, and the patient-therapist relationship. The method itself explains only a part of the outcome variance. This fact calls for study populations large enough to identify the treatment effects that can be specifically ascribed to the method. In addition, high demands on quality must be fulfilled, e.g., consistent application of the treatment methodology, which in turn calls for qualified supervision. Certain methods are easier to learn, e.g., brief interventions, while others place higher demands on therapist competence concerning both training and practice (e.g., cognitive behavioral therapy and interactional therapies). To assure methodological quality, studies have been relying increasingly on manuals. In psychological treatment, therapist quality, mainly the ability to empathize and achieve a working alliance, has also been shown to influence the results of treatment [15, 20, 71]. The therapist should be able to achieve collaboration with different patients. Awareness that this factor contributes to the outcome has prompted several treatment studies, e.g., Project MATCH, to include a measure of the working alliance [36].
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2.1.6
Questions Addressed
Does psychosocial treatment have an effect in comparison with no treatment? In this review, which is limited to randomized controlled studies, the effects of treatment methods are evaluated by comparing them either with no treatment or with another treatment. Studies that compare treatment with no treatment answer the question of whether a treatment method has any effect at all. These studies can be divided into four groups: 1. The comparison group is neither treated nor assessed. Even an assessment itself has an influence on the control group. Hence, these studies are limited to studies of natural courses and do not include a personal examination, e.g., register studies of health service utilization or mortality. This type of comparison is not included here. 2. The comparison group undergoes an initial assessment and followup examinations; it is informed about the study, but is not given any treatment. Even if no treatment is provided, such a study design has an influence on the control group. However, it is unclear how strong this influence is in different cases. 3. The comparison group is placed on a waiting list. The comparison is then limited to the time period defined by the waiting list, usually a few months. Also in this case, the comparison group is subjected to an initial assessment and followup examinations. According to the literature, however, a waiting list is considered to have a negative influence on the patient [86]. 4. “No treatment” also includes a comparison with minimal treatment, i.e., more extensive treatment is compared with one session of advice or feedback of results from the assessment. Are some methods superior to others? Comparisons with other treatments can be performed in several different ways. In principal, they can be divided into three categories:
1. Comparison with “standard treatment” 2. Comparison with another specified treatment, i.e., a treatment that is clearly theory-based and where the method is manual guided and supervised 3. Comparison that includes adding an extra treatment component in addition to a common primary treatment, for the study group. Comparisons can also be made between individual and group treatment based on the same treatment method.
2.1 Introduction
2.1.7
Intensity and Aftercare
A comparison may address the intensity of the same type of treatment program. This can be done in different ways. ● Minimal treatment contact, e.g., an occasional interview or an entire program ● Few or many sessions within the same program, e.g., 4 sessions compared to 12 sessions ● Short or long contact involving the same number of sessions in the same program, i.e., the duration of the program ● Therapist-managed or self-managed treatment. For this purpose, a manual of some kind is distributed. This type of treatment is sometimes called “bibliotherapy”. Comparisons between different types of care also concern the intensity of treatment. Here, studies will be presented which compare the effect from different forms of intensity; types of care (outpatient care, inpatient care) and the duration and extent of the methods (length of time, few or many sessions). In this context, studies on aftercare are also presented. Aftercare may take place in the form of a specific methodology, so-called booster sessions, or followup support contacts. 2.1.8
Subgroups of Alcohol Dependence
During the past decade, patients with alcohol dependence who have other concurrent diseases, mainly other psychiatric disorders, have received increasing attention since comorbidities influence treatment study designs and outcomes. Severe psychiatric conditions are often included among exclusion criteria in treatment studies. However, uncertainties exist in many studies concerning the occurrence of dual diagnoses, especially personality disorders. Only a few of the randomized controlled studies evaluate treatment methods in this group. Randomized studies identified in this area are presented in this chapter. Homeless alcohol-dependent patients have received increasing attention, and interventions for this group are evaluated in some randomized studies. Psychiatric and somatic comorbidity also occurs in this group. It is often discussed whether treatment results differ between men and women, and whether special methods should be used to treat women. This issue will be addressed where controlled studies present separate analyses for women and men, although this is uncommon.
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2.2
Method and Material 2.2.1
Search Strategies
This review is limited to randomized controlled trials. Using the keywords “alcoholism” and “randomized controlled trial”, a MEDLINE search yielded 722 studies through January 1999. Additional searches were performed in the NIAAA study base EtOH, and in Current Contents. Reference lists from earlier reviews and published studies were also reviewed. Unpublished dissertations and results published in books were not included in the analysis. Furthermore, the search was limited to studies describing results from psychosocial treatment of alcohol problems. Studies on pharmacological treatment, on treatment of adolescents, and secondary prevention (with certain exceptions for studies comparing treatment with no treatment) have been excluded. Ultimately, 139 studies were included. In March 2002, a renewed literature search was conducted (following the original publication of this report in Swedish in 2001). This search yielded an additional 25 randomized, controlled studies. The results from this renewed search are summarized in the last part of the results section. 2.2.2
Result Protocol
In addition to presenting numbers of patients and gender distribution, Tables 2.11 through 2.22 present problem severity based on a 3-grade scale, brief descriptions of the intervention and control groups, the duration of treatment, followup time, the percentage of patients followed up, methodological quality of the studies (Qscore), treatment results, and a summary of these factors. The foundation for these data varies considerably from study to study. Data are often missing concerning the characteristics of the patient and the delivery of treatment (e.g., therapist competence). A description of alcohol problems is the variable that appears most often in the studies, and it was deemed possible to categorize problem severity into three groups: mild = 1, moderate = 2, heavy = 3. The “mild” group (n=28) consists of populations not judged to be severely alcohol dependent, often referred to as “problem drinkers”. The “heavy” group (n=23) includes patients with severe complications from drinking, e.g., homelessness. Hence, most of the populations (n=88) have been categorized as “moderate”. The results nearly always present consumption specified in terms of total abstinence, controlled drinking, or number of drinking days. Some studies also discuss change in other problem areas. Observation periods and followup times vary. Confirmation of the results by family members or biochemical analyses is desirable, but often missing. Data on changes in drinking behavior served as a minimum requirement for studies to be included in this review. Total abstinence and controlled consumption, as outcome measures, have been subject to considerable debate. It is
2.3 Results
essential to describe whether the different methods achieve change in only one or in both of these parameters. Studies usually report only the percentage of those achieving complete abstinence, but less often present data on controlled consumption and changes in the percentage of drinking days. Also, treatment goals (which are not always stated) vary among the different studies. 2.2.3
Meta-analysis
Meta-analysis is used to combine results from different studies, giving consideration to variations in the size of the patient groups and the differences in confidence. This project was initially intended to estimate the effect sizes related to all treatment methods, largely because many studies were based on relatively few patients and therefore lacked sufficient statistical power to address the issues. Unreflective use of meta-analysis may lead to unreasonable conclusions due to heterogeneity in central variables. In many cases it was not feasible to perform meta-analysis in this review. To illustrate the potential of the meta-analysis method, smaller groups of studies with similar patient databases have been studied, however, following the meta-analytic procedures outlined in the introduction to this volume. Seven meta-analyses of this type were performed and are presented in the results section. The results are summarized in Table 2.10 and Figures 2.1 and 2.2.
2.3
Results 2.3.1
Does psychosocial treatment have any effect? Comparisons with no treatment
Studies that compare treatments with “no treatment” answer the question of whether these treatments have any effect, but do not specify the effect in comparison to other treatments. These comparisons do not control for several nonspecific factors surrounding all treatment, e.g., expectation of change or the importance of receiving attention. In the studies presented below, all patients were initially assessed, i.e., including those not receiving any treatment. Hence, a therapeutic effect from the assessment interview cannot be excluded. Sixteen studies were found (see Table 2.11a,b) of which 10 included comparisons with no treatment [23, 26, 33, 41, 66, 85, 99, 124, 131, 148]. Three of the studies included drunken drivers, of which two studies are lacking followup data concerning alcohol habits [23, 41, 99]. Six studies included comparisons with individuals on a waiting list for treatment [4, 14, 28, 51, 65, 116]. Comparison with no treatment Of eight studies (excluding the two drunken driver studies without data on alcohol habits) six included patients with a low problem severity [23, 26, 33, 66, 85, 124,
51
52
2 Psychosocial Treatment for Alcohol Dependence
131, 148]. Three of these show better results with intervention; two of the studies use behavioral therapy techniques and one uses physical exercise. Of the three studies [33, 66, 148] that do not show any differences, one [66] concerns intervention from primary care. In one study [23], the group is followed up on repeated occasions without intervention, and one study [148] shows an initial improvement after 3 weeks of intervention focused on coping with stress, which, however, is not sustained at 6-month followup. Two studies concern patients with a greater problem severity. One is a study of mentally impaired, homeless patients where a positive treatment effect was observed by the use of case management, with or without supportive housing, compared to no treatment [26]. The second is a smaller study that attempted to establish a counseling contact with alcohol-addicted social “outcasts” [131]. No effects could be observed from the intervention. Two of the three studies on drunken driving report no measures of consumption. One of the studies shows no difference in the rate of relapse in drunken driving or in time before arrest [41]. The second study investigated mortality after 8–13 years and found that people in rehabilitation tended to have lower mortality and a lower rate of death from accidents and violence. A small study compared standard treatment after drunken driving with education directed toward controlled consumption and no intervention, respectively. It was found that better psychosocial adjustment was achieved in the first two studies, and that the group receiving treatment aimed at controlled consumption had a significant reduction in the number of occasions of uncontrolled consumption [41, 99, 23]. Comparison with waiting list It should be noted that waiting lists generally are valued negatively in the treatment literature. Of the 6 studies found, 5 show poorer results for people on a waiting list, regardless of method and intensity, compared to people treated. In the study showing no difference, patients were asked to record and report their consumption during the waiting time and take Antabuse. After 4 weeks they were admitted for inpatient care as promised [51]. Meta-analysis 1: Treatment versus no treatment A problem in this analysis, as in most others, is which inclusion and exclusion criteria to apply. Table 2.11a presents 10 studies which include comparisons with no treatment. To be included in meta-analysis, the studies must contain comparable outcome data on alcohol consumption. When effect sizes were calculated and an attempt was made to include them in a meta-analysis, they were found to be highly heterogeneous. To achieve homogeneity, the analysis was therefore limited to studies with similar problem severity. Given these limitations, only 3 studies remain. One problem is that different studies use different outcome measures and different followup periods. Hence, Kivlahan reports the number of drinks per week at 4 and 8 months, respectively [85]. A mean value was then calculated for 6 months. In the two other studies, one reports number of drinks per month (at 6 month’s followup) and the other percentage of days with uncontrolled drinking after 6 months [66, 23].
2.3 Results
Meta-analysis 2: Treatment versus waiting list Five of the six studies found are included. (The study by Eriksen was excluded because of missing alcohol data [51]). Here, a new study, identified in the renewed literature search 2002, was included (Kelly et al., 2000 [184]), bringing the total to six studies. Problem severity is generally low, but is in some cases moderate. Followup periods and outcome measures vary: Miller follows the subjects for 6 weeks and measures drinks per week, Harris follows for 2.5 months and measures improved drinking patterns, Alden follows for 3 months and measures how partners who are abusive drinkers reduce their alcohol consumption, Cadogan follows for 6 months and measures the percentage of completely abstinent patients, and Kelly follows for 4 weeks and measures the level of alcohol consumption [116, 65, 4, 14, 28, 184]. This group of six studies was sufficiently homogenous for meta-analysis. Meta-analysis 3: More extensive treatment compared to a single interview Six studies were found in the original literature search. Most concern patients with moderate problem severity. Comparison treatments are mainly standard treatments without any specific focus. The study by Edwards reports on the number of completely abstinent weeks during one year, at 12-month followup [47]. Chick reports on the percentage of patients without alcohol problems after 2 years [32]. Zweben reports on the percentage of days of moderate drinking at 12 months [181]. Bennie reports on the number of completely abstinent weeks after 6 months [16]. Chapman reports on the percentage of completely abstinent subjects at 18 months, and Sannibale reports on the percentage with improved drinking patterns after 15 months [31, 154]. In the renewed literature search, a seventh study was identified, where Sellman (Sellman et al., 2001 [185]) reports on the rate of abstinence after six months of followup. Results from meta-analyses 1–3 Three studies that compared treatment with no treatment at all found an overall weighted effect size (ES) of 0.27 (meta-analysis 1; d, fixed model). Studies that used patients on waiting lists for comparison reported greater treatment effects, d=0.66. For those who are alcohol dependent, more extensive treatment yields better effects than an occasional interview, d=0.22. Combining these three analyses, an overall effect size of 0.37 was obtained (random model). All three meta-analyses were individually negative for heterogeneity, but the combined analysis was positive, calling for a random model. Comment The results from meta-analysis 3 may seem surprising in the light of some of the treatment literature. Several of the studies, in particular the classic study by Edwards, have been generally perceived to indicate that the extent of treatment has no significance [47].
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2 Psychosocial Treatment for Alcohol Dependence
Summary The psychosocial treatment literature contains only a few studies that compare treatment to no treatment. Generally, treatment is observed to be effective. In the studies that found no difference between treatment and no treatment, it cannot be excluded that the assessment itself may have had a positive influence. For alcoholdependent individuals, more extensive treatment has a better effect than a single treatment session. See also Section 2.1.7, which describes studies that compare the duration of treatment in outpatient care, e.g., comparing more extensive treatment to a single interview. 2.3.2
Are some methods superior to others?
The effects of most of the treatment methods are evaluated by comparing with other treatment methods. Specific treatments are compared either with standard treatment or with other specific treatments. The effect of standard treatment as an independent intervention is rarely evaluated.
2.4
Motivational Methodology (see Table 2.12)
The motivation studies report effects from motivational interviewing and motivation-enhancing treatment. This section also includes studies comparing the effects of self-treatment (bibliotherapy) with therapist-managed treatment. Motivational interviewing of somewhat varying design has been analyzed in three studies (see Table 2.12a). All three studies were designed to give patients in the study group one or more motivational interviews in addition to their regular treatment. Two of these studies are of high methodological quality and report positive effects [18, 24]. No effect was found in the third study [88]. This study, which has a lower methodological quality, is aimed at physically “worn out” alcoholics and raises questions whether the interviews fulfill the criteria for “motivational interviewing”. Apart from these three studies, promising results are reported from a study in a maternal health clinic where pregnant women were randomized to either a motivational interview or to standard treatment [64]. High-consuming (but not alcoholdependent) women reduced their consumption more when they participated in motivational interviews. Meta-analysis 4: Motivational interviewing Only three studies could be included in this meta-analysis, one of which was borderline [88]. In the first two, the effect from adding a motivating interview prior to standard treatment is compared to not doing so [18, 24]. Problem severity is moderate except in the study by Kuchipudi, where it is substantial [88]. All the studies have short followup times (3 to 4 months) and all use alcohol consumption/sobriety as outcome measures.
2.4 Motivational Methodology
Adding a motivational interview to other planned treatment yields better results, ES = 0.26. A substantial difference can be noted between two positive studies, well supported by MI methodology, and a third, negative study. The ES in the first two studies was 0.78 and 0.70, respectively, while ES in the third was 0.02 [18, 24, 88]. In the study by Kuchipudi, where the intervention is performed with patients hospitalized for somatic disease, the motivational intervention seems more focused on persuasion than actual “motivational interviewing” as suggested by Miller and Rollnick [88, 114]. Brief CBT-focused counseling that involves motivational methodology was addressed in five studies (see Table 2.12b) [151, 152, 154, 116, 170]. In comparison with more extensive treatment, no difference in results can be observed, i.e., brief counseling has the same effect as more extensive treatment. In comparison with a waiting list, however, better results are observed [116]. Heather reports from two studies performed in English primary care (see Table 2.12c). One study found no effect from counseling alone compared to no treatment [66]. All patients, however, underwent initial assessment, which must be considered to be a significant confounder. Furthermore, only a small proportion of the counseling group completed the intended program. In the second study, patients were offered a self-help manual and varying levels of telephone support [67]. No difference in effect was observed with different levels of telephone support, but alcohol consumption decreased in all intervention groups compared to a control group that only received a brochure. The value of a self-help manual, or bibliotherapy, has been analyzed in five studies (see Table 2.12d) [111, 112, 151, 65, 152]. All five studies report that bibliotherapy had the same effect as 6–10 therapist-managed treatment sessions. The patients in these studies consistently had less severe alcohol problems. A comparison between bibliotherapy (specific instructions to reduce alcohol consumption) and general alcohol information demonstrated a significantly better effect from bibliotherapy [167]. Meta-analysis 5: Bibliotherapy. Five studies are included, all of which describe patients with limited problem severity. The comparison treatments are all CBT programs with a focus on training of self-control. Sanchez-Craig measures complete abstinence or moderate drinking after 12 months, and the study is replicated in 1991 [151, 152]. Miller measures alcohol consumption at 3-month followup and describes improvements in the drinking pattern after 8 months [112, 113]. Harris describes improvements in the drinking pattern after 15 months [65]. The intervention consists mainly of written self-help material and includes 1–3 interview contacts [65, 112, 113, 151, 152]. For patients with limited alcohol problems, occasional interviews in combination with self-help material appear to yield an effect the same as or better than traditional therapist-managed treatment; ES = 0.19 (see meta-analysis 5). The analysis here is limited since all studies have been performed with a CBT focus aiming at self-control training. However, the results are consistent, and all studies point in the same
55
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2 Psychosocial Treatment for Alcohol Dependence
direction. In these studies, bibliotherapy and therapist-managed treatment seem to be equally effective. Combining the studies in meta-analyses 4 (motivational interviewing) and 5, both of which describe limited treatment measures, results in an overall weighted ES of 0.32. Motivational enhancement treatment, MET, is evaluated in two randomized studies (see Table 2.12e) [143a,b]. In “Project MATCH”, no effect difference is found between 4 sessions of MET and 12 sessions of CBT, while 12-step treatment shows a somewhat higher proportion of sober persons [144, 147]. Robertson, however, reports a significantly better effect from CBT treatment than that from MET [147]. Both studies have problems in interpretation. Thus, in “Project MATCH” the MET patients met the evaluators more often than their therapists during the 18 months of followup. The frequent followup probably had an equalizing effect on the results. Robertson’s study, on the other hand, was very small, only 37 patients. To some extent, it appears that the poorer results in the MET group can be attributed to three patients. Summary Motivational interviewing increases the effect of another treatment, but has not itself been subjected to randomized study. Brief, motivation-enhancing treatment appears to have the same effect as more extensive treatment. The effect of bibliotherapy is the same as or better than that of therapist-managed treatment for patients with a low level of alcohol dependence. The studies, with the exception of “Project MATCH”, have mainly recruited patients with a lower level of alcohol dependence.
2.5
Methods Specifically Aimed at Changing the Drinking Problem Itself 2.5.1
Cognitive Behavioral Therapy (CBT) (see Tables 2.1 and 2.13a–e)
The CBT studies involve a number of different techniques that share the feature of combining learning theory and behavioral therapy. However, pure behavioral therapy is rarely applied and is usually combined with cognitive methods. The CBT methods generally emphasize direct changes in behavior. CBT methods include training in coping with psychosocial stress factors, “coping skills”, often with special training for social skills (under the assumption that deficient social skills increase the risk for problem drinking), identification of risk situations for problem drinking, and training strategies to handle these, techniques for improved impulse control, training in techniques to control alcohol intake, management of relapse “relapse prevention”.
2.5 Methods Specifically Aimed at Changing the Drinking Problem Itself
This report groups the CBT literature into five categories: 1. Broad spectrum treatment with a CBT focus 2. CRA treatment (Community Reinforcement Approach) 3. Self-control training 4. Cue exposure 5. Other methods (anxiety treatment and self-confrontation by means of video recording) The outcome of the CBT studies is dependent on which type of comparison is made. In the studies that compare an experimental CBT treatment to “standard treatment” [5, 13, 23, 120, 125, 134, 163], a majority of studies report positive results (four out of seven). This is contrasted with the studies that compare the experimental treatment to another specific treatment where a smaller share of studies (five out of fifteen) report positive results [5, 13, 36, 44, 54, 77, 80, 92, 109, 110, 119, 134, 136, 143, 144, 153, 159, 160, 182]. In two studies, negative results are found compared to other specific treatment: 12-step treatment and dynamic/interactional therapy [143, 153]. 2.5.2
Broad Spectrum Treatment with CBT Focus
Broad spectrum treatment involves different combinations of measures directed both to the dependence condition in itself and to several psychosocial problems with which alcohol dependence is associated. Here are included, e.g., different forms of “relapse prevention” and “coping skills training“ (see Table 2.13a). Twelve studies belong to this group. Most have recruited patients with severe dependence disorder and/or complicating psychosocial conditions. Most studies have followup periods of at least 12 months. In none of the two studies comparing broad spectrum CBT with standard treatment are better results achieved at 12 months of followup [5, 125]. However, Allsop finds clearly better results from CBT treatment at 6 months, results which however do not persist at 12 months [5]. The author notes that for the heavy group of patients which this concerns, greater attention must be given the factors in the community environment (unemployment, relationship problems, etc.) which increase the risk of relapse. Among the studies where comparison is made with another specified treatment, positive results are achieved in two cases. One of the studies is performed by Ferrell, who finds better two-year results for broad spectrum CBT than a variant of interactional therapy “human relations training” [54]. The second is made by Monti, who finds better results with a broad treatment program focused on communication training compared to a more psychologically directed treatment to handle negative affect and alcohol craving [119]. Six studies find no differences in comparison with other specific treatment. Several of the comparisons are made with less extensive treatment and confirm the above observation that more extensive treatment generally does not yield better results. In Project MATCH, 12 sessions of “Cognitive behavioral coping skills” are compared with 4 sessions of “Motivational
57
58
2 Psychosocial Treatment for Alcohol Dependence Table 2.1.
Studies of CBT treatment.
Study
Nelson 82/83 [125] Allsop 97 [5] Olson 81 [134]
Comparison treatment
Standard treatment Standard treatment Standard treatment (environmental therapy) Project MATCH [143] Other specific treatment: 12-step and MET, respectively Ferrell 81 [54] Other specific treatment: Human relations training Miller 80 [110] Other specific treatment: Self-control training Skutle 87 [160] Other specific treatment: Self-control training (bibl. or therapist-managed) Kadden 89/ Other specific treatment: Cooney 91 [80, 36] Interactional therapy Litt 92 [92] Other specific treatment: Interactional therapy Ito 88 [77] Other specific treatment: Interactional therapy Monti 90 [119] Other specific treatment: CBT mood management Öjehagen 92 [182] Other specific treatment: Dynamic/interactional therapy Sandahl 98 [153] Other specific treatment: Dynamic/interactional therapy Sjöberg 85 [159] Other specific: Dynamic therapy Miller 80 [110] Combination with self-control training Skutle 87 [160] Combination with self-control training Monti 90 [119] Addition to individual communication training O’Farrell 93 [129] Addition after marital therapy Graham 96 [63] Group – individual
Effect
Problem severity
Followup ≥12 months
1=2 1=2 1>2
3 3 2
+ + +
1<2
2
+
1>2
2
+
1=2
1
+
1=2
1
+
1=2
2
+
1=2
2
+
1=2
2
–
1>2
3
–
1=2
2
+
1<2
2
+
1=2 1=2 1=2 1=2
2 1 1 3
– + + –
1>2 1=2
2 2
+ +
Enhancement Treatment” (MET) and with 12 sessions of “Twelve-step facilitation therapy” [143]. Both Miller and Skutle compare broad spectrum CBT with more limited self-control training [110, 160]. Kadden and Cooney (same study) as well as Litt and Ito report no basic differences between the results from CBT and interactional therapy, even though interesting matching effects are found (see below) [36, 80, 92, 77]. In four studies, the effects of adding more extensive broad spectrum CBT to other CBT treatment are compared, either in the form of enhancement during ongoing treatment or in the form of addition after basic treatment has been provided. In three cases out of four, this did not yield better results. The exception is O’Farrell, who finds that addition of relapse prevention during one year after behavioral marital therapy (which itself has a positive effect) yields a better effect [129]. Monti did not find any additive effect from involving one partner in a CBT-focused treatment
2.5 Methods Specifically Aimed at Changing the Drinking Problem Itself
program with emphasis on communication training [119]. Miller saw no differences in results in the comparison between broad spectrum CBT and self-control training (either in bibliotherapeutic or therapist-managed form) or self-control training enhanced by relaxation training, communication training, and training in self-assertion [110]. Skutle did not achieve better results by adding more extensive CBT treatment to self-control training, whether this was performed in bibliotherapy form or in therapist-managed form [160]. In a comparison between individual treatment and group treatment with CBTfocused relapse prevention, Graham found no difference between the results, and both groups improved markedly [63]. This study also compared giving relapse prevention as followup treatment to two greatly differing primary treatments: residential 12-step treatment and relatively unspecific “eclectic” treatment in outpatient care. Nor in this comparison were any differences observed. Meta-analysis 6: cognitive behavioral therapy Six studies are included in this analysis (see Figure 2.2) and mainly involve patients with major problem severity. These studies use broad-spectrum treatment with a CBT focus and different methodological foci, e.g., relapse prevention and cue exposure. The comparison treatments consist of different forms of standard treatments, in some cases with focus on self-confidence training or relaxation training [44, 54, 125]. The followup periods in these studies are all 6 months, except in the Nelson study which has a followup period of 2 months. In most studies the outcome measure is total abstinence, but not in the Allsop study which measures improved drinking patterns, nor Drummond who uses an alcohol problem index [5, 44]. The combined effect size (d, fixed model) was 0.73. Summary Only a few studies compare broadly designed CBT treatment with standard treatment for patients with extensive alcohol problems. The meta-analysis of these studies shows positive effects. However, positive effects in short term followup decrease at 12-month followup. In comparison with other specific treatment, no better effect is found. 2.5.3
CRA Treatment – Community Reinforcement Approach (see Tables 2.2 and 2.13b)
In CRA treatment, principles for operant behavior modification are combined with social system theory, where aspects of the local community are used to award behavioral change. Natural obstacles to drinking are expressed in operant terms. The probability that the patient will resist drinking increases if it jeopardizes other sources of satisfaction. Sobriety-enhancing factors are searched in relationships with partners or other family members, working life, leisure activities, etc. Seven randomized studies in the alcohol area have been found. The first were based on small samples of 16, 18, and 43 patients [9, 10, 74]. However, the effects were large concerning both drinking behavior and social adjustment. In a later, methodologi-
59
60
2 Psychosocial Treatment for Alcohol Dependence Table 2.2.
Studies of CRA treatment.
Study
Comparison treatment
Effect
Problem Followup severity ≥12 months
1. Azrin 76 [9] 2. Azrin 82 [10] 3. Hunt 73 [74] 4. Smith 98 [162] 5. Sisson 86 [157] 6. Mallams 82 [98] 7. Miller 92 [115]
Standard treatment Standard treatment Standard treatment Standard treatment Standard treatment Standard treatment Other specific treatment (12-step treatment) Other specific treatment: Antabuse
1>2 1>2 1>2 1>2 1>2 1>2 1=2
2 2 2 3 2 2 2
+ – – + – – +
1>2
2
–
8. Azrin 82 [10]
cally more ambitious study, Miller finds no advantage of CRA treatment compared to 12-step treatment [115]. In a study of homeless persons, Smith reports that CRA has better effects on drinking behavior than the usual 12-step treatment; however, no differences concerning social adjustment are observed [162]. Furthermore, certain CRA components have been particularly investigated. A study of the social club (which is one such component) found that a group who received support to participate in the activities of the club had significantly better results regarding both drinking habits and social function than a group which did not receive such support [99]. In similar ways, Sisson studied the effect from involving a partner or other family member in a CRA program [157]. Significantly more people with alcohol problems whose partners were included in the study group sought treatment compared to the control group, and they reduced their alcohol consumption considerably more. The scientific basis of the CRA treatment is limited by the fact that the same group of researchers in the United States has performed most of these CRA studies. The generalizability from the earlier studies is limited by the fact that CRA was consistently compared with poorly defined standard treatment and where the CRA therapists in some cases also performed the control treatment. Therefore, it should be noted that when a comparison is made with another specific treatment – a 12-step programme – no advantages of CRA treatment are found. Meta-analysis 7: CRA treatment Seven studies are included in the analysis. The patients are alcohol dependent with a moderate to high problem severity. All of the comparison therapies use some variation of 12-step treatment. The older studies, however, apply a poorly defined standard treatment. Only one study draws a comparison with a qualified form of 12-step treatment [115]. Most report followups at 6 months. Mallams, however, reports at 3 months, Sisson at 5 months, and Miller at 12 months [99, 157, 115]. The outcome measures vary; e.g., Hunt and Azrin measure the time the patient drinks alcohol [9, 74]. Azrin measures number of drinking days and Mallams reports reduced drinking [10, 99]. Sisson uses as a measure the share of drinking partners who reduce their drinking as a consequence of an intervention for family members; Miller and
2.5 Methods Specifically Aimed at Changing the Drinking Problem Itself
Smith use alcohol consumption per week [115, 157, 162]. From these seven studies a significant ES of 0.59 is seen. The original CRA studies made comparisons with standard treatment and yielded very large effect sizes (between 1.07 and 1.56) [9, 10, 74]. When a comparison is made with another specific, manual-based treatment (like 12-step treatment) no superior effect is achieved, ES = 0.06 [115]. Summary CRA treatment shows a better effect than standard treatment, but the same effect as other specific treatment. It represents a treatment alternative for patients with severe alcohol dependence. 2.5.4
Self-control Training (see Tables 2.3 and 2.13c)
Effects from CBT-focused, self-control training are described in 11 randomized studies. Self-control training is treatment that aims at giving the patient better control over his/her alcohol consumption. Both training in identifying, avoiding, or mastering risk situations for problem drinking and training in controlled intake are included. Usually the goal is not to achieve complete abstinence. The goal is to keep the blood alcohol level below a certain limit, e.g., of 0.8‰, mainly by keeping the consumption rate down. Here are not included studies which have trained patients in laboratory-similar environments with or without aversion techniques (e.g., by provoking nausea, pain, or apnea). Mainly patients with relatively limited alcohol problems have been recruited to these studies. An important exception is the Foy study where patients with a high degree of alcohol dependence were recruited [60]. Apart from a broad CBT program, the study group, but not the control group, received training in controlled drinking. The result at the 6-month followup was considerably poorer for the study group. At 12 months, however, no differences were observed. Thus, self-control training seems contraindicated for this group, although the damage is possibly limited by the natural course. This finding can be compared with the results from Sobell’s classic study of 1973, where it was found that behavioral therapy with controlled drinking as a goal yielded results equally as good as behavioral therapy with complete abstinence as a goal [163]. In the Sobell study, the treatment was classic behavioral therapy with aversion treatment as the central element. The results from the Sobell study were criticized by Pendery, who reported that all patients in Sobell’s study, except one, either became totally abstinent or went back to heavy drinking [138]. Three studies compare self-control training to no treatment [23, 66, 65]. Heather finds no effect [66]. In the two other studies, a positive effect is reported [23, 65]. However, Heather’s study holds some reservations. This study had the character of a “brief intervention” in primary care and consisted of only two conversations. Furthermore, in the majority of cases the patients did not receive the intended treatment.
61
62
2 Psychosocial Treatment for Alcohol Dependence Table 2.3.
Studies of self-control training.
Study
1. 2. 3. 4. 5. 6.
Brown 80 [23] Heather 87 [66] Harris 90 [65] Brown 80 [23] Baker 75 [13] Caddy 76 [27]
7. Miller 78 [109] 8. Foy 84 [60] 9. Foy 84 [60] 10. Miller 80 [111] 11. Skutle 87 [160] 12. Miller 81 [112] 13. Harris 90 [65] 14. Duckert 92 [45]
Comparison treatment
Effect
Problem Followup severity ≥12 months
No treatment No treatment Waiting list (+ assessment) Standard treatment Standard treatment Other specific treatment: aversion treatment Other specific treatment: aversion treatment Addition to broad spectrum CBT Addition to broad spectrum CBT Bibliotherapy – therapist-managed treatment Bibliotherapy – therapist-managed treatment Bibliotherapy – therapist-managed treatment Bibliotherapy – therapist-managed treatment Group-individual treatment
1>2 1=2 1>2 1>2 1=2 1>2
1 1 1 1 2 2
+ – + + – +
1=2
2
+
1=2 1<2 1=2
2 2 1
+ +
1=2
1
+
1=2
1
–
1=2
1
+
1=2
1
+
Two studies describe comparisons with standard treatment, where self-control training yields better results in one study but the same result in another [13, 23]. In two studies, self-control training has been compared with aversion treatment; also here better results are seen for self-control training in one, but not in the other [27, 109]. Four studies compared self-treatment (bibliotherapy) with a focus on selfcontrol training with therapist-managed treatment, but no differences were found in the results (compare with the section above on bibliotherapy). In one study, Duckert compared individual treatment with self-control training to group treatment without finding any difference [45]. Summary Self-control training has generally been offered to persons with relatively limited alcohol problems. Self-control training has shown a positive effect in comparison with no treatment or standard treatment. The extent of the treatment does not correlate with the effects; bibliotherapy yields the same effect as therapist-managed treatment. 2.5.5
Cue Exposure (see Tables 2.4 and 2.13d)
Cue exposure involves exposure to alcohol in environments where consumption is not possible. The aim is that such exposure will gradually extinguish alcohol crav-
2.5 Methods Specifically Aimed at Changing the Drinking Problem Itself Table 2.4.
Studies of cue exposure.
Study
Comparison treatment
Effect
Problem Followup severity ≥12 months
Drummond 94 [44]
Other specific treatment: relaxation treatment Standard treatment Standard CBT
1>2
3
–
1>2 1>2
2 1
– –
Monti 93 [120] Sitharthan 97 [158]
ing, conditioned through long-term high consumption. Previous studies have clarified that exposure leads to stronger physiological reactions such as increased salivation and sweating in alcohol-dependent individuals compared to nonalcohol dependent. However, only a few clinical studies have been performed with cue exposure, and only three randomized studies are reported in the literature. These are all small studies with a limited duration of followup and can be viewed as developmental studies. Since they all report positive results, even though they were compared with different types of treatments (relaxation treatment, regular CBT, standard treatment) and recruited patients of various problem severity, the method should be considered as promising and lead to further study. 2.5.6
Other
The heading “other” includes a study that compared CBT-directed treatment for anxiety (under the assumption that the patients’ alcohol problems are associated with an elevated anxiety level) with more traditional relaxation training [136]. No difference in the results on alcohol consumption was found, but CBT reduced anxiety more than the other alternatives did. A study where patients are confronted with their behavior under intoxication via video recordings shows no effects compared to standard treatment [13]. Nor is any difference in effect found in a comparison with self-control training in the same study. 2.5.7
Twelve-Step Treatment (see Tables 2.5 and 2.14)
This section includes four studies with a total of 2045 patients where 12-step programs are evaluated (see Table 2.14). Treatment is based on the philosophy of Alcoholics Anonymous, including the concept of alcoholism as a disease. Twelvestep treatment is given as specific treatment and these studies do not include support by participation in AA meetings only. Twelve-step treatment is compared with both standard treatment and other specific treatments. In two of the studies the treatments are given individually and in outpatient care, while the Keso study describes inpatient care [84, 115, 143]. One study that includes patients who had both alcohol and cocaine dependence shows results only at the end of the treatment [29].
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Comparison with standard treatment (2 studies) Both studies show better results from 12-step treatment. Keso compared with standard treatment in inpatient care and Carroll compared with general support via “case management” in cocaine- and alcohol dependence [84, 29]. The study by Keso also showed that more patients remained in the 12-step treatment, the treatment environment of which was perceived as more involving, supportive, and promoting problem solving than the traditional treatment [84]. Comparison with other specific therapy (3 studies) In Carroll’s study, a comparison is also made with CBT and furthermore with and without addition of disulfiram, where no differences exist between 12-step treatment and CBT [29]. The Project MATCH study, the aim of which was to test different matching hypotheses, also compared the results obtained using the three included specific treatment methods: cognitive behavioral therapy (CBT), motivation-enhancing therapy (MET), and 12-step treatment [143]. The treatments were given in outpatient care and approximately half of the patients had initially received inpatient care. The three methods achieved similar results, but a somewhat higher proportion of those patients who had not received initial inpatient care were completely abstinent after the 12-step treatment. In the study that compares 12-step treatment with CRA in outpatient care, the same results are achieved with 12-step treatment as with CRA [115]. As mentioned above, support via self-help groups (AA) is not included under this heading. In several studies, participation in AA groups is included as a component of standard treatment. In one study, AA group participation has been compared with different treatments, e.g., the study which compares inpatient care with outpatient care intervention in the form of AA group participation three times per week during one year (see Intensity [177]). This study reported poorer results from AAparticipation alone compared with patients who received AA support after initial treatment in inpatient care. In summary, 12-step programs show better results than standard treatment. Compared to other specific treatment the same results are found, however, with a somewhat higher share of totally abstinent.
Table 2.5.
Studies of 12-step programs.
Study
Comparison treatment
Effect Problem Followup severity ≥ 12 months
1. Keso 90 [84] 2. Carroll 98 [29] Carroll 98 [29] 3. Proj. match 97 [143] Proj. match 97 [143] 4. Miller 92 [115]
Standard (IP) General support, case management (OP) Other specific treatment: CBT (OP) Other specific treatment: CBT/MET (OP) Other specific treatment: CBT/MET (IP) Other specific treatment: CRA (OP)
1>2 1>2 1=2 1>2 1=2 1=2
OP = Outpatient, IP = Inpatient
2 2 2 2 2 2
+ – – + + –
2.6 Methods Aimed at the Factors Behind Alcohol Dependence
2.6
Methods Aimed at the Factors Behind Alcohol Dependence (see Tables 2.6 and 2.15a–c)
Nine studies are included in this section (see Table 2.15), three of which are based completely or partly on the same material; a total of 514 patients. This concerns methods focusing on factors behind the alcohol problem, early or present, which may influence the tendency to use alcohol. These treatment methods do not involve any direct training in changing the drinking behavior itself. Experimental treatment is compared in two studies with standard treatment and in the others with other specific methods. Two additional studies are presented in this section. These are early studies that evaluated “psychotherapy” in relation to standard treatment, e.g., with Antabuse [25, 180]. The content of psychotherapy is unclearly described and the theory support not stated. It is possible that they do not differ methodologically from the unclearly specified supportive therapies they are compared with. 2.6.1
Dynamically Oriented Treatments
Studies of classical dynamic therapies, with the main focus on interpretations of defenses and the significance of underlying conflicts for the alcohol problem, are lacking. In the four studies (see Table 2.15a) which have been reviewed, treatments with a dynamic focus, of which three hold comparisons with other specific therapies, are compared with standard treatment. The methodological quality is lower in the older studies. However, the duration of the followup is usually over one year. Comparison with standard treatment An early study of inpatient care randomized patients to environmental therapy in addition to transaction analysis (TA), behavioral therapy, or TA + behavioral therapy, and compared these to milieu therapy alone [134]. The transaction analysis (TA) is described as a form of insight-oriented psychotherapy combining psychodynamic and interpersonal principles with communication theory. Comparison with other specific therapies In Olson’s study, the TA therapy shows poorer results when it is compared with other specific treatment, e.g., behavioral therapy [134]. These differences exist at 6 months and at 18 months, but not after 4 years. Another three studies make comparisons with other specific therapies, cognitive behavioral (group therapy), and individual behavioral therapy, respectively [153, 159, 182]. The studies by Sandahl and Öjehagen involve more structured interactional elements with focus on the drinking behavior [153, 182]. Sandahl’s study of group therapies shows better results for the dynamic therapy [153]. The other two studies find no differences. In Öjehagen’s study, matching results in relation to the personality structure are found (see Section 2.8) [182].
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2 Psychosocial Treatment for Alcohol Dependence Table 2.6.
Methods aimed at the factors behind alcohol dependence.
Study
Comparison treatment
Effect
Problem Followup severity ≥12 months
1. Olsson 81 [134] Olsson 81 [134] 2. Sandahl 96 [153] 3. Sjöberg 85 [159] 4. Öjehagen 92 [182]
Standard, environmental therapy (IP) Other specific treatment CBT (IP) Other specific treatment CBT (OP) Other specific treatment CBT (OP) Other specific treatment: behavioral therapy (OP)
1=2 1<2 1>2 1=2 1=2
2 2 2 2 2
+ + + + +
1=2
2
+
1=2 1=2
2 2
+ –
1=2 1=2
2 2
+ +
Interactional 5. Kadden 89/ Other specific treatment CBT (OP) Cooney 91 [80, 33] 6. Litt 92 [92] Other specific treatment CBT (OP) 7. Ito 88 [77] Other specific treatment: relapse prevention (IP) Other “psychotherapy” 8. Bruun 62 [25] Standard: Antabuse (OP) 9. Zimberg 74 [180] Standard: medication, Antabuse, support (OP) OP = Outpatient care, IP = Inpatient care
Interactional therapies Interactional therapy (see Table 2.15b), focusing on current relationships, has been tested as group therapy in three studies and was compared with other specific therapies, cognitive behavioral therapy, and relapse prevention. Two studies are based on the same study population. They both report results at the termination of the treatment and after 18 months of followup [36, 80]. A third study is based on the same population, but investigates male subjects only [92]. Furthermore, an inpatient care study is reported [77]. There are no overall effect differences between the interactional and the other specific therapies. However, the studies by Cooney and Litt report matching effects based on the degree of mental disorder (see Section 2.8) [36, 92]. Other dynamic therapies The focus of the two older therapies is unclearly described. They show no effect in comparison with standard/Antabuse treatment [25, 180]. The number of sessions is greater in these therapies. These studies receive lower quality scores than the other psychotherapy studies. Summary Studies of classic dynamic therapies for alcohol problems are lacking. Few differences appear in studies that compare modern dynamic, interactional therapies to other specifically focused therapy. Transactional analysis shows poorer effects than other specific treatment. Matching effects between type of therapy and patient characteristics appear in some studies. Here, therapies aimed at factors behind depend-
2.7 Standard Treatment
ence appear to be less suitable in treating patients with more severe mental disorders compared to treatments that actively focus on abusive drinking behavior.
2.7
Standard Treatment (see Tables 2.7 and 2.16)
These methods are also referred to as nonspecific treatment, in that they usually do not contain any focused strategy in relation to the abusive drinking behavior and are often less well described than the specific, theory-supported methods. A common approach is supportive counseling in combination with social work interventions. In some cases, disulfiram treatment is also included. This group includes 19 studTable 2.7.
Study
Standard, generally supportive treatments. Comparison treatment
1. Ogborne 79 [131] No treatment Other support/extent 2. Baker 75 [13] Counseling + video confrontation + role play 3. Gilbert 88 [62] Active contact telephone/house (call) in outpatient care 4. Pittman 72 [139] Unspecific treatment: Antabuse, medication 5. Powell 85 [142] Antabuse + medication/followup of physical health only Specific treatment 6. Allsop 97 [5] Relapse prevention: with or without role-playing 7. Azrin 82 [10] Antabuse supervision by family members/CRA 8. Azrin 76 [9] CRA 9. Carroll 98 [29] CBT+disulfiram/12-step + disulfiram 10. Eriksen 86 [52] Social skills training 11. Hunt 73 [74] CRA 12. Jones 82 [79] Discussion group/social skills training 13. Keso 90 [84] 12-step 14. Monti 93 [120] Addition cue exposure + coping skills 15. Nelson 82-83 Increase self-confidence. [125] Role play/demonstration 16. Pomerleau 78 Behavioral therapy [140] 17. Sannibale 88 Cognitive therapy/min intervention [154] 18. Sobell 73 [163] Behavioral therapy controlled consumption/total abstinence 19. Telch 84 [173] Symbolic aversion technique/control
Effect
Problem severity
Followup ≥12 months
1=2
3
–
1=2
2
+
1=2
2
+
1>2
2
+
1=2
2
+
1<2
3
+
1<2
2
–
1<2 1<2 1<2 1<2 1<2 1<2 1<2 1=2
2 2 3 2 2 2 2 3
+ – + – + + – –
1<2
1
+
1=2
1
+
1<2
1
–
1>2
2
–
67
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2 Psychosocial Treatment for Alcohol Dependence
ies (see Table 2.16) involving 1208 patients. One of these studies draws a comparison with no treatment. The rest compare other nonspecific treatment, medical treatment, various types of standard treatment (4 studies), and different specific treatments (14 studies). The quality of the studies that make comparisons with specific treatments is somewhat better than in the other studies. The followup time exceeds 12 months in more than half of the studies. Sometimes it is not entirely clear whether the treatment alternatives that have been studied are specific or nonspecific. Twelve-step treatment, for instance, may be specific when it is applied in a systematic fashion with trained therapists and qualified supervision. In many cases, however, it is clear that several of these elements are missing. Twelve-step treatment in these cases would be classified as nonspecific, or standard treatment. Comparison with no treatment A study of homeless men with severe abusive drinking reports no differences in effect [131]. The study included only a small number of patients in the group receiving counseling. Comparison with other nonspecific treatment, medication, various levels of “standard treatment” None of these studies show any differences in outcome. Active case finding increases attendance in outpatient care, but this has no direct association with the result [62]. More extensive support shows no difference in relation to fewer contacts or medical treatment/controls [142]. In the latter study, family members/patients were contacted once per month, which itself may influence the course. Comparison with specific treatment Eleven studies concern patients with moderate/high problem severity, and nine of these studies show poorer effects with “counseling, supportive contact” alone [5, 9, 10, 29, 52, 74, 79, 84, 120]. One of the studies shows the same effect compared with different ways to increase self-confidence, and one study shows better results from supportive treatment than with “covert sensitization”, i.e., using symbolic aversion techniques [125, 177]. In two out of three studies that concern patients with less severe drinking problems, standard treatment shows a poorer effect compared to behavioral therapy [140, 163]. Pomerlau’s traditional support involves confrontative AA methodology [140] and yields poorer results than behavioral therapy. Summary In summary, many different types of comparisons are included, e.g., several earlier studies, some of which are of poor methodological quality. The support therapies are less well defined and do not have as clear a focus on abusive drinking behavior as the specific therapies and yield poorer results. The same kind of support is not evaluated in more than one study.
2.8 Marital Therapies and Interventions Focused on Family Members
2.8
Marital Therapies and Interventions Focused on Family Members (see Table 2.17)
This section includes 17 studies, two of which have been followed up twice, and three studies based on the same basic material [94, 95, 103, 127, 128, 129, 130]. In total, 1078 patients are included plus their partners and family. Two of the studies focus the intervention only at the partner (n=35). The other 15 studies evaluate marital therapies, where different methods (specific or standard) are used to address the relationship and its influence on alcohol consumption, and treatments that involve the partner/family to various degrees in treatments that focus on the problem drinker. Some studies compare the importance of different durations of the treatments. The quality of the studies is generally good. The followup times vary, but in several studies they do not exceed 12 months. An earlier study shows better results from marital therapy compared to a waiting list [28]. Marital/family therapy treatment in comparison with individual therapy (10 studies) Three studies find better results with marital therapies [21, 119, 127, 128]. In two of these, comparisons are made with individual counseling [119, 127]. Monti shows that active patient treatment (focused on “coping” with events and emotional reactions), with and without the partner, yields better results than individual treatment aimed at managing negative effect [119]. In three studies based on the same material, the main method is cognitive behavioral therapy. One of these includes a varying number of family sessions [95]. No differences are found, apart from certain matching results in relation to patient and network characteristics. Comparison between marital therapy of varying scope and duration (3 studies) One sample, which was followed up twice, added treatment for relapse prevention for 1 year after marital therapy (behavioral therapy) [129, 130]. Couples who received relapse prevention showed better results 6 months after completed treatment. Patients with heavier alcohol dependence and more difficult marital problems showed better results for up to 30 months when relapse prevention was added. The study by Zweben shows no difference between one session of counseling or eight conjoint sessions [181]. Longabaugh, mentioned above, finds no difference between four or eight family sessions [95]. Comparing treatments that include partner/family members as support in the treatment (3 studies) These studies involve family members, e.g., by contract, and include Antabuse intake or encouragement to participate in a social club, all of which yield better results than when family members are not involved [3, 83, 99]. Intervention focusing at family members only (2 studies) Treatment for family members, individually or as a group, compared to a waiting list, increases the patients’ tendency to seek treatment and reduce their consump-
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tion [14]. In the Sisson study, a CRA directed program for family members leads to reduced drinking compared to usual family contacts [157]. Summary Marital therapy shows better results than a waiting list and equal or superior results compared with individual treatment. Involving family members in the patient’s treatment yields positive results, and it seems feasible that intervention focused only on the partner has an effect on the patient’s consumption. In comparisons between specific marital therapies, no differences appear, but some matching results.
2.9
Studies Showing Matching Results (see Tables 2.8 and 2.18a–d)
Several studies found that different treatment methods interact with different patient characteristics so that “correctly matched” patients have better results than “mismatched” patients. This has caused an increased interest in finding that characteristics in the individual interact with which methods as guidance in the choice of treatment. This review shows the matching results in relation to specific treatment methods, the intensity of treatment (number of contacts, duration), treatment structure, and therapeutic approach. In total, 18 studies have been found from 10 different samples, from which different sub-analyses and followups were performed (see Table 2.18). Replication studies where matching effects have been shown by the same method, measurement, patient characteristics, and other relevant conditions are lacking. Two kinds of matching effects may occur: 1. The results between two treatments differ only for patients with high levels of a certain characteristic, but not for those with low values 2. The results from the treatments differ for those with both high and low values, but in different directions, i.e., different treatments can be recommended for both groups. The specific methods with matching results are CBT, with or without inclusion of family members, interactional and dynamically directed therapies. These have shown that in patients with a psychiatric disorder (global measurement of psychopathology and personality disorder), CBT is superior to interactional therapy and equal to the 12-step program [36, 143, 144]. In the latter, the same measurement was used for global psychopathology. For patients with no psychiatric disorder, interactional, dynamic therapy may be superior or equal to CBT [36]. During the 1990s, the large multicenter study Project MATCH, was conducted with the aim of studying matching effects [143, 144]. Since the aim was not to describe treatment effects, no control group was included for the three treatment groups. Based on an extensive literature review, where a large number of smaller studies described matching effects, 12 primary matching hypotheses and 8 secondary matching hypotheses were identified. Most of these hypotheses were rejected, with three exceptions:
2.9 Studies Showing Matching Results
1. Individuals with a high level of anger obtain better results in the less-confrontational and less goal-oriented “Motivational Enhancement Treatment” (MET) compared with CBT and the 12-step programs. The result is the opposite for patients with a low level of anger, who obtain poorer results with MET than with CBT and the 12-step programs. The results concern patients without previous inpatient care. 2. Patient with a low level of dependence had better results in CBT than in 12-step treatment. These results included patients who had had inpatient care before participating in the study. 3. Furthermore it was observed that if the patient’s network does not support sobriety, better results were obtained in 12-step treatment compared with MET. This is probably associated with the fact that the 12-step treatment more often resulted in contact with AA groups after treatment. If the network is less important, individual support may be better than involving family members, according to an earlier study [93]. Based on previous matching results, the study was based on the hypothesis that CBT would produce better results for patients with psychiatric disorders. However, the 12-step program showed the same results as did CBT. Furthermore, patients with no psychiatric disorder were more often completely abstinent after the 12-step treatment than after treatment with CBT. It should be noted that the level of psychiatric disorder (global measurement) was somewhat lower than in other alcohol dependence populations. It should be noted that all three treatments contained common ingredients for change, though the included treatments in Project MATCH are clearly separated in their methodology [143, 144]. The therapists who were included were all trained in the studied treatment methods and the compliance with the treatment manual was supervised. The importance of the recurrent followups every third month has been discussed, since these may contribute to a positive change. The followups focused directly on the factors the treatments intended to change. All these conditions tend to reduce possible differences in outcome between the treatments. In summary, however, the results from Project MATCH indicate that matching of clients based on individual characteristics to the three methods does not markedly increase the effectiveness of any one of the three treatment methods [143, 144]. Results from other matching studies indicate that patients with lower self-esteem (less autonomous) obtain better results if they are treated individually instead of using couple therapy [103]. The age of the patient may also be of importance from the point of view of the effect of involving family members – the effect seems more pronounced for middle-aged persons than for elderly, where individual CBT shows greater effect [146]. An addition of relapse prevention sessions during one year after marital therapy has yielded better results for patients with more severe relationship problems [130]. This addition also gave better results at the end of the initial therapy for patients with low levels of self-efficacy than if they did not get this addition [104]. This considerably longer contact (one year) with relapse prevention sessions (couples) as well as more extensive supportive treatment has yielded better results than briefer
71
72 Table 2.8.
2 Psychosocial Treatment for Alcohol Dependence
Studies where matching effects were found. Matching variables
Primary study Problem Psychiatric Perso- Importance Structure Age Other Approach Network (number of studies) severity disorder, nality of network problems support pers. to the for sobriety disorder patient Annis (1) [8] Kadden (3) [80] Longabaugh (5) [93] McLellan (1) [107] Miller (1) [116] Nielsen (1) [126] O´Farrell (2) [130] Orford (1) [135] Project Match (2) [143, 144] Öjehagen (1) [182]
x x
x x
x x
x
x x x
x x x x
x x
x x
x
contact [130, 135]. At a one-year followup (of the group followed up two years by Orford), however, no matching results were found [47, 48, 49, 135]. The patient’s need for structure and the degree of structure in the treatment also impact on whether patients complete treatment [126]. A more confrontative approach has been shown to be poorer for patients with a low self-esteem [8]. Patients who looked at their drinking as a bad habit drank less if they received client-centered feedback than if this was given in a confrontative manner [116]. If treatment for the drinking problem is combined with measures for other problems, retention in treatment increases and the outcome for these problems is improved [107]. The latter indicates the importance of adding individual support when needed besides focusing on the drinking problem. Interaction among the following eight patient characteristics has been demonstrated in different studies: problem severity (4 studies), psychiatric disorder (3 studies), personality (4 studies), the importance of the network for patients, the need for structure, age, presence of other problems, the patient’s view (1 study each), and the support from a network for sobriety (2 studies). Summary Matching results have usually been found in a number of studies comparing specific therapies. The most common results, although not tested more than once with the same design, concern problem severity, personality, and psychiatric/personality disorder. Since a large, well-executed study was basically negative, the support for matching must be considered weak. It should be noted however, that matching in this study was not tested using the same methods and same type of patients as in previous studies. Patients with moderate or severe dependence may achieve better results in longer, more extensive treatment. However, there is general support for tailoring treatment plans to the patient’s needs, e.g., concerning need for psychi-
2.10 Comparing the Intensity of Treatment and Aftercare
atric treatment, family therapy, employment counseling, and other problem areas, in addition to treatment for dependence itself.
2.10
Comparing the Intensity of Treatment and Aftercare
This section addresses comparisons of the effects from different intensities of treatment (see Table 2.19). This includes comparisons between different types of care (outpatient care, inpatient care) and differences in the duration and extent of treatment (length of time, number of sessions). In this context, studies concerning aftercare are also presented. These can be given as “booster sessions” or as other methods (specific or standard) that prolong treatment contact. The treatments compared here are usually unspecific and the content varies among the different studies. This section includes 26 studies involving 5158 patients. Also presented here is a review including some of the studies mentioned [56]. Inpatient care compared with outpatient care and daycare (see Table 2.19a): 11 studies These vary in their design. In all but one, which includes one year of treatment, the initial treatments are short, i.e., 9 weeks at most [177]. Two show differences in effect. Walsh reports better results at 2-year followup of initial inpatient care followed by AA group participation than from AA group participation alone or from optional treatment [177]. It should also be noted that two thirds of the patients had drug problems in addition to alcohol problems. Thirty-nine percent used cocaine, of whom those who initially had been given inpatient care were sober more often and had functioned better during the 2-year followup than the others, while those who had participated only in an AA group more often used cocaine. It may be questioned whether AA participation should be considered equal to treatment. Readmissions were more common among cocaine-dependent patients who had been referred to AA participation only. Potamianos reports better effects from daycare treatment than from traditional inpatient and outpatient care [141]. Other studies show no differences. In an 18-month followup of homeless women, Smith found no difference between those who initially had been treated in a treatment center for 3 months and then had 9 months of outpatient care compared with those who had received all of their treatment in outpatient care [161]. The same findings are reported by Sosin in an aftercare study of homeless alcohol-dependent persons, where no differences in effects were found between programs which offered an initial 3 months of supportive housing and programs which only offered support through case management [165]. Duration and intensity in inpatient care (see Table 2.19c,d): 5 studies Four studies addressing this topic were performed during the 1970s. Hence, they include longer inpatient stays than is common today. One of these studies compares high and low staffing ratios in inpatient care in combination with more or
73
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fewer outpatient resources [169]. When staffing ratios are low, dialog between the patients is emphasized as a resource. A low staffing ratio was found to yield better results as regards consumption of alcohol and drugs. Longer, more intensive inpatient treatment was not found to yield better results. Three of the studies reported frequent followup contacts. A group of patients in one of these studies improved further during the second followup year, while patients who at one year showed good and poor results, respectively, did not change further after one year [179]. In another study, no differences were reported in neuropsychological function among those treated in inpatient care for 2 and 7 weeks, respectively [176]. Duration of outpatient care (see Table 2.19c): 12 studies, of which 3 report two followups In six studies, several treatment sessions are compared with one session. The treatment methods in these studies vary. Bennie finds that withdrawal treatment, i.e., with five house calls including medication, yields twice as long a period of total abstinence than a house call without medical intervention [16]. Chick finds greater improvement in alcohol-related problems from more extensive treatment [32]. A 1year followup of Edward’s classic study, which compared more extensive treatment with one interview, found no statistically significant differences in results on the group level [47]. However, it can be noted that the group receiving one interview during the year of followup had also become the object of other interventions (mainly in the form of frequent contacts with the spouse), which probably had an equalizing effect. The 2-year followup of this study shows that patients with more severe alcohol problems obtained better results if they had received more treatment (see matching results) [135]. In several of these studies, the work has involved frequent followup contacts, which may have influenced small or nonapparent differences in results. In other studies (see Table 2.19d), which compare more and fewer number of hours or longer time: 3 months versus 6 months, or 1 year versus 2 years, no differences in results are found [81, 97, 142, 143, 144, 182]. Also in these studies, the followup contacts may have interfered with the effect of the duration. In a study by O’Farrell concerning marital therapy with 6 months of behavioral therapy, 15 sessions with relapse prevention were added during one additional year, which thus increased the duration [129]. This study has been followed up for 30 months, and better results are noted for those receiving relapse prevention 6 months after this was completed. Aftercare (see Table 2.19e) Eight studies have evaluated aftercare (two of which came from the same basic material [129]). The studies compare no aftercare (three studies) with different forms of aftercare, e.g., including family members and active support for outpatient interventions of varying intensity after inpatient care (four studies). Only one study (O’Farrell gives aftercare, following marital therapy, in the form of relapse prevention for one year) shows an effect [129, 130]. Different levels of active case finding, the content of which is not specified, show no differences in effect. One study included active contact of varying intensity, but had difficulty in fully maintaining the different contacts [133].
2.11 Subgroups of Alcohol-Dependent Patients
In summary, these studies (regarding different intensity, including aftercare) show few differences in results. For alcohol-dependent persons, more extensive treatment has a better effect than one session.
2.11
Subgroups of Alcohol-Dependent Patients Patients with co-existing psychiatric disorders In most countries, the treatment of substance use disorders and psychiatric disorders is the responsibility of different authorities. This has caused problems for patients with dual diagnoses who need to receive simultaneous help for both problems. A large proportion of all patients who enter treatment for alcohol dependence have a psychiatric disorder, either primary or secondary to the dependence disorder [123]. To the degree treatment studies involve psychiatric disorder, this is usually described by a global measure, e.g., the Addiction Severity Index, ASI, and more rarely as a psychiatric diagnosis [105]. To date, few controlled studies report results from the combined treatment of both disorders. Most studies focus on one of the problem areas. The research on problem drinking has mainly assessed different psychosocial methods targeted at alcohol dependence and/or psychopharmacological treatments for the mental disorders. The latter would also be expected to have an effect on the drinking problem, and this has been confirmed to a minor extent (reported in the chapter on psychopharmacological treatment). The focus has rarely been on concurrent treatment of both conditions. Patients with severe mental disorders have usually been excluded. However, in psychiatric research, some studies integrate the treatment for dependence with psychiatric treatment. A review of 10 studies of integrated treatment programs, 2 of which are experimental, show better results from integrated treatment than if the treatments are organizationally divided [42]. Nine randomized studies have been found which address problem drinkers with severe mental disorders as well as with personality disorders (see Table 2.20). Cognitive behavioral therapies showed better results for mental disorders than interactional therapies or traditional AA groups [36, 57, 94]. Those treated for both their psychiatric disorder (compulsive disorder) and their dependence achieved better results than those treated for alcohol dependence only, with or without combining treatment with relaxation [53]. One study notes better results from integrating alcohol dependence treatment within specialized psychiatric teams for patients with severe mental disorders [172]. A study that compared integrated treatment in special teams with “standard case management”, the latter of which used working methods similar to a special team, shows few differences between the models [43]. Summary There are still few randomized controlled studies concerning the heterogeneous group of persons with concurrent psychiatric and substance use disorders. Studies
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evaluating therapies on both conditions are rare. This limited research base indicates that better results are achieved when the treatment of the dependence condition is integrated with the treatment of the psychiatric disorder. Cognitive behavioral therapeutic treatments have shown better results than interactional therapy in some studies. However, further studies are needed to answer the question whether the dependence itself should be treated with a special methodology in patients with a concurrent mental disorder. Homeless (see Tables 2.9 and 2.21) In most industrialized countries the care of homeless alcohol-dependent persons changed during the 1970s since intoxication was decriminalized and intoxicated persons were taken to detoxification units in health care instead being placed in police custody. Initially, the measures for this group focused exclusively on the abusive drinking, then often limited to the treatment of withdrawal. Since the 1980s the strategy has gradually changed to combining measures for the dependence condition with measures for other problem areas. This development was driven in part by studies showing that the older treatment models with focus on treatment of withdrawal had no effect [6, 76]. Eleven randomized treatment studies have been identified, including 2527 patients, of whom 453 women (18%). The review was limited to studies where alcohol is described as the main dependence disorder, though many patients describe problems with several substances. Most of the studies have been performed recently, eight being from 1995 or later and representing a holistic approach. Most studies were difficult to perform, especially concerning dropout from treatment; the quality scores are relatively low (Q-value median 19). For example, in most cases sufficient data to enable calculation of effect sizes are not reported. However, it is noted that the positive studies are of a higher quality (median 22) compared to the negative (median 17.5). The results in five studies are positive [26, 38, 108, 162, 165]. Here, the comparisons are made with either no treatment or standard treatment. Two of the positive studies apply distinct behavioral therapy techniques. CRA treatment is applied in the Smith study [162]. Miller uses “contingency management”, i.e., benefits like housing, work, and treatment are conditional on sobriety [108]. The other three studies apply “intensive case management” (CM) [26, 38, 165]. Six studies are negative [7, 22, 35, 89, 131, 161]. Two describe CM programs, two are older and report less modern programs based on shelters and visiting, one reports on a social model, one is a multi-modal and eclectic program, one describes a comparison between inpatient and outpatient care. “Case management” programs for homeless clients were investigated in five studies involving 1784 patients in total. As noted above, three are positive and two are negative. Braucht finds no further effect by adding intensive CM to a special program for the homeless, Lapham finds no differences when intensive CM is compared with regular counseling or no treatment [22, 89]. However, a feature common to each of these studies is that all of the groups improved over time.
2.11 Subgroups of Alcohol-Dependent Patients Table 2.9.
Studies of treatment for homeless alcohol-dependent patients.
Study
Population
Treatments compared
Miller 1975 [108]
20 men
Smith 1998 [162]
106, 14% women
Sosin 1995 [165]
418, 26% women
Burnam 1995 [26]
276, 16% women
Cox 1998 [38] Annis 1979 [7] Braucht 1995 [22]
298, 9% women 70 men
Conrad 1998 [35]
358 men
Lapham 1995 [89]
469, 13% women
Ogborne 1979 [131] Smith 1995 [161]
40 men
1. Behavioral therapy, 2 months contingency management 2. Standard treatment for homeless abusers 1. CRA 12 months 2. Standard treatment (12-step + work support, housing + psych) 1. Case management only (as 12 months aftercare after detoxification IP) 2. CM+supportive housing 3. No aftercare 1. Housing + coordinated treatment 9 month for dependence, psych disorder 2. As in 1, but no supportive housing, more case management (not coordinated treatment) 3. No treatment 1. Intensive case management 18 months 2. Standard treatment 1. Half-way house (supportiv housing) 3 months 1. 2. No halfway house 1. Special unit for homeless 6 months alcohol-dependent patients 2. 1 + Case management 1. Social model treatment home 24 months with CBT focus+AA/NA+OP 2. Standard treatment: 3 weeks inpatient care + referral to different treatment units 1. Intensive case management + 10 months 4 months protected housing 2. Regular counseling + 4 months protected housing 3. 4 months protected housing, no counseling 4. Control group, no intervention 1. Counseling 3 months 2. No treatment 1. Environmental therapeutic 18 months community with supportive housing the first 3 months + 12-step treatment 2. As in 1, but no supportive housing the first 3 months
323, 15% women
149 women
Followup
Qmax 27 Effect 22
1>2
24
1>2
19
1=2>3
23
1=2>3
22
1>2
14
1=2
16
1=2
19
1=2
19
1=2=3 =4
14 22
1=2 1=2
77
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Six of the eleven studies compare groups that received treatment in inpatient care or supportive housing with groups who only receive treatment as outpatients [7, 26, 35, 89, 161, 165]. These studies address the question of whether homeless substance abusers can be treated as outpatients or whether homelessness itself is the primary problem. No differences in results are found in any of the comparisons studied, although they are based on several different treatment programs. Summary The studies are characterized by substantial problems in keeping patients in treatment programs. Yet, positive effects are found in treating homeless alcoholdependent patients when behavioral therapy and case management methods are used. Good effects require combining interventions against dependence with interventions aimed at other life problems. However, supportive housing or inpatient care does not seem to improve the results in comparison to outpatient services.
2.12
Therapist Factors
With psychological/psychosocial treatment in general, and with treatment for substance dependence in particular, the characteristics of the caregiver and his or her ability to involve the patient in therapy has an impact on the outcome. It has been found that the results from the same treatment of patients with the same characteristics may vary considerably among different therapists, and the importance of the therapist may even be greater than the methodology used. Manuals are used to control for this factor. Furthermore, requirements are established regarding training with current methodology and continuous supervision. The literature on therapist influence is extensive in general psychological treatment, and the therapist’s ability to establish a working alliance, and its importance for the outcome, is given special attention (see meta-analysis [72] and reviews [61, 73]). Few randomized studies address the treatment of substance use problems. Some of these concern drug dependence, e.g., the studies by Luborsky and McLellan [96, 106]. Therapist variables that have been shown to be important and contribute to the alliance are the capacity for empathy, an unconditional positive approach, genuineness, and compassion. Seven randomized studies (see Table 2.22) were found concerning the therapist factors, the therapist’s interpersonal skills, and the therapeutic alliance. A confrontative approach may be less suitable and may increase resistance, especially for patients with a negative self-image and for the elderly [8, 82, 116]. Furthermore, interpersonal skills and the degree of empathy are shown to have an impact on treatment outcome [174, 110]. The importance of the alliance has also been assessed in Project MATCH, based on an analysis by 75 therapists [36]. This showed that an early positive alliance (between patient and therapist) was related to retention in treatment, and the number of sober days during and after treatment, regardless of the treatment method.
2.13 Gender-related Effects
This study reports on the unique contribution of the alliance to the result after control for therapist and patient factors and other predictors, and the alliance explains 3% of the variance. Öjehagen showed that an early alliance was better in behavioral therapy than in more dynamic treatment. Furthermore, the author found an association between the alliance and an early positive change in mood, but not in longterm improvement of abusive drinking [183]. Summary The therapist’s interpersonal skills, degree of empathy, and ability to achieve a working alliance is shown to influence treatment outcome. A confrontative approach may be negative for individuals with a negative self-image.
2.13
Gender-related Effects
A topic that has been subject to considerable debate is whether men and women require different types of treatment for alcohol problems. Nevertheless, few controlled studies have been done in this area. Overall, it is noted that women who attend treatment have a better prognosis than men. A long-term followup showed that the probability that women would be problem-free 8 years after treatment was 1.63 times greater than for men; 55.3% of the women were in remission at that time, compared to 43.4% of the men [75]. However, epidemiological studies on the natural course of alcohol dependence do not indicate any significant gender differences after consideration has been given to differences in alcohol habits between men and women in the population [155]. Several individual studies report better treatment results for women, particularly in patients with moderate alcohol problems [12, 147, 151, 152, 156]. However, it is unclear whether there are genderspecific effects in more severe alcohol problems. In a study of homeless chronic abusers, better results are found for women [89]. Another study of homeless abusers found no gender differences [150]. Few randomized studies have been reported on treatment specifically designed for women. An exception is the study by Dahlgren that reports better results for women who are treated in a specialized womens’ unit compared to traditional, gender-mixed treatment [40]. However, in this study the gender factor is difficult to distinguish from a number of other factors, e.g., treatment methodology, extent of treatment, and form of care. Hence, an experimental treatment initiated in inpatient care that includes dynamically oriented counseling is compared with standard treatment given to both men and women. Furthermore, negative expectations may have appeared among the women who had sought help at a womens’ unit, but were randomized to standard treatment. No other controlled studies of treatment specifically designed for women were found. Some studies (nonrandomized) report matching effects. Women improve more with education and medically-oriented programs, while men improve more with group therapy [39, 164]. These findings, among others, motivated the study of
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matching effects based on gender in project MATCH. However, no such effects were found [143, 144]. Nevertheless, the results for women in this study were better than the results for men. In alcohol-dependent women with psychiatric disorders, the psychiatric disorders more often preceded the dependence disorder in women compared with men [17]. It has also been found that sexual abuse, often at an early age, is found in the history of women with alcohol problems, which may require special methods apart from treatment of the alcohol problem [166, 171]. Summary The studies on gender differences show that treatment outcome for women has been equal to or superior to that for men. Female alcohol-dependent patients have experienced sexual abuse more often than other women have. If psychiatric disorders exist concurrently, these disorders have usually preceded the dependence disorder. Only one controlled study was found in the literature describing effects from treatment specifically designed for women. However, this study does not allow any conclusions, and therefore the results are inconclusive at this time.
Favors control treatment
Figure 2.1. Meta-analyses 1–3. Effect sizes with Hedges’s correction. A filled square denotes the effect size of an individual study. The size of the square is related to the size of the study. The horizontal line indicates the 95% confidence interval (CI).
Favors specific treatment
A filled diamond denotes the summary effect of a meta-analysis. Effect sizes are calculated either as odds ratios or standardized mean differences, depending on the nature of the outcome measure.
216
7. The community reinforcement approach
193 350
5
174
4. Motivational interviewing (in addition to standard treatment) 5. Bibliotherapy
6. Cognitive behavioral therapy
3
472
3. Treatment vs one session of feedback/advice
7
6
7
6
283
2. Treatment vs waiting list
Number of studies 3
Number of patients
Meta-analyses 1-7.
1. Treatment vs no treatment 207
Treatment
Table 2.10.
2.2
2.7
1.0
2.0
1.7
1.3
1.0
Severity
3-12 m
2–6 m
3–15 m
3–4 m
6–24 m
6w–6m
4–6 m
Length of followup
12-step treatment
Therapist-led therapy oriented towards self control training Standard treatment
Standard treatment
Standard treatment
Waiting list
No treatment
Treatment in comparison group
-alcohol consumption -improved drinking pattern -abstinence -improved drinking pattern -index of alcohol problems -time spent drinking -partner’s drinking -alcohol consumption -drinking days
-alcohol consumption -days with uncontrolled drinking -alcohol consumption -abstinence -improved drinking pattern -partner’s drinking -abstinence -alcohol consumption -alcohol problems -improved drinking pattern -abstinence -alcohol consumption
Outcome measure
0.59
0.73
0.19
0.26
0.22
0.66
0.27
ES (fixed model)
2.13 Gender-related Effects 81
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2 Psychosocial Treatment for Alcohol Dependence
Favors control treatment
Figure 2.2. Meta-analyses 4–7. Effect sizes with Hedges’s correction. A filled square denotes the effect size of an individual study. The size of the square is related to the size of the study. The horizontal line indicates the 95% confidence interval (CI).
Favors specific treatment
A filled diamond denotes the summary effect of a meta-analysis. Effect sizes are calculated either as odds ratios or standardized mean differences, depending on the nature of the outcome measure.
2.14
Renewed Literature Search
In March 2002, a renewed literature search was conducted, covering the time period February 1999 – February 2002. Using the same search terms, an additional 25 randomized, controlled studies were found. One was included in meta-analysis 2 and one in meta-analysis 3 [184, 185]. Five studies reported results on matching [186–188, 194, 195], in addition to the studies by Rychtarik et al. [149] and Holder et al [69] that have already been commented upon; five reported work with significant others [189–193]; two dealt with length and intensity of treatment [194, 195]; four were on cognitive behavioral treatment approaches [196–198, 207]; six reported results from studies with co-morbid patients [187, 188, 199, 200, 205, 206]; two were comparisons between group and individual treatment [201, 202]; and the remaining two studies dealt with other topics: volunteer assistance, contingency management
2.14 Renewed Literature Search
and motivational interviewing [203, 204]. None of these additional studies changes our previous conclusions. In several instances our conclusions have been further supported. Studies on matching In three new studies, matching between specific methods and patient characteristics have not improved outcome [186–188]. The studies by Kadden et al. [187] and Kalman et al. [188] failed to replicate earlier matching results in prospective designs. The results supporting matching results between problem severity and intensity of treatment have been discussed earlier [149] and similar results have subsequently been reported by Connors et al. [194]. Delivering more extensive/ intensive treatment to patients with higher problem severity was found to be costeffective (see comments in discussion). This finding was further supported by Weisner and coworkers [195], where patients with mid-level psychiatric severity had higher rates of abstention in the day hospital, with higher cost-effectiveness as compared to out-patient treatment. Studies on significant others Our conclusions on marital therapy remain [191]. Improvements from interventions focusing on the partners of alcohol dependent patients have been reported from three studies, while there was no reduction in drinking of the patient [189, 192, 193]. One study focused on adult children of alcohol dependent persons who were themselves alcohol dependent and found better outcome among those participating in mutual help group meetings as compared to educational groups [190]. Studies on length and intensity of treatment Problem-drinking women without histories of severe physical dependence were assigned to two treatment enhancement programs; drinking reduction treatment alone (DRT) or DRT plus life skills and/or booster sessions [194]. The latter program led to significant improvement among women with heavier problems, but not among light drinkers. No outcome or cost-effectiveness differences were found between treatment in day hospital and traditional outpatient treatment [195]. No effect was found adding volunteer assistance to a behavioral self-management program [203]. Studies on cognitive behavioral treatment Four new studies on CBT were found. Burtscheidt et al. [196] and Wölwer et al. [205] compare CBT with cognitive therapy and with treatment as usual. No difference in outcome between CBT and cognitive therapy was found, but both therapies were superior to treatment as usual in terms of relapse rates. Heather compares moderation oriented cue exposure (MOCE) with behavioral self control treatment (BSCT) and finds no overall differences in outcome, although BSCT appears superior to MOCE for patients with high problem severity [197]. Monti compares a CBT approach (a combination of cue exposure and communication skills training) with treatment as usual (here consisting of education and relaxation training) and finds
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fewer days of heavy drinking with the CBT approach [198]. Morgenstern and coworkers [207] compare CBT with treatment as usual (TAU) and find no difference. This is a case where non-specific, standard treatment produces similar results as specific treatment. The authors note that therapists in the TAU condition knowing they were in a comparison condition, may have changed their clinical behavior. Differences in outcome may also have been minimized because of extensive research procedures. Studies on co-morbid patients Among patients with personality disorders, no differences have been found between specific methods focusing the substance abuse [187, 188], nor between specific methods and unspecific support [205]. No advantage on alcohol consumption or panic symptoms was found in an inpatient treatment for alcoholism by adding CBT focusing on panic symptoms in those comorbid with panic disorder [199]. However, there was a high dropout from the CBT. For persons with serious mental illness and substance use disorders, an integrated mental health and substance use program found a lower alcohol use 2 months postdischarge as compared to standard hospital treatment [200]. Another study on patients with severe mental illness, schizophrenia, found a significantly greater improvement including reduction in substance use, by adding motivational interviewing, cognitive behavioral therapy, and family intervention to ordinary psychiatric care [206]. Studies comparing group and individual treatment. Two studies comparing group treatment with individual treatment were found. Marques compares CBT treatment given in a group format with CBT in an individual format and finds no differences in outcome [201]. Monras compares treatment as usual with a combination of treatment as usual and group treatment, and finds longer periods of abstinence in the group treatment combination [202]. Contingency management (CM). Petry reports a trial comparing treatment as usual with and without a contingency management component [204]. After 8 weeks of followup a significantly higher proportion of patients were retained in treatment in the CM group. Discussion The first important implication from this review is that the interventions against alcohol problems should be differentiated according to the severity of the alcohol problem. Although alcohol dependence in its most pronounced form is a chronic condition, this concerns a minority of all people with alcohol dependence (Institute of Medicine, 1990). For people with less pronounced dependence (those who have been described as “mild” in this review), the amount and duration of treatment seem to be of less importance. For this group, self-help manuals or a few treatment sessions seem to have as good or better effects than more extensive treatment. Two important studies have been published since the final search for studies included in this review. Rychtarik et al. (2000) report on matching effects between problem
2.14 Renewed Literature Search
severity and inpatient/outpatient care. Patients with greater problem severity had more sober days if they received inpatient treatment, and vice versa; patients with lower alcohol involvement had more sober days if they were treated in outpatient care than in inpatient care. The study by Holder et al. (2000) shows that short treatment (MET) is cost-effective, but that a higher cost-effectiveness is achieved by offering more extensive treatment (12-step treatment or cognitive behavioral therapy) to patients with certain prognostically unfavorable factors (e.g., a high level of alcohol dependence or psychiatric comorbidity). These findings are crucial in the planning of interventions to prevent and treat alcoholism. In most countries there is a strong bias toward treatment for the small group with the most severe problems. This means, to a large extent, that there is a lack of treatment adapted to the needs of the considerably larger group of alcoholdependent drinkers with less pronounced problems. Applying the epidemiological paradox, the group generating the most disease, suffering, and costs is not treated appropriately [87]. For the intermediate group, i.e., people with moderate dependence severity (the largest group in this review), there are too few therapists trained in the specific methods best suited for this group. Consequently, these individuals, to a large extent, are not offered appropriate services. The second important conclusion is that specific treatment is more effective than nonspecific treatment. Specific treatment has a theoretical base, is conducted by therapists with specific training, and is manual guided and supported by systematic supervision. Examples of treatment methods, which include all or most of these components, include motivation-enhancing treatment, cognitive behavioral therapy, including the community reinforcement approach, 12-step treatment, and structured interactional therapy. Nonspecific treatment (often referred to as treatment as usual or standard treatment) usually includes supportive counseling in combination with social work interventions. In some cases disulfiram treatment is also included. These treatments are generally less well defined, and their focus on drinking behavior is not as clear as it is with the specific therapies, and they also yield poorer results. Severe alcohol problems are often chronic and remittent. Even moderate alcohol dependence often causes recurrent problems. However, most treatment studies in the alcohol field, including the randomized studies in this review, have not been optimally designed to study treatment in a long-term perspective. Usually the effects from different types of treatment interventions, lasting 1 to 3 months, have been studied. Then, at times, some type of followup contacts/aftercare have been included for up to one year, which may have added to the effect from the treatment. Treatment effects have usually been evaluated at 12 months after start of treatment, or sooner. While this limits the possibilities to draw conclusions concerning longterm effects, it is also a reflection of a clinical reality where most of the treatments are short or not specified in time. There is a need for further studies on the stability of treatment effects over longer periods and of the effect of less intensive treatment of longer duration. Most of the conclusions in this review are based on narrative analyses of the studies included. Meta-analyses have been performed when it has been found appro-
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priate because of the design of the studies, characteristics of the sample, and outcome. Particular attention should be given to the problems that arise when making different types of comparisons in meta-analyses, either comparing with some type of unspecific “standard treatment” or with some type of specific treatment. In analyzing the results from the meta-analyses summarized in Table 2.10, attention should be given to the comparative treatments which are presented. For example, the CBT treatments in meta-analysis 6 have mostly been compared with standard treatment, producing a large weighted effect size, while other meta-analyses, to a varying degree, present comparisons between specific treatments. Hence, different effect sizes for different treatments cannot be utilized to establish a list that ranks effective treatments. The review is also limited by the fact that most of the studies report outcomes only in terms of drinking behavior, and then often complete abstinence. In reality, improvement may occur without total abstinence. Such improvement is reflected in reduced drinking, improvement in social functioning, mental health, and quality of life. The lack of data on these indicators may lead to an underestimation of real treatment effects. In a longer time perspective, permanent sobriety is unrealistic as a treatment goal. For example, project MATCH shows that after 3 years the percentage of sober subjects during the final months was 27% to 36%, while the remainder reported controlled consumption and/or abuse. Occasional followup contacts over a long period that address central problem areas, mainly the abusive behavior itself, can be described as “extensive” treatment and can represent a good use of resources. However, the results are not equally convincing in showing that “intense” initial treatment is beneficial. For example, the patients who were randomized to four treatment sessions with motivational enhancing treatment in project MATCH had the same outcome as those randomized to twelve sessions with cognitive behavioral therapy or twelve sessions of 12-step treatment. Hence, initial treatment can be kept fairly limited, e.g., between four and eight sessions, even when the patient has pronounced dependence problems. However, initial treatment should be evidence based and complemented in two ways: (i) the addition of professional input to address specific problems of a social, psychiatric, or medical character that have been identified by a qualified initial assessment (not least, it is important to consider psychiatric disorders) and (ii) regular followup contacts addressing both the drinking itself and the general life situation in a long-term (3 to 5 years) perspective. An alternative or complement to this long-term followup is, from the outset, to help the patient establish contact with a supportive network. The caregiver’s role is then to help the patient to initiate or resume the contacts with his/her family or other close persons, with working life and social activities – in particular with organizations which promote alcohol and drug abstinence. A number of long-term followups support this focus [75]. This raises the question of what should be considered as “treatment” for severe dependence. Membership in AA or similar organizations, support from family members, religious associations, or supportive working places, are all factors with high predictive value for long-term sobriety. There-
2.14 Renewed Literature Search
fore, it seems reasonable that treatment programs should try to link patients into supportive networks when such needs appear. A large number of treatment methods have been shown to be effective when evaluated within the scope of research projects. However, these have usually been efficacy studies, i.e., studies performed under optimal conditions. The effects achieved when applying the methods in regular alcohol treatment are not equally well studied. A recently published review from treatment in the Veterans Administration (VA) in the United States presents a large analysis of treatment performed without a research structure [121]. This analysis is more characteristic of an effectiveness study, i.e., a study under normal conditions, with regular personnel. Three types of treatments were analyzed: 12-step treatment, cognitive behavioral therapy, and a combination of these, called “eclectic treatment”. The results agree with the Project MATCH study in that 12-step treatment seems to be somewhat more effective, and eclectic treatment is given an intermediate position. However, good results were reported for all three treatment types. Such studies are an important complement to randomized studies. A large gap exists between research and practice. Many of the scientifically documented methods, even those included in the VA study mentioned above, require training which most caregivers do not have. Hence, a large share of the treatment offered is unspecific in character. Central measures to increase the effectiveness of care for alcohol-dependent patients, therefore, involve raising the educational level among caregivers. The use of manuals and method-adapted, qualified supervision are important elements here. Conclusions Treatment is effective. This conclusion is based primarily on a narrative review of 23 studies comparing treatment with no treatment. Ten were comparisons with no treatment, where five favored treatment; six were comparisons with waiting list controls, where all favored treatment; and seven were comparisons with a single session of treatment, where four favored treatment. It was possible to include 16 of these studies in formal meta-analyses (see Figure 2.1). The meta-analyses were conducted on these three groups of studies and on all of the studies. Tests of heterogeneity were negative for the three group analyses and positive for the analysis of all studies. The combined effect size (random model, Hedge’s correction) of all 16 studies was 0.37 (95% CI, 0.18, 0.57), supporting the conclusion that treatment is effective. Specific treatment is better than standard treatment. In 22 comparisons of specific treatment with nonspecific treatment, 16 favor specific treatment. No specific treatment was found superior to another, however. In 30 comparisons between specific treatments, 19 found no differences. Where differences were found, seven studies favored the experimental treatment, and four favored the control treatment.
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Marital therapy and family intervention yield positive results. Marital therapy shows better results than a waiting list and equal or superior results compared with individual treatment. Involving family members in the patient’s treatment yields positive results. Support for matching to a specific treatment method is weak. Matching effects appear in several studies. However, replication is lacking. The results are not supported by a large, well-designed study, i.e., Project MATCH, which tests interaction between patient characteristics with three different types of treatment (Project MATCH, 1997; 1998). Hence, different specific methods appear to be equally successful among patients with moderate problem severity. Generally, the association between setting and intensity of treatment (inpatient, outpatient, amount, duration) and outcome is weak. Comparisons of inpatient and outpatient treatment are inconclusive, as are results from treatments using the same method but of different duration. However, the findings support adapting the extent of treatment to the problem severity.
For persons with limited problems (moderate or low dependence), limited treatment yields the same effect as more extensive treatment. The value of a self-help manual, or bibliotherapy, has been analyzed in five studies, where all report that bibliotherapy had the same effect as 6 to 10 therapist-managed treatment sessions. Brief treatment, with a few sessions, appears to have the same effect as more extensive treatment. For persons with greater problem severity, better results are seen with more treatment. In the treatment of patients with psychiatric comorbidity and/or homelessness there is a need to focus on other problems concurrently. So far, few studies have evaluated specific methods focusing on both the substance use disorder and the psychiatric disorder. Positive outcomes from treatment for homeless patients with alcohol dependence have been found when applying behavioral therapy and intensive case management. Supportive housing or inpatient care does not seem to improve the results compared to outpatient treatment.
2.14 Renewed Literature Search
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▲
On the following pages you can see the tables 2.11 to 2.23
90
2 Psychosocial Treatment for Alcohol Dependence Table 2.11a. Treatment compared to no treatment, a) comparison group: 0 treatment. Study
Population
PS1
Treatment
Duration
Brown [23] 1980
N=60 All men
1
1. Behavioral self-control training 2. Information, lecture, film 3. No treatment
15 h 15 w
Burnam [26] 1995
N=276 16% women, homeless abusers with severe mental disorders
3
1. Housing incl. intervention 3 months for abuse, mental disorder, intensive + 3 months n=67 more when required 2. As 1 but no housing support, more case management n=144 3. No treatment
Connors [33] 1992
N=80 67% men
1
1. Aftercare 8 times in group 6 months 2. Aftercare 8 times individual telephone contact 3. No aftercare 4. No treatment
Initial treatment= 2 months Aftercare= 6 months
Ditman [41] 1967
N=301 10% women
1
1. Alcohol clinic (psych-oriented treatm.) 2. AA-support 3. No treatment
1 month
Heather [66] 1987
N=104 78 men 26 women
1
1. Behavioral self-control training 2. Simple counseling 3. No treatment
2 primary care visits
Kivlahan [85] 1990
N=43 25 men 18 women
1
1. CBT 2. Alcohol information 3. Assessment only
8w
Mann [99] 1994
N=220 All men
1
1. Information about effects of 16 sessions alcohol 8w 2. Identification of individual problems + rehab options 3. No rehabilitation
1)
PS: Problem severity (1 = slight; 2 = moderate; 3 = severe).
2.14 Renewed Literature Search
91
Followup
Quality score max. 27
Outcome
Effect
12 months
17
Number of sober days of 90 (at 1-year followup) 1 2 3 Baseline 47.35 37.15 56.3 12 months 58.45 48.00 53.6
1>2>3
3, 4, 9 months: 79%, 76%, 70%
23
Alcohol abuse: treatment groups 1, 2 >3 at 3 months, but not at 6 months
1=2>3
6 months, 12 months after the completion of aftercare (18 months after completion of initial treatment)
23
18 months: no difference 1–3 or between 1–3 and 4 sober days per month, 6 months/ 12 months 1–3 1–3. 8.23±7.83/8.81±9.24
1, 2, 3 = 4
4. 9.13±6.48/9.36±10.85 12 months, 71%
17
Arrest for drunkenness: no difference in in relapse, or time to relapse
1=2
6 months
19
Alcohol consumption in units (mean value + SD) 1=2=3 1 2 3 Baseline 170.3 (88.6) 178.0 (96.1) 231.7 (156.6) 6 months 136.8 (84.7) 147.5 (123.2) 195.2 (144.6)
4, 8, 12 months, 83.7% followed up
21
Alcohol intake before treatment – 8 months followup (M±SD) followup 1. 14.8±11.3 follow up: 8.9±7.8 2. 19.4±16.2 follow up: 17.6±13.0 3. 15.6±11.8 follow up: 13.0±9.7
1>2>3
8–13 years
18
Followup mortality 1. 7.7% vs 2. 11% (tendency) – accidents, violent death 1<2 (tendency)
1>2 survival (ns)
Table continues on next page
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2 Psychosocial Treatment for Alcohol Dependence Table 2.11a. (cont.) Study
Population
PS1
Treatment
Duration
Murphy [124] 1986
N=60 All men, collegestudents
1
1. Physical exercise (running) 2. Medication 3. No treatment
8w
Ogborne [131] 1979
N=40 Homeless men
3
1. Counseling 2. No treatment
max. 6 months
Rohsenow [148] 1985
N=36 Men only, collegestudents
1
1. Stress management 2. No treatment
3w (total 6 h)
1)
PS: Problem severity (1 = slight; 2 = moderate; 3 = severe).
2.14 Renewed Literature Search
93
Followup
Quality score max. 27
Outcome
Effect
6 w; 31/60. 52% 1=9 2=9 3=13
18
Significantly less consumtion group 1 compared to 3 w 3–6 and 7–70 Group 2 no significant difference 1 or 3
1>3
3 months 16/20=80% 12/20=60%
14
No differences
1=2
5–6 months
21
Significant reduction consumption baseline – 2,5 months followup in experimental group, but not in control group Return baseline value after 5.5 months High consumption days did not differ among groups, nor did anxiety level
1=2
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2 Psychosocial Treatment for Alcohol Dependence Table 2.11b. Treatment compared with no treatment, comparison with patients on the waiting list. Study
Population
PS1
Treatment
Duration
Alden [4] 1988
N=144 67 women 77 men
1
1. Self-supervised behavior 2. Alcohol counseling 3. Waiting list n=54 for 12 weeks, thereafter rand. 1 or 2
12 w
Barber [14] 1995
N=23 partners 22 wives, 1 husband
2
1. Individual treatment 4–5 w 2. Group 4–5 w 3. Waiting list
5–6 sessions 4 months
Cadogan [28] 1973
N=40 5 women
2
1. Marital therapy 3–6 months 2. Waiting list
3–6 months
Eriksen [51] 1986
N=17 2 women
2
1. IC 7 w + self registered alcohol consumption 3 months 2. Waiting list 4 w + self-reg., thereafter inpatient care + self-reg. 3 months
1. 7 w IC 2. 4 w WL + IC
Harris [65] 1990
N=34 17 women
1
1. Self-supervised behavior: bibliotherapy 2. Self-supervised behavior: therapist-managed treatment 3. Waiting list, with self-regulation of alcohol consumption 4. Waiting list
10 sessions 10 w OC
Miller [116] 1993
N=42 24 men 18 women Problemdrinkers
1
Therapist style feedback on alcohol habit inventory 1. Confrontative = 14 2. Client-centered = 14 3. Waiting list = 14
1 session
1)
PS: Problem severity (1 = slight; 2 = moderate; 3 = severe).
2.14 Renewed Literature Search
95
Followup
Quality score max. 27
Outcome
Effect
12 and 24 months, 88% 127/144 1. 53/47 2. 52/46
21
After 12 w those who had been on a waiting list had poorer results than those who had been treated during that time. Otherwise no differences no drinking behavior
1=2>3
12 w
21
Patient seeks treatment/modifies consumption significantly more often in group 1 and 2 compared to 3 10/16 vs. 0/7
1=2>3
6 months after discharge
18
Sober/moderate consumption 1. 9/4 of 20 2. 2/5 of 20
1>2
3 months after completed inpatient care
18
No difference sobriety/consumption, well-being, sleep
1=2
15 months
21
Improved at 15 months (complete sobriety + controlled drinking + reduced drinking) 1 2 3 4 7 (78%) 5 (63%) 4 (50%) 5 (55%)
1=2>3=4
12 months, 83%
26
Alcohol consumption at 7 w (WL-group not yet treated): Group: 1+2 (IC) 3 (IC) Days/w 3.7 (2.7) 5.8 (2.1) SEC/w 18.9 (26.9) 35.5 (37.2)
1=2>3
Of those receiving directive (confrontative) feedback no differences versus the patients view, but the more confrontation the more increase in abuse
96
2 Psychosocial Treatment for Alcohol Dependence Table 2.12a. Motivation-enhancing treatment, motivational interviewing. Study
Population
PS1
Treatment
Duration
Bien [18] 1993
N=32 30 men 2 women
2
1. Standard treatment (12-step ground treatment in outpatient care) 2. 2 hours assessment + 1 motivational interview 1 hour + standard treatment
2 sessions (+ standard) treatment
Brown [24] 1993
N=28 21 men 7 women
2
1. Standard treatment (12-step inpatient care) 2. 2 hours assessment + 1 motivational interview 1 hour + 1
2 sessions (+ standard) treatment
3
1. Somatic hospital treatment 2. Motivational interview during hospital stay + 1
3 sessions (+ standard) treatment
Kuchipudi [88] N=114 1990 All men
1)
PS: Problem severity (1 = slight; 2 = moderate; 3 = severe).
2.14 Renewed Literature Search
97
Followup
Quality score max. 27
Outcome
Effect
3, 6 months
26
ES alcohol consumption (global measurement): 3 months 0.72 6 months 0.14 Significant effect at 3 months, not at 6 months
2>1
3 months
24
Improved at 3 months (sober or controlled drinking) 1 2 64% 29% Not improved 36% 71%
2>1
16 w, 89% followup
19
Drinking behavior at 16 weeks 1 2 Improved 20/55 21/59 Not improved 35/55 38/59
1=2
98
2 Psychosocial Treatment for Alcohol Dependence Table 2.12b. Motivation enhancing treatment, brief, CBT-oriented counseling. Study
Population
Sanchez-Craig N=90 [151] 52 men 1989 38 women
Sanchez-Craig N=96 [152] 61 men 1991 35 women
PS1
Treatment
Duration
1
1. Brief counseling + brochure 2 pages 2. Brief counseling + manual 40 pages 3. Therapist + manual 40 pages
1. 3 sessions 2. 3 sessions 3. 6 sessions
Repeat of S–C 89: 1. Brief counseling + brochure 2 pages 2. Brief counseling + manual 40 pages 3. Therapist + manual 40 pages
1. 3 sessions 2. 3 sessions 3. 6 sessions
1
3–6 w
3–6 w
Sannibale [154] N=96 1988 All men
1
1. Grouptreatment/ind standard 2. Group/ind. cognitive therapy 3. Mini-intervention 1 conversation
7w
Miller [116] 1993
1
Therapist style feedback on alcohol habit inventory 1. Confrontative 2. Client-centered 3. Waiting list
1 session
Swenson [170] N=351 1981 All men
2
1. 1 session 30 minutes + home task 2. 4 sessions (32 hours) 3. 6 sessions (15 hours)
1, 4 and 6 sessions, respectively
Reynolds [145] N=78 1995 Pregnant women
1
1. 10 minutes counseling + self-help manual 2. Standard treatment in maternal health care
10 minutes + manual
1)
N=42 24 men 18 women Problemdrinkers
PS: Problem severity (1 = slight; 2 = moderate; 3 = severe).
2.14 Renewed Literature Search
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Followup
Quality score max. 27
Outcome
Effect
3 months, (84%) 6 months, (80%) 12 months, (71%)
23
Days with heavy drinking: men 1 2 3 Admission 43 38 50 12 months 34 23 28
1=2=3
Days with heavy drinking: women 1 2 3 Admission 44 40 42 12 months 8 9 13 3 months, (83%) 6 months, (77%) 12 months, (72%)
23
Days with moderate drinking: men 1 2 3 3 months 24 33 53 12 months 10 38 47 Days with moderate drinking: women 1 2 3 3 months 77 75 50 12 months 69 75 60
15 months N=80, (83%)
20
No difference treatment groups
Women have better outcome than men
1=2=3 Women have better outcome than men
1=2=3
NB frequent followup 12 months, (83%)
26
Alcohol consumption at 7 w (WL-group not yet treated Group: 1+2 (SD) 3 (SD) Days/w 3.7 (2.7) 5.8 (2.1) SEC/w 18.9 (26.9) 35.5 (37.2)
1=2>3
Of those given directive (confrontative) feedback no differences versus the patients view, but the more confrontation the more increase in abuse 6 months, (73%) 12 months, (67%) 18 months, (62%)
16
No differences in alcohol consumption or in social problems at followup
1=2=3
2 months, (92%)
17
Complete sobriety at 2 months 1. 88% 2. 69%
1>2
100
2 Psychosocial Treatment for Alcohol Dependence Table 2.12c. Motivation enhancing treatment, primary care studies. Study
Population
PS1
Treatment
Duration
Heather [66] 1987
N=104 78 men 26 women
1
1. Self-supervised behavior 2. Simple counseling 3. No treatment
2 visits in primary care
Heather [67] 1990
N=107 69 men 38 women
1
1. 8 self-help manual, 100 pages 2. 1 + offer of telephone support 3. 1 + offer of telephone counseling 4. Simple brochure, 2 pages (control group)
Manual + telephone contact
1)
PS: Problem severity (1 = slight; 2 = moderate; 3 = severe).
2.14 Renewed Literature Search
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Followup
Quality score max. 27
Outcome
Effect
6 months
19
Alcohol consumption in units (mean value + SD) 1 2 3 Baseline 170.3 (88.6) 178.0 (96.1) 231.7 (156.6) 6 months 136.8 (84.7) 147.5 (123.2) 195.2 (144.6)
1=2=3
6 months
17
Alcohol consumption at 6 months (M + SD) 1 2 3 4 46.1 (46.7) 47.1 (48.7) 50.1 (46.5) 63.3 (54.5)
1=2=3>4
102
2 Psychosocial Treatment for Alcohol Dependence Table 2.12d. Motivation enhancing treatment, self-help manual, bibliotherapy. Study
Population
PS1
Treatment
Duration
Harris [65] 1990
N=34 17 women
1
1. Self-supervised behavior: bibliotherapy 2. Self-supervised behavior: therapist-managed treatment 3. Waiting list, with self-registration of alcohol consumption 4. Waiting list
10 sessions 10 w OC
Miller [111] 1980
N=41 21 men 20 women
1
1. Bibliotherapy 2. Behavioral therapy, self-control 3. 2 + relaxation training + social skills training 4. 2 + CBT broad spectrum
2–4: 6 w + 12 w
Miller [112] 1981
N=31 23 men 8 women
1
1. Behavioral self-control training: bibliotherapy 2. Behavioral self-control training: therapist-managed treatment
1. 1 session + 3 telephone calls 2. 10 sessions, 10 w
1
1. Brief counseling + brochure 2 pages 2. Brief counseling + manual 40 pages 3. Therapist + manual 40 pages
1. 3 sessions 2. 3 sessions 3. 6 sessions
Repeat of S–C 89: 1. Brief counseling + brochure 2 pages 2. Brief counseling + manual 40 pages 3. Therapist + manual 40 pages
1. 3 sessions 2. 3 sessions 3. 6 sessions
1. Brief counseling + brochure 2 pages 2. Brief counseling + manual 30 pages with practical advice how to reduce drinking 3. Brief counseling + pamphlet with general alcohol information
1 visit
Sanchez-Craig N=90 [151] 52 men 1989 38 women
Sanchez-Craig N=96 [152] 61 men 1991 35 women
Spivak [167] 1994
1)
N=140 99 men
1
1
PS: Problem severity (1 = slight; 2 = moderate; 3 = severe).
3–6 w
3–6 w
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103
Followup
Quality score max. 27
Outcome
Effect
15 months
21
Improved at 15 months (complete sobriety + controlled drinking + reduced drinking) 1 2 3 4 7 (78%) 5 (63%) 4 (50%) 5 (55%)
1=2>3=4
8 months assessment
21
Drinking pattern 6 and 12 months, share of improved: 1. 60% 60% 2. 73% 46% 3. 40% 60% 4. 80% 70%
1=2=3=4
3 months
20
Alcohol consumption in standard units 1 2 Baseline 48 57 3 months 16 24
1=2
No statistically significant differences 3 months, (84%) 6 months, (80%) 12 months, (71%)
23
Days with heavy drinking: men 1 2 3 Admission 43 38 50 12 months 34 23 28 Days with heavy drinking: women 1 2 3 Admission 44 40 42 12 months 8 9 13
3 months, (83%) 6 months, (77%) 12 months, (72%)
23
Days with moderate drinking: men 1 2 3 3 months 24 33 53 12 months 10 38 47 Days with moderate drinking: women 1 2 3 3 months 77 75 50 12 months 69 75 60
3 months, ( 78%) 12 months, (75%)
22
Reduction (%) of heavy drinking days 12 months Men Women 1. 59 82 2. 60 77 3. 29 19
1=2=3 Women had better outcome than men
1=2=3 Women had better outcome than men
1=2>3
104
2 Psychosocial Treatment for Alcohol Dependence Table 2.12e. Motivation enhancing treatment, motivation enhancing treatment. Study
Population
PS1
Treatment
Duration
Project MATCH [143] 1997
OC directly: N=952 685 men 267 women
2
1. 12-step (12 sessions) 2. CBT (12 sessions) 3. Motiv (4 sessions)
1, 2=12 sessions 3=4 sessions
1
1. Motivation enhancing therapy 2. Cognitive behavioral therapy, self-control training
1. 3–4 sessions 2. 9 sessions
IC before OC: N=774 619 men 155 women Robertson [147] N=37 1986 30 men 7 women
10 w OC 1)
PS: Problem severity (1 = slight; 2 = moderate; 3 = severe).
2.14 Renewed Literature Search
105
Followup
Quality score max. 27
Outcome
Effect
15 months after treatment start (90%)
27
Followup 12 months after completion of treatment. Percentage sober (month 4–15) 3. 15% = 2. 15% <1. 24% (OC) No difference IC
1 year: OC 3=2<1
Enbart IC: 36 months after completion of treatment
15.5 months, 89.2%
3 years OC: 3=2<1
Followup 36 months after completion of treatment. Share of sober (month 37–39) (OC) 3. 27% = 2. 24% <1. 36%
23
Alcohol consumption/month in units 1 2 Baseline 354.4 (53.4) 385.9 (65.6) Followup 268.9 (252.0) 129.4 (86.0)
2>1 Women better outcome
106
2 Psychosocial Treatment for Alcohol Dependence Table 2.13a. CBT-based studies, broad spectrum treatment with CBT orientation. Study
Population
PS1
Treatment
Duration
Allsop [5] 1997
N=60 All men
3
1. Relapse prevention: role play, skills training 2. Relapse prevention: discussion only, no activity 3. Standard treatment: detoxification, information, group discussion
8h 2w OC
Ferrell [54] 1981
N=22 6 women
2
1. Self-assertion training 2. Relationship training
10 sessions 1 month IC
Graham [63] 1996
N=91 58 men 33 women
2
1. Relapse prevention: group treatment, unit A 2. Relapse prevention: group treatment, unit B 3. Relapse prevention: individual treatment, unit A 4. Relapse prevention: individual treatment, unit B
12 sessions 3 months OC/IC
Ito [77] 1988
N=39 All men
2
1. Hospital care 28 days + relapse prevention 2. Hospital care 28 days + interactive therapy
8 sessions 4w IC
Kadden [80] 1989
N=96 63 men 33 women
2
1. Interactional therapy 2. Cognitive behavioral therapy
6 months
Litt [92] 1992
N=79 All men
2
Matching study: type I vs. type II 1. Skills training 2. Interactional therapy
26 sessions 6 months OC
Miller [110] 1980
N= 41 21 men 20 women
1
1. Bibliotherapy 2. Behavioral therapy, self control 3. 2 + relaxation + social skills training 4. 2 + CBT broad spectrum
2–4: 6 w + 12 w
1)
PS: Problem severity (1 = slight; 2 = moderate; 3 = severe).
2.14 Renewed Literature Search
107
Followup
Quality score max. 27
Outcome
Effect
6 months, 1 year
23
Complete sobriety: Moderate cons. no. w: 6 months 12 months 6 months 12 months 1: 44.4% 20% 20 14.1 2: 5% 5% 15 11.5 3: 5% 0 9.4 12.3
6 months: 1>2>3
1>2
6 w, 6, 12, 24 months
17
Complete sobriety 1 6 months 62.5 12 months 37.5 24 months 5.0
2 33.3 11.1 0
1 year
23
Number of drinking days of 90 1 2 3 Baseline 45.1 59.2 48.2 12 months 12.1 8.3 10.4
4 42.6 7.9
1 month 76.5% 73.3%
12 months: 1=2=3
1=2=3=4
6 months, 87% followup
17
Complete sobriety 1. 2.
6 months 50% 42.1%
1=2
Course during 6 months of aftercare. Total followup 86 (90%)
23
No clear difference between the treatments 1=2 Interaction mental disorder-method: Personality disorder: cognitive therapy > interactional therapy. No personality disorder: interactional therapy > cognitive therapy. Cognitive dysfunction: interactional therapy > cognitive therapy
2 years
18
Correctly matched patients significantly better outcome type I-IT, and type II-CS, respectively No total differences between treatments
1=2
8 months assessment
21
Drinking pattern 6 and 12 months, % improved: 1. 60% 60% 2. 73% 46% 3. 40% 60% 4. 80% 70%
1=2=3=4
Table continues on next page
108
2 Psychosocial Treatment for Alcohol Dependence Table 2.13a. (cont.) Study
Population
PS1
Treatment
Duration
Monti [119] 1990
N=69 All men
3
1. CBT/social training 2. 3 communication training + family participation 3. 3 communication training + managing emotional reactions
12 hours 4w IC
Nelson [125] 1982/83
N=33 All men
3
1. Self-assertion training – role play 2. Self-assertion training – demonstration
6 sessions 2w IC
O’Farrell [129] 1993
N=59 Couples with alcoholic husband
2
1. Behavioral marital therapy + relapse prevention 2. Behavioral marital therapy only
5 months BMT± 15 sessions RP (4 months)
Project MATCH [143] 1997
OC directly: N=952 685 men 267 women
2
1. 12-step (12 sessions) 2. CBT (12 sessions) 3. Motivation (4 sessions)
1, 2=12 sessions 3=4 sessions
IC before OC: N=774 619 men 155 women Sandahl [153] 1998
N=59 22 men 37 women
2
1. Dynamic group therapy 3. CBT therapy in group
4–5 months 15 sessions
Sjöberg [159] 1985
N=32 26 men
2
1. Dynamic therapy 2. CBT
5 sessions 6w
Skutle [160] 1987
N=43 34 men 9 women
1
1. 8 bibliotherapy (behavioral self control training) 2. 5 therapist-managed behavioral self control training 3. 2 skills training 4. comb 2 + 3
1. 2 sessions 2. 6 sessions 3. 6 sessions 4. 8 sessions 6–8 w OC
2
1. Dynamic treatment 2. Multimodal behavioral therapy
1 or 2 years random in both treatments
Öjehagen [182] N=72 1992 60 men 12 women
1)
PS: Problem severity (1 = slight; 2 = moderate; 3 = severe).
2.14 Renewed Literature Search
109
Followup
Quality score max. 27
Outcome
Effect
6 months, 77%
21
6 months: 1 2 3 % complete sobriety days: 90 91 85 Drinks/drinking day: 7.35 9.61 18.40
1=2>3
2 months, 82%
17
Complete sobriety 2 months 1 + 2 3 77.8% 55.6% Not statistically significant
1=2
12 months
24
% sober days 6 months 12 months
1>2
15 months after start of treatment (90%)
27
Followup 12 months after completion of treatment % sober (month 4–15) 3. 15% = 2. 15% <1. 24% (OC) Ingen skillnad IC
OC only: 36 months after completion of treatment
1 96.8 94.0
2 87.6 81.9
Followup 36 months after completion of treatment % sober (month 37–39) (OC) 3. 27% = 2. 24% <1. 36%
1 year: OC 3=2<1 3 years: OC 3=2<1
1 year after completion of treatment 1. 23/25: 92% 2. 21/24: 87.5%
19
Past 6 months sober/No intoxication drinking 1>2 1. 13/23 = 57% 2. 6/21 = 28% Sober days last 3 months vs. 3 months before: 1>2
At completion of treatment (100%)
18
No difference in relapse
1=2
3, 6, 12 months, 95.5% followed up
20
Alcohol consumption in standard drinks 1 2 3 4 Baseline 32 33 30 46 6 months 17 11 13 8 12 months 14 13 11 14
1=2=3=4
1 year and 2 years, respectively, after completion of treatment followed up 1. 29/36 = 81% 2. 34/36 = 94%
24
No difference between treatment option 1 or 2 or between 1 or 2 years of treatment Matching effect: 1. Dynamic therapy: patient with better mental status better outcome and those with poorer mental status poorer outcome 2. Cognitive therapy: outcome less associated with mental status
1=2
110
2 Psychosocial Treatment for Alcohol Dependence Table 2.13b. CBT-based studies, CRA-treatment (Community Reinforcement Approach, i.e. local, organized supportive interventions). Study
Population
PS1
Treatment
Azrin [9] 1976
N=18 All men
2
1. CRA + Antabuse insurance program 30 hours 2. Standard treatment: recommenIC dation Antabuse, family member support, advice and support
Azrin [10] 1982
N=43 36 men 7 women
2
1. CRA + Antabuse insurance program 2. Antabuse insurance program 3. Standard treatment: recommendation Antabuse, family member support, advice and support
6 hours 6w OC
Hunt [74] 1973
N=16 Men
2
1. CRA 2. Standard treatment: 12-step
50 hours IC
MAllms [98] 1982
N=35 25 men 10 women
2
1. CRA support for participation in social club 2. Standard treatment + info about social club
6 sessions 6w
Miller [115] 1992
N=238 83% men
2
1. 2. 3. 4.
12 sessions 1 session/w
Sisson [157] 1986
N=12 Family members
2
1. CRA for partner 2. Standard treatment for family members
7–8 h 7w OC
Smith [162] 1998
N=106 91 men 15 women
3
1. CRA 2. Standard treatment (12-step + work support, housing + psych)
3 months
1)
12-step without Antabuse 12-step + Antabuse CRA + Antabuse CRA without Antabuse
PS: Problem severity (1 = slight; 2 = moderate; 3 = severe).
Duration
2.14 Renewed Literature Search
111
Followup
Quality score max. 27
Outcome
Effect
6 months 24 months (incomplete data)
22
6 months: 1 compared with 2 Time drinking alcohol: 2% vs. 55% Unemployed: 20% vs. 56% Away from home: 7% vs. 67% Institutional treatment: 0% vs. 45%
1>2
6 months
24
Outcome 6 months: Days Amount/ Days with Unem- Away from drinking episode Antabuse ployed home 1.0.9 0.7 oz 24.8 2.2% 0 2.7.9 1.7 oz 19.3 3.2% 0 3.16.4 4.1 oz 0 10.9% 4.4%
1>2>3
6 months
18
Time drinking alcohol: 14% vs. 79% Unemployed: 5% vs. 62% Away from home: 16% vs. 36% Institutional treatment: 2% vs. 27%
1>2
3 months
16
Alcohol consumption (ounces alc/day) 1 2 Baseline 4.67 3.56 Followup 0.85 3.32 Difference –3.83 (±5.92) –0.24 (±2.38)
1>2
12 months, 67.2% 24 months, 78.2%
26
Alcohol consumption (SEC/week) 1 2 3 Baseline 50.2 55.4 50.7 6 months 6.6 8.1 19.8 24 months 12.0 8.5 15.3
1=2=3=4
5 months
18
Days with alcohol consumption: 3 months 1.4/30 2.26/30
1>2
6 months, (84.0%) 12 months, (76.4%)
24
Alcohol consumption (drinks per week) median + SD at 12 months 1 2 35.59 (22.4) 46.67 (22.8)
1>2
4 57.6 9.5 14.8
112
2 Psychosocial Treatment for Alcohol Dependence Table 2.13c. CBT-based studies, self-control training Study
Population
PS1
Treatment
Duration
Baker [13] 1975
N=40 All men
2
1. 2. 3. 4.
5–6 h
Brown [23] 1980
N=60 All men
1
1. Behavioral self-control training 2. Information, lectures, film 3. No treatment
15 h 15 w
Caddy [27] 1976
N=60 49 men 11 women
2
1. Aversion treatment + behavioral self-control training 2. Behavioral self-control training 3. Aversion treatment (electric shock)
10 sessions 10 w OC
Duckert [45] 1992
N=135 84 men 51 women
1
1. Behavioral self-control training: group treatment 2. Behavioral self-control training: individual treatment
12 sessions 12 w
Foy [60] 1984
N=62 All men
2
1. Broad spectrum CBT + controlled drinking training 2. Broad spectrum CBT only
15 h 4w IC
Harris [65] 1990
N=34 17 women
1
1. Self-supervised behavior: bibliotherapy 2. Self-supervised behavior: therapist-managed treatment 3. Waiting list, with self-reporting of alcohol consumption 4. Waiting list
10 sessions 10 w OC
Heather [66] 1987
N=104 78 men 26 women
1
1. Self-supervised behavior 2. Simple counseling vs. 3. No treatment
2 visits in primary care
1)
Stand. treatment group Counseling + self-control training Counseling + video confrontation Counseling + (modeling) role play
PS: Problem severity (1 = slight; 2 = moderate; 3 = severe).
2.14 Renewed Literature Search
113
Followup
Quality score max. 27
Outcome
Effect
6 weeks, 6 months
18
% sober days (6 months): 1. 64.8 2. 55.1 3. 50.3 4. 47.3
1=2=3=4
12 months
17
Number of sober days of 90 (at 1-year followup) 1 2 3 Baseline 47.35 37.15 56.3 12 months 58.45 48.00 53.6
1>2>3
6, 12 months
15
% improved drinking pattern 1 2 6 months 80 60 12 months 76 65
1>2>3 3 30 50
3, 9, 15, 21 months
21
Alcohol consumption (1/year) group group individ. individ. men women men women Baseline 38.4 18.0 30.0 25.2 3 months 14.4 15.6 12.0 9.6 21 months 14.4 7.2 13.2 12.0
1=2
6, 12 months
22
Complete sobriety, days: 1 6 months 108.8 12 months 207.6 Days with >237 ml: 6 months 44.1 12 months 88.2
2>1
2 134.5 255.6 21.6 50.4
15 months
21
improved at 15 months (Complete sobriety + controlled drinking + reduced drinking) 1 2 3 4 7 (78%) 5 (63%) 4 (50%) 5 (55%)
1=2>3=4
6 months
19
Alcohol consumption in units (mean value + SD) 1 2 3 Baseline 170.3 (88.6) 178.0 (96.1) 231.7 (156.6) 6 months 136.8 (84.7) 147.5 (123.2) 195.2 (144.6)
1=2=3
Table continues on next page
114
2 Psychosocial Treatment for Alcohol Dependence Table 2.13c. (cont.) Study
Population
PS1
Treatment
Duration
Miller [109] 1978
N=46 32 men 14 women
2
1. Aversion treatment (self-admin. electric shock) 2. Behavioral self-control training 3. Controlled drinking training
10 sessions 10 w OC
Miller [111) 1980
N= 41 21 men 20 women
1
1. Bibliotherapy 2. Behavioral therapy 3. 2 + relaxation + social skills training 4. 2 + CBT broad spectrum
2–4: 6 w + 12 w
Miller [112] 1981
N=31 23 men 8 women
1
1. Behavioral self-control training: bibliotherapy 2. Behavioral self-control training: therapist-managed treatment
1. 1 session + 3 telephone calls 2. 10 sessions 10 w
Skutle [160] 1987
N=43 34 men 9 women
1
1. Bibliotherapy (behavioral self-control training) 2. Therapist-managed behavioral self-control training 3. Skills training 4. Comb 2 + 3
1. 2 sessions 2. 6 sessions 3. 6 sessions 4. 8 sessions 6–8 w OC
1)
PS: Problem severity (1 = slight; 2 = moderate; 3 = severe).
2.14 Renewed Literature Search
115
Followup
Quality score max. 27
Outcome
Effect
3 months 1 year
20
Alcohol consumption in SEC 1 2 3 Baseline 39 33 38 3 months 29 14 16 12 months 14 11 9 No statistically significant differences
1=2=3
8 months assessment
21
Drinking pattern 6 and 12 months, % improved: 1. 60% 60% 2. 73% 46% 3. 40% 60% 4. 80% 70%
1=2=3=4
3 months
20
Alcohol consumption in standard units 1 2 Baseline 48 57 3 months 16 24 No statistically significant differences
1=2
3, 6, 12 months, 95.5% followed up
20
Alcohol consumption in standard drinks 1 2 3 4 Baseline 32 33 30 46 6 months 17 11 13 8 12 months 14 13 11 14
1=2=3=4
116
2 Psychosocial Treatment for Alcohol Dependence Table 2.13d. CBT-based studies, Cue exposure (training to refrain from drinking in usually tempting situations). Study
Population
PS1
Treatment
Duration
Drummond [44] 1994
N=35 All men
3
1. 7 cue exposure 2. 6 relaxation exercises
10 h 10 days IC
Monti [120] 1993
N=40 All men
2
1. Standard treatment 2. 1 + cue exposure + skills training
6h 2w IC
Sitharthan [158] 1997
N=47 21% women
1
1. Cue exposure 2. CBT
6 sessions
1)
PS: Problem severity (1 = slight; 2 = moderate; 3 = severe).
Table 2.13e. CBT-based studies, Other methods. Study
Population
PS1
Treatment
Duration
Baker [13] 1975
N=40 All men
2
1. 2. 3. 4.
5–6 h
Ormrod [136] 1991
N=36
2
1. Behavioral therapy anxiety 2. Relaxation training
1)
Standard treatment group Self-control + counseling + training Video self-control + counseling Counseling + (modeling) role play
PS: Problem severity (1 = slight; 2 = moderate; 3 = severe).
6h 4w OC
2.14 Renewed Literature Search
117
Followup
Quality score max. 27
Outcome
Effect
6 months
23
Time to relapse in heavy abuse (days) 1. 140 2. 90
6 months, 88%
22
Drank alcohol/High consumption 3–6 months 1. 79% 50% 2. 44% 31%
1<2
6 months, 81%
24
Drinking days/months Baseline 6 months 1. 21.64 (7.99) 6.23 (8.24) 2. 18.40 (7.99) 11.93 (10.18)
1>2
Followup
Quality score max. 27
Outcome
Effect
6 weeks, 6 months
18
% sober days (6 months): 1. 64.8 2. 55.1 3. 50.3 4. 47.3
1=2=3=4
3 months, 81%
22
Behavioral therapy for anxiety led to lower anxiety levels compared with relaxation training, but no effect on alcohol consumption
1=2
Alcohol consumption (index) 340 550
1>2
118
2 Psychosocial Treatment for Alcohol Dependence Table 2.14.
12-step treatment.
Study
Population
PS1
Treatment
Duration
Carroll [29] 1998
N=117 73% men Alcohol and cocaine dependence
2
1. 2. 3. 4. 5.
12 w
Keso [84] 1990
N= 141 117 men 24 women
3
1. 12-step 2. Standard treatment
6w
Miller [115] 1992
N=238 198 men 40 women
2
1. 2. 3. 4.
12 sessions 1 session/w
Project MATCH [143, 144] 1997/1998
OC directly: N=952 685 men 267 women
2
1. 12-step (12 sessions) 2. CBT (12 sessions) 3. Motiv. (4 sessions)
CBT + disulfiram 12-step + disulfiram Case M + disulfiram CBT 12-step
12-step without Antabuse 12-step + Antabuse CRA + Antabuse CRA without Antabuse
IC before OC N=774 619 men 155 women 1)
PS: Problem severity (1 = slight; 2 = moderate; 3 = severe).
1, 2=12 sessions 3=4 sessions 3 months
2.14 Renewed Literature Search
119
Followup
Quality score max. 27
Outcome
Effect
12 w = at completion of treatment
27
Positive effect from disulfiram on abstinence from cocaine and alcohol Active therapies CBT and 12-step better than support by case management
1/4, 2/5 >3 1=4= 2=5
12 months after completion of treatment Every second month (6 times) 77% followup at 12 months
25
Sober days 8–12 months: 1. 26.3% vs. 2. 9.8% % sober during entire followup period: 1. 14% vs. 2. 1.9% Drop-out rate: 1. 7.9% vs. 2. 23.6%
1>2
12 months, 67.2% 24 months, 78.2%
26
Alcohol consumption (drinks/week) 1 2 3 Baseline 50.2 55.4 50.7 6 months 6.6 8.1 19.8 24 months 12.0 8.5 15.3
1=2=3=4
15 months after start of treatment, (90%)
27
OC only: 36 months after completion of treatment
4 57.6 9.5 14.8
Followup 12 months after completion of treatment % sober (month 4–15) 1. 24% > 3. 15% = 2. 15% (OC) No difference IC
1 year: OC 1>2=3
Followup 36 months after completion of treatment: % sober (month 37–39) (OC) 1. 36% > 2. 24% = 3. 27%
3 years: OC 1>2=3
120
2 Psychosocial Treatment for Alcohol Dependence Table 2.15a. Studies aimed at underlying factors of abuse. Dynamically oriented therapies. Study
Population
PS1
Treatment
Duration
Olson [134] 1981
N=137 94 men 43 women
2
1. Environmental + TA therapy 2. Environmental therapy + behavioral therapy 3. Environmental therapy + TA + behavioral therapy 4. Environmental therapy
30 days
Sandahl [153] 1998
N=59 22 men 37 women
2
1. Dynamic group therapy 3. CBT in group
4–5 months 15 sessions
Sjöberg [159] 1985
N=32 26 men 6 women
2
1. Dynamic therapy 2. CBT
5 sessions 6w
2
1. Dynamic treatment 2. Multimodal behavioral therapy
1 or 2 years random in both treatments
Öjehagen [182] N=72 1992 60 men 12 women
1)
PS: Problem severity (1 = slight; 2 = moderate; 3 = severe).
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Followup
Quality score max. 27
Outcome
Effect
113 interviewed 4 years (82%)
20
Sober 0–6 months/ 6 months–1.5 years/3.5–4 years 1. 16/26=62% / 8/26=31% / 2. 19/22=86% / 12/22=65% / 3. 28/34=82% / 22/34=65% / 4. 20/31=65% / 16/31=52% /
2>4>3>1 12/26=46% 16/22=73% 24/34=71% 21/31=68%
1 year after completed treatment 1. 23/25: 92% 2. 21/24: 87.5%
19
Past 6 months sober/no intoxication drinking 1. 13/23 = 57% 2. 6/21 = 28% Sober days last 3 months vs 3 months before; 1>2
1>2
At completion of treatment (100%)
18
No difference in relapse
1=2
1 year and 2 years, respectively, after completion of treatment Followed up 1. 29/36 = 81% 2. 34/36 = 94%
24
No difference between treatment option 1 or 2 or between 1 or 2 years of treatment. Matching effect: 1. Dynamic therapy: patient with better mental status better outcome and those poorer mental status poorer results 2. Cognitive therapy: results less associated with mental status
1=2
122
2 Psychosocial Treatment for Alcohol Dependence Table 2.15b. Studies aimed at underlying factors of abuse. Interactional therapies. Study
Population
PS1
Treatment
Duration
Cooney [36] 1991
N=96 63 men 33 women
2
1. Interactional therapy 2. Cognitive behavioral therapy
6 months + 2 sessions until 12 months (total 20 sessions)
Ito [77] 1988
N=39 All men
2
1. Hospital care 28 days + relapse prevention 2. Hospital care 28 days + interactional therapy
8 sessions 4w IC
Kadden [80] 1989
N=96 63 men 33 women
2
1. Interactional therapy 2. Cognitive behavioral therapy
6 months
Litt [92] 1992
N=79 All men
2
1. Skills training 2. Interactional therapy
26 sessions 6 months OC
1)
PS: Problem severity (1 = slight; 2 = moderate; 3 = severe).
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Followup
Quality score max. 27
Outcome
Effect
0.5 and 1.5 years after completion of treatment (1 year and 2 years after initiation of aftercare)
22
No difference between treatments Interaction: personality disorder, cognitive dysfunction – method Matching effect, see matching report
1=2
6 months, 87% followup
17
Complete sobriety 1 month / 6 months 1. 76.5% / 50% 2. 73.3% / 42.1%
1=2
6 months = at completion of treatment Total followup 86 (90%)
23
No clear difference between treatments Interaction mental disorder – method: Personality disorder: cogn therapy > interact. therapy. No personality disorder: interact. therapy > cogn. therapy. Cogn. dysfunction: interact. therapy > cogn. therapy
1=2
2 years
18
No differences in total between the treatments
1=2
124
2 Psychosocial Treatment for Alcohol Dependence Table 2.15c. Studies aimed at underlying factors of abuse. Others: Psychotherapy. Study
Population
PS1
Treatment
Duration
Bruun [25] 1962
N=303 All men
2
1. Psychotherapy unspecified A-clinic = 203 2. Antabuse M-clinic = 100 3. Normal group = 402
1 = 32 sessions 2 = 10 sessions
Zimberg [180] 1974
N=107 All men
3
1. Psychotherapy ind./group, counseling mixed = 58 2. Medication/antabuse/ ind. support = 49 3. Self-selected daycare from group = 6
12 months
1)
PS: Problem severity (1 = slight; 2 = moderate; 3 = severe).
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Followup
Quality score max. 27
Outcome
Effect
2–3 years after inclusion 1 = 174 (86%) 2 = 86 (86%) 3 = 349 (87%)
16
Sober or moderate consumption 1. 38/174 (22%), improved 47/174=27% 2. 16/86 (19%), improved 23/86=27%
1=2
1 year after initiation of treatment 1 + 2 = 78/107 = 73% Total: 83/113 = 73%
18
Sober 23 w or more during past year 1. 9/420=21%, minimal consumption/no problems 17=40% 2. 10/36=28%, minimal consumption/no problems 16=44% (3. 1/5=20%)
1=2
126
2 Psychosocial Treatment for Alcohol Dependence Table 2.16.
Standard treatment.
Study
Population
PS1
Treatment
Duration
Allsop [5] 1997
N=60 All men
3
1. Relapse prevention: role play, skills training 2. Relapse prevention: role play, self confidence training 3. Standard treatment: abstinence treatment, information, group discussion
8 hours 2w OC
Azrin [9] 1976
N=18 All men
2
1. CRA, including Antabuse 2. Standard treatment: abstinence treatment, information, group discussion
30 h IC
Azrin [10] 1982
N=43 36 men 7 women
2
1. CRA + Antabuse supervision program 2. Antabuse supervision program 3. Standard treatment: recommendation antabuse, family member support, advice and support
6h 6w OC
Baker [13] 1975
N=40 All men
2
1. Standard treatment group 2. Self-control + counseling + training 3. Video self confrontation + counseling 4. Counseling + (modeling) role play
5–6 h
Carroll [29] 1998
N=117 85 men 32 women Alcoholand cocaine dependence
2
1. 2. 3. 4. 5.
12 w
Eriksen [52] 1986
N=24 Inpatient care
3
1. Advice/support as usual 2. Advice/support + social skills training
8w 8 sessions
Gilbert [62] 1988
N=96 All men
2
1. OP as usual after IP treatment 2. 1 + telephone reminder 2-3 days before visit 3. OP by house call
Active followup (2, 3) 6 months
1)
CBT + disulfiram 12-step + disulfiram Case M + disulfiram CBT 12-step
PS: Problem severity (1 = slight; 2 = moderate; 3 = severe).
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Followup
Quality score max. 27
Outcome
Effect
6 months 1 year
23
Complete sobriety:
Moderate consumption, number of weeks 6 months 12 months 6 months 12 months 1. 44.4% 20% 20 14.1 2. 5% 5% 15 11.5 3. 5% 0 9.4 12.3
6 months: 1>2>3
1>2
12 months: 1=2=3
6 months 24 months (incomplete data)
22
6 months: 1 compared with 2 Time drinking alcohol: 2% vs. 55% Unemployed: 20% vs. 56% Away from home: 7% vs. 67% Institutional treatment: 0% vs. 45%
6 months
24
Outcome 6 months: Days Amount/ Days with drinking occasion Antabuse 1. 0.9 0.7 oz 24.8 2. 7.9 1.7 oz 19.3 3. 16.4 4.1 oz 0
6 weeks 6 months
18
% sober days (6 months): 1. 64.8 2. 55.1 3. 50.3 4. 47.3
1=2=3=4
12 w = at completion of treatment
27
Positive effect of disulfiram on abstinence from cocaine and alcohol. Active therapies CBT and 12-step better than support by case management
1/4, 2/5 >3 1=4= 2=5
1 year 23/24
20
Group: 1 Alcohol cons. 23 cl/w Sober days 32% Days working 45%
1< 2
Every 3rd month until 1 year
22
Active followup increased attendance OP treatment, but did not result in better outcome concerning alcohol consumption
1>2>3 Unem- Away ployed from home 2.2% 0 3.2% 0 10.9% 4.4%
2 14.2 cl/w 77% 97%
1=2=3
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128
2 Psychosocial Treatment for Alcohol Dependence Table 2.16.
(cont.)
Study
Population
PS1
Treatment
Duration
Hunt [74] 1973
N=16 Men
2
1. CRA 2. Standard treatment: 12-step
50 hours IC
Jones [79] 1982
N=68 48 men 20 women
2
1. IP (standard 12-step treatment) 2. 1 + discussion group (emotional factors involved) 3. 1 + social skills training 6 sessions twice/w
28 days
Keso [84] 1990
N=141 117 men 24 women
3
1. 12-step 2. Standard treatment
6w IC
Monti [119] 1993
N=40 All men
2
1. Standard treatment 2. 1 + cue exposure + skills training
6 hours 2w IC
Nelson [125] 1982/83
N=33 All men
3
1. Self assertion training – role play 2. Self assertion training – demonstration
6 sessions 2w IC
Ogborne [131] 1979
N=40 Homeless men
3
1. Counseling 2. No treatment
Maximum 6 months
Pittman [139] 1972
N=250 221 men 29 women
2
1. IP + OP medication, support, 3–6 w 2. IP, standard detoxification, 7–10 days
1. Max 6 w 2. Max 10 days
Pomerleau [140] 1978
N=32 22 men 10 women
1
1. Traditional support, confrontation AA 9 w; aim sobriety 2. Behavioral therapy 5.5 w, direction control consumption
approximately 9 months 19 sessions
1)
PS: Problem severity (1 = slight; 2 = moderate; 3 = severe).
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Followup
Quality score max. 27
Outcome
Effect
6 months
18
Time drinking alcohol: 14% vs. 79% Unemployed: 5% vs 62% Away from home: 16% vs 36% Institutional treatment: 2% vs 27%
1>2
11–14 months after discharge 45% followed up
18
Alcohol consumption during the followup year 2, 3 >1 (2=3)
1< 2=3
12 months after completion of treatment every second month (6 times) 77% followup at 12 months
25
Share of sober days 8–12 months: 1. 26.3% vs 2. 9.8% Share of sober the entire followup period: 1. 14% vs 2. 1.9% Dropout rate: 1. 7.9% vs 2. 23.6%
1>2
6 months, 88%
22
Drank alcohol / High consumption 3–6 months: 1. 79% 50% 2. 44% 31%
1<2
2 months, 82%
17
Complete sobriety 2 months 1 + 2 77.8% Not statistically significant
1=2
3 months 1. 16/20 = 80% 2. 12/20 = 60%
14
Only 10 in the interview group had a regular contact. Number of improvement not stated. Improved situation, 3 patients total
1=2
1 year after discharge interview 232 (93%)
14
Sober the entire followup/min. 7 months during followup 1. 19/163 = 12% / 47/163 (29%) 2. 3/69 = 4% / 15/69 (22%) ns More intensive treatment: tendency better outcome consumption and social variables
1=2
1 year after completion of treatment followup 87%
18
Dropout: improvement:
1<2
1.43% 1.50%
2.11% 2.72%
3 55.6%
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130
2 Psychosocial Treatment for Alcohol Dependence Table 2.16.
(cont.)
Study
Population
PS1
Treatment
Duration
Powell [142] 1985
N=174 All men
2
1. Supportive measures, Antabuse, 100 h 2. Antabuse + medication prescription once/month 3. Somatic followup, no medication once/month
1 year
Sannibale [154] N=96 1988 All men
1
1. Group treatment/individual standard = 42 2. Group/individual cognitive therapy = 43 3. Mini-intervention 1 interview
7w
Sobell [163] 1973
N=70 All men
1
1. Behavioral therapy, controlled consumption 2. Behavioral therapy, complete sobriety 3. Standard treatment control consumption 4. Standard treatment, complete sobriety
1, 2 = 17 sessions
Telch [173] 1984
N=28 26 men 2 women
2
1. Group therapy, support 2. 12 symbol aversion treatment 3. Control group conversation
6w 1. once/w 2, 3. twice/w
1)
PS: Problem severity (1 = slight; 2 = moderate; 3 = severe).
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Followup
6 months, 1 year after completion of detoxification 85%
15 months N=80 (83%)
Quality score max. 27
21
20
131
Outcome
Effect
Share drinking past 6 months/mean value of severity of the drinking 1. 39% of 49 / 9.5±7.6 (M±SD) 2. 39% of 49 / 10.5±8.2 3. 37% of 50 / 9.5±7.6
1=2=3
No difference among treatment groups
1=2=3
NB! Frequent followup
6 w (100%); 6 months (100%)
20
Drinking behavior at 6 weeks (% days) 1 2 3 4 Controlled drinking 41.8 7.2 10.7 12.9 Complete sobriety 31.0 42.1 39.3 60.3 Drinking behavior at 6 months (% days) 1 2 3 4 Controlled drinking 27.3 14.5 9.1 2.9 Complete sobriety 37.9 16.6 29.4 62.6
1=2>3=4
4w
20
Drinks/drinking day 1. 1.46±1.82 (n=9) 2. 1.51±1.87 (n=11) 3. 1.23±1.55 (n=8) Comparison difference before-after larger 1>2, 3
1>2, 3
132
2 Psychosocial Treatment for Alcohol Dependence Table 2.17a. Marital therapy and interventions directed at family members. Marital therapy. Study
Population
PS1
Treatment
Duration
Bowers [21] 1990
N=16 14 men Alcohol problems
2
1. CBT marital therapy in group hours 2. Standard individual therapy, info, support
14 w
Cadogan [28] 1973
N=40 2 Husband alcohol problems
1. Marital therapy 3–6 months 2. Waiting list
3–6 months
Longabaugh [94] 1994
N=139 96 men 43 women
2
1. Cognitive behavioral therapy patient only 2. Relat. increasing cogn. (family members participate 4–8 sessions)
4–6 months + some boostersessions until 12 months = 20 sessions total
Longabaugh [95] 1995
N=229 158 men 71 women
2
1. CBT including 8 rel. increasing sessions with family members 2. CBT including 4 family member sessions + occupational therapy 3. CBT therapy group (patient only)
6 months 20 sessions, of which 2 are given 6–12 months after initiation of treatment
McCrady [100] 1979
N=33 20 men
2
1. IP + OP ind. + marital 2. OP ind. + marital 3. IP + OP patient only
–
McKay, Longabaugh [102] 1993
N=51 2 Husband alcohol problems
1. CBT individual treatment 2. CBT including marital therapy (partner participate 4–8 sessions)
4 months 20 sessions once/w completion of treatment
McCrady [101] 1986
N=45
1. Marital therapy focus alcohol + the relationship 2. Marital therapy focus alcohol 3. Family members participate, focus patient
16 w 15 sessions
1)
2
PS: Problem severity (1 = slight; 2 = moderate; 3 = severe).
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Followup
Quality score max. 27
Outcome
Effect
6, 12 months 28/32 (88%) 1. 15/16 2. 13/16
20
Average number of drinks/w: 6 months: 1>2, 12 months: 1>2 Sobriety: no difference. When consumption: 1 drank less than 2. Satisfaction with the relationship 1>2
1>2
6 months after discharge
18
Sober/moderate consumption 1. 9 of 20 /4 of 20 2. 2 of 20 /5 of 20
1>2
6 months after completion of treatment (18 months after initiation of treatment)
22
No difference between treatments Results not stated in relation to treatment. Matching results: 1>2 in antisocial personality disorder – method
1=2
6 months after completion of treatment Subsample 188 165/188 = 88% 1=58, 2=50 3=57
23
Abstinent % days past 3 months, 1 year after completion of treatment 1. 50/58 = 86% 2. 47/57 = 83% 3. 45/50 = 90% ns Matching results in relation to network characteristics
1=2=3
6–8 w 6–8 months
21
All groups reduced relationship problems, anxiety, depression, deterioration due to alcohol. Only 1 significant reduction in consumption, but others also reduction
1=2=3
6 months after initiation of, treatment ie 2 months after
22
% days abstinence 1–3 months, 4–6 months: 1=2, role functioning: 2>1 Matching results: 1. ind. therapy >2. marital therapy more dependent. Marital therapy tends to give better family function than individual therapy for independent patients (according to partner)
1=2
6 months after treatment 92.3% patient 89.3% family memb. No difference 1–3
25
Sobriety, abuse days 1=2=3 1>2. reduction of consumption earlier, relapse later, satisfaction with the relationship 1>3. still in treatment, maintained satisfaction with relationship
1=2=3
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134
2 Psychosocial Treatment for Alcohol Dependence Table 2.17a. (cont.) Study
Population
PS1
Treatment
Duration
Monti [119] 1990
N=69 All men
3
1. CBT/social training 2. 3 communication training + family participation 3. 3 communication training + CBT management of emotional reactions
12 hours 4w IC
O’Farrell [127] 1985
N=34 Husband alcohol problems
2
1. Behavioral marital therapy (including Antabuse contract) + individual counseling 2. Interactional marital therapy + individual counseling 3. Individual counseling
8 sessions 10 w
O’Farrell [128] 1992
N=34 Husband alcohol problems
2
1. Behavioral marital therapy (including Antabuse contract) + individual counseling 2. Interactional marital therapy + individual counseling 3. Individual counseling
8 sessions 10 w
O’Farrell [129] 1993
N=59 2 Husband alcohol problems
1. After marital therapy addition of relapse prevention couple 2. 0 added relapse prevention sessions
Initial marital therapy = 5–6 months + relapse prevention = 12 months
2
1. After marital therapy addition relapse prevention couple 2. 0 added relapse prevention sessions
Initial marital therapy = 5–6 months + relapse prevention = 12 months
2
1. Systemic marital treatment 8 sessions 2. One couple conversation
Max. 2 months
Behavioral therapy couple, thereafter with or without addition of relapse prevention O’Farrell [130] 1998
N=59 Husband alcohol problems Behavioral therapy couple, thereafter with or without addition relapse prevention
Zweben [181] 1988
1)
N=218
PS: Problem severity (1 = slight; 2 = moderate; 3 = severe).
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Followup
Quality score max. 27
Outcome
Effect
6 months, 77%
21
6 months: % complete sobriety days: Drinks/drinking day:
12–14 w after treatment start (88%) i.e., at the end of treatment
22
Sobriety, abuse not stated, instead % no consumption + no negative consequences 1>2, 3 satisfactory relationship 1>3 relationship, communication 1>2 drinking days Tend 1>2, 3 consumption and satisfactory relationship
1=2=3
2 years after treatment
22
1>3 satisfactory relationship 1=2=3 consumption
1=2
12 months after initial marital treatment
24
% sober days 1 6 months 96.8 12 months 94.0
1>2
18, 24, 30 months after completed marital therapy, i.e., 18 months after completion of relapse prevention
23
Relapse prevention has better outcome through 6 months after relapse prevention. Patients with more severe marital and abuse problems have better outcome through 30 months than if they received marital therapy alone. All who received relapse prevention had better relationship through 30 months
1>2
12 months: dropout treatment of followup 116=47%
22
No differences abuse days or other outcome measures 1>2 satisfaction treatment (no influence results)
1=2
1 2 3 90 91 85 7.35 9.61 18.40
2 87.6 81.9
1=2>3
(1, 2>3 1>2, tend)
136
2 Psychosocial Treatment for Alcohol Dependence Table 2.17b. Marital therapy and interventions aimed at family members. Family members are involved as support in the treatment. Study
Population
PS1
Treatment
Duration
Ahles [3] 1983
N=50 Men only
2
1. Aftercare with treatment contract including family members, support, calendar 2. Standard aftercare
6 months 8 sessions
Keane [83] 1984
N=25 All men
2
1. Antabuse intake in the presence of a family member according to contract = 8 2. 1 + positive feedback = 8 3. Antabuse use no contract = 9
3 months
Mallams [98] 1982
N=35 25 men 10 women
2
1. Standard + CRA – support for participation in social club 2. Standard treatment + info about social club
6 sessions 6w
1)
PS: Problem severity (1 = slight; 2 = moderate; 3 = severe).
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Followup
Quality score max. 27
Outcome
Effect
1 year after discharge per telephone 72% 1. n=18 2. n=18
16
Sober months 3, 6, and 12: 1>2, continuously sober until 6 months, tend 12 months: 1>2 Sober month 1–6 / 7–12 / working month 12 1. 77.8% / 38.9% / 46.7% 2. 16.7% / 11.1% / 13.3%
1>2
3 months
20
Got prescription Antabuse 3 months according to pharmacy 1 + 2: 14/16 = 88%, 3: 5/9 (56%) After 3 months use 14/16 in group 1 + 2 and 7/9 in group 3 Antabuse (ns)
1=2=3
3 months
16
Alcohol consumption per day 1 2 Baseline 4.67 3.56 Followup 0.85 3.32 Difference –3.83 (±5.92) –0.24 (±2.38)
1>2
138
2 Psychosocial Treatment for Alcohol Dependence Table 2.17c. Marital therapy and interventions aimed at family members. Intervention partners. Study
Population
PS1
Treatment
Duration
Barber [14] 1995
N=23 22 wives 1 husband
2
1. Individual treatment 4–5 w 2. Group 4–5 w 3. Waiting list
5–6 sessions 4 months
Sisson [157] 1986
N=12 Family members
2
1. CRA for partner 2. Standard treatment for family members
7–8 hours 7w OC
1)
PS: Problem severity (1 = slight; 2 = moderate; 3 = severe).
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Followup
Quality score max. 27
Outcome
Effect
12 w
21
Patient seeks treatment/modifies consumption significantly more often group 1 and 2 compared to 3 (10/16 vs 0/7)
1=2>3
5 months
18
Days with alcohol consumption: 3 months 1. 4/30 2. 26/30
1>2
140
2 Psychosocial Treatment for Alcohol Dependence Table 2.18a. Matching studies. Matching to specific treatment methods. Study
Population
PS1
Treatment
Duration
Cooney [36] 1991
N=96 63 men 33 women
2
1. Interactional therapy 2. Cognitive behavioral therapy
6 months + 2 sessions until 12 months (total of 20 sessions)
2
1. Interactional therapy 2. Cognitive behavioral therapy
6 months
2
1. Coping skills (CS) 2. Interactional therapy (IT)
26 sessions 6 months OC
2
1. 12-step (12 sessions) 2. CBT (12 sessions) 3. Motiv. (4 sessions)
1, 2 = 12 sessions 3 = 4 sessions 3 months
Patient characteristics: mental disorder, cognitive dysfunction Kadden [80] 1989
N=96 63 men 33 women Patient characteristics: mental disorder, cognitive dysfunction
Litt [92] 1992
N=79 All men Patient characteristics: alcohol abuse type I and II
Project MATCH [143, 144] 1997
OC directly: N=952 685 men 267 women IC before OC: N=774 619 men 155 women
Patient characteristics: mental ill health, (global measurement), degree of dependence, motivation, antagonism (personal) 1)
PS: Problem severity (1 = slight; 2 = moderate; 3 = severe).
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Followup
Quality score max. 27
Outcome
Effect
0.5 and 1.5 years after completion of treatment (1 year and 2 years after aftercare was initiated)
22
No difference between treatments Interaction: personality disorder, cognitive dysfunction – method 2>1 mental disorder 1>2 no mental disorder 1>2 cognitive dysfunction
1=2
Course during 6 months treatment Total followup 86 (90%)
23
No clear difference between treatments Interaction mental disorder – method: Personality disorder: cognitive therapy > Interactional therapy No personality disorder: Interactional therapy > cognitive therapy Cognitive dysfunction: interactional therapy > cognitive therapy
1=2
2 years
18
No differences in total between treatments Correctly matched patients significantly better outcome type I with IT, and type II with CS, respectively
1=2
15 months after initiation of treatment 1 year after completion of treatment (90%)
27
12-step > CBT at low level of mental problems 5–11 months after treatment direct OP
1 year: 1>3=2
MET > 12-step low motivation 12th month after treatment direct OP CBT > 12-step low dependence (IP-study) 12-step > CBT high dependency (IP-study) MET > CBT, 12-step: high antagonistic (OP) CBT > MET: low antagonistic (direct OP)
Table continues on next page
142
2 Psychosocial Treatment for Alcohol Dependence Table 2.18a. (cont.) Study
Population
PS1
Treatment
Duration
Project MATCH [144] 1998
OC directly: N=952 685 men 267 women
2
1. Cognitive behavioral therapy, CBT 2. 12-step 3. Motivation enhancement therapy, MET
1, 2 = 12 sessions 3 = 4 sessions 3 months
2
1. Dynamic treatment 2. Multimodal behavioral therapy
1 or 2 years random in both treatments
Patient characteristics: antagonism (personal), tolerance of the network for consumption Öjehagen [182] N=72 1992 60 men 12 women Patientcharacteristics: mental status
1)
PS: Problem severity (1 = slight; 2 = moderate; 3 = severe).
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Followup
Quality score max. 27
Outcome
Effect
3rd year after completion of treatment past, 3 months
27
MET > CBT, 12-step high antagon. personal CBT, 12-step > MET low antagon. personal (% sober days, drinks/drinking day)
1=2=3 (OP)
12-step > MET if network tolerant alcohol consumption (% sober days, drinks/ drinking day) (mediating effect from AA-participation after treatment)
1 year and 2 years, respectively, after completion of treatment Followed up 1. 29/36 = 81% 2. 34/36 = 94%
24
No difference between treatment alternative 1 or 2 or between 1 or 2 years of treatment Matching effect: 1. Dynamic therapy: patient with better mental status better outcome and those with poorer mental status poorer outcome 2. Cognitive therapy: outcome less associated with mental status (ns)
1=2
144
2 Psychosocial Treatment for Alcohol Dependence Table 2.18b. Matching studies. Matching to treatment which involves partner. Study
Population
PS1
Treatment
Duration
Longabaugh [93] 1993
N=229 153 men 76 women
2
1. Individual CBT 2. Marital therapy CBT
4–6 months + some booster sessions until 12 months = total of 20 sessions
Patient characteristics: social support, sobriety, need of social support Longabaugh [94] 1994
N=139 96 men 43 women Patient characteristics: antisocial personality disorder
2
1. Cognitive behavioral therapy patient only = 53 2. Relat increasing cogn. = 86 (family members participate 4–8 sessions)
4–6 months + some booster sessions until 12 months = 20 sessions total
Longabaugh [95] 1995
N=229 158 men 71 women
2
1. CBT including 8 rel. increasing sessions with family members 2. CBT including 4 family member sessions + occupational therapy 3. CBT therapy group (patient only)
6 months 20 sessions, of which 2 until 12 months after initiation of treatment
2
1. CBT individual treatment 2. CBT including marital therapy (partner participates 4–8 sessions)
4 months 20 sessions once/w
2
1. CBT (group) not family members 2. 1 + 8 sessions relationship enhancing treatment 3. 1 + 4 sessions relationship enhancing treatment + 4 sessions occupational therapy
20 sessions 4–6 months
Patient characteristics: importance of the network to the patient, the importance of the network for sobriety McKay, Longabaugh et al. [102] 1993
Rice [146] 1993
N=51 Patient characteristics: not independent (personality) N=229 150 men 79 women Patient characteristics: age groups: 18–29, 30–49, 50+
1)
PS: Problem severity (1 = slight; 2 = moderate; 3 = severe).
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145
Followup
Quality score max. 27
Outcome
Effect
Monitors patient 12 months, i.e., until end of intervention n=107 47% complete info.; 80% partial info.
24
1. CBT (ind.) = 2. relationship enhancement in good social support 1. CBT (ind.) >2. relationship enhancement in weak social support Relationship enhancement treatment poorer if patient not in need of social support
1=2
6 months after completion of treatment (18 months after initiation of treatment)
22
No difference between treatments Outcome not stated in relation to treatment 1>2 in antisocial personality disorder 1–2 no personality disorder
1=2
6 months after end of treatment Subsample 188 165/188 = 88% 1=58, 2=50 3=57
23
Matching effects in relation to varied number of family member sessions (8 or 4 sessions) 2>1 in patient whose network not supportive for sobriety or when network of less importance 1>2 patient whose network did not give support for sobriety + when network is of less importance, or when a supportive network of great importance existed
1=2=3
6 months after initiation of treatment, i.e., 2 months after end of treatment
22
% days of abstinence 1–3 months, 4–6 months, 1=2, 2>1 role functioning
1=2
3–6 months after initiation of treatment 83%
23
1. Less independent: individual therapy > marital therapy 2. Independent patient: Marital therapy tend better family function > individual therapy No differences between treatment methods Matching method – age group: 1=2=3: treatment method no significant differences 18–29 years 2>1 relationship-enhancing treatment better 30–49 years (ns) 1>3 cognitive therapy better 50+ (p<05)
1=2=3
146
2 Psychosocial Treatment for Alcohol Dependence Table 2.18c. Matching studies. Matching to different intensity, structure, and supportive measures for other problems. Study
Population
PS1
Treatment
Duration
McKay, Maisto et al. [103] 1993
N=53 Men only
2
After marital therapy OP: 1. Aftercare (15 sessions/couple) 2. No aftercare
Initial treatment aftercare = 1 year
McLellan [107] N=130 1997 Patient characteristics: presence of other problems
2
1. Standard program 2. 1 + extra sessions (3) other problems
IC: 21 days OC: 45 days
Nielsen [126] 1998
2
1. Highly structured treatment (contract) 2. Poorly structured treatment
12 months
2
1. Behavioral marital therapy (BMT) + 15 relapse prevention session couple 2. BMT without adding relapse prevention
Initial treatment = 5–6 months + relapse prevention = 12 months
2
1. More extensive treatment 2. One counseling interview (followup partner once/month first year)
1. 12 months
Patient characteristics: faith in own ability
N=119 90 men 29 women Patient characteristics: need of structure
O’Farrell [130] 1998
N=59 Couple, husband: alcohol problems Patient characteristics: severity of abuse, severity of marital problems
Orford [135] 1976
N=100 All men (married) Patient characteristics: physical dependence
1)
PS: Problem severity (1 = slight; 2 = moderate; 3 = severe).
2.14 Renewed Literature Search
Followup
Quality score max. 27
Outcome
1 year
23
Only correlations stated
147
Effect
1>2 those with less faith in own ability 1=2 good faith in own ability
6 months followup = 111, 85% 94 (72%) included in all data analyses
23
For patients who had other problems 2>1 = they stayed longer in treatment and improved more in these fields
1=2
Followup 12 months (86%) Followup 24 months (82%)
23
Improvements regardless of structure of treatment Correctly matched smaller interruptions from treatment; fewer relapses, better health
1=2
18, 24, 30 months after completed BMT, i.e., 18 months after completion of relapse prevention
23
Relapse prevention better outcome until 6 months after relapse prevention For all who received relapse prevention better relationship until 30 months For patients with more severe marital and abuse problems relapse prevention better outcome until 30 months than if they were given BMT only
1>2
2 years, 84%
20
No differences at a group level
1=2
Matching results: physical dependence1>2 no physical dependence: 1<2
148
2 Psychosocial Treatment for Alcohol Dependence Table 2.18d. Matching results. Matching to different approach. Study
Population
PS1
Treatment
Duration
Annis [8] 1983
N=150 Interns
2
1. Confrontation group = 100 2. No confrontation, traditional institutional care = 50
1=8w
1
Therapist-style feedback on alcohol habit inventory 1. Confrontative 2. Client-centered (3. Waiting list)
1 session
Patient characteristics: positive/ negative self-image Miller [116] 1993
N=42 24 men, 18 women Problem drinkers Patientcharacteristics: view on abuse; poor habit or illness
1)
PS: Problem severity (1 = slight; 2 = moderate; 3 = severe).
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149
Followup
Quality score max. 27
Outcome
Effect
12 months
19
No difference relapse between 1 and 2 Confrontation: 1<2 interns with poor self-esteem 1>2 interns with higher self-esteem
1=2
12 months, 83%
26
Of those given client-centered feedback: those who viewed abuse as a poor habit drank less than those who viewed abuse as an illness The more confrontation the more resistance and more abuse
1=2>3
150
2 Psychosocial Treatment for Alcohol Dependence Table 2.19a. Studies comparing the intensity and aftercare of treatment. Comparing inpatient care – outpatient care. Study
Population
PS1
Treatment
Duration
Chapman [31] 1988
N=121 98 men 23 women
2
1. IP (med./therapy/AA) 6 w 2. OP (unspecified + partner) 6 w 3. 1 confrontative conversation with partner
6w
Edwards [46] 1967
N=40
2
1. Hospital treatment IP 8.9 w 2. OP 7.7 w 1 visit/w
1. 8.9 w 2. 7.7 w
Eriksen [51] 1986
N=17
2
1. Inpatient care 7 w + self-reg. 3 months 2. Waiting list 4 w + self-reg., thereafter inpatient care + self-reg. 3 months
4w
Longabaugh [93] 1993
N=174
2
1. Hospital treatment = 14.1 days (60) Day care = 14.7 days (114)
2w 1. 11 sessions 2. 15 sessions
McLachlan [104] 1982
N=100 82 men 18 women
2
1. Inpatient care treatment 4 w 2. Day care
4w
Pittman [139] 1972
N=250 221 men 29 women
2
1. IP + OP medication, conversational support, 3–6 w 2. IP, standard detoxification, 7–10 days (C)
1. Max. 6 w 2. Max. 10 days
Potamianos [141] 1986
N=151 105 men 46 women
2
1. Trad. IP + OP 2. Day care
1)
2.
PS: Problem severity (1 = slight; 2 = moderate; 3 = severe).
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151
Followup
Quality score max. 27
Outcome
Effect
6, 18 months after initiation 84/113, 86% 1. 32/36 2. 23/35 3. 29/34
21
No difference at 6 months and 18 months: sobriety, moderate consumption drinks/drinking day
1=2=3
Every month through 1 year 100% followed up
22
No differences in outcome concerning drinking patterns and consequences Assessment monthly
1=2
3 months after completed inpatient care
18
No difference sobriety/consumption, well-being, sleep
1=2
Once/month 6 months
22
2. As good as 1, but at a lower cost Several measurements
1=2
4 and 12 months after completion of treatment Followup: 97/100 = 97%
21
Sober: 1. 17/48 2. 17/49 Max. 14 drinking days/year: 1. 29/48
1 year after discharge Interview 232 (93%)
14
Sober the entire followup period/minimum 7 months during followup 1. 19/163 = 12% / 47/163 (29%) 2. 3/69 = 4% / 15/69 (22%) ns More intensive treatment: tends to better outcome consumption and social variables
1=2
3, 6, 12 months 115 patients (79%) 1. 53/70 2. 62/81
20
Daily alcohol consumption (mean value 1 w before interview) 2>1 (multiple regression analysis) 1. 106 g/day 2. 89 g/day Sober 12 months: 1 = 10%, 2 = 17%: No difference other measurements Assessment 3, 6 and 12 months
2>1
1=2 2. 29/49
No difference between the treatments Two followups within 12 months
Table continues on next page
152
2 Psychosocial Treatment for Alcohol Dependence Table 2.19a. (cont.) Study
Population
PS1
Treatment
Duration
Smith [161] 1995
N=149 All women
3
1. Environmental therapeutic community with supportive housing the first 3 months + 12-step treatment 2. As in 1, but no supportive housing the first 3 months
3 months intensive treatment + 9 months low intensive
Sosin [165] 1995
N=418 309 men 109 women
3
1. Case management (CM) only (as aftercare after detoxification in IP) 2. CM + supportive housing 3. No aftercare
1. 3 months 2. 6 months
Walsh [177] 1991
N=227 217 men 10 women
2
1. IP: hospital 3 w, AA/w + control sobriety + work 1 year 2. Participation AA (OP) 3 times/w 1 year + control sobriety at work 3. Treatment of choice
All 1 year
Wanberg [178] N=180 1974 146 men 34 women
2
1. Inpatient care 2 w (hospital) 2. Outpatient care, 3 sessions in 2 weeks
2 w and 3 sessions/2 w respectively
Review: Outpatient care – Inpatient care Finney [56] 1996
1)
Review OP compared IP 14 studies of which 10 rand. included here
10 studies are included in this analysis: Edwards [46] 1967 Pittman [139] 1972 Wanberg [178] 1974 Mosher [122] 1975 Stein [168] 1975 Eriksen [51] 1986 McLachlan [104] 1982, Chapman [31] 1988, Chick [32] 1988, Walsh [177] 1991
PS: Problem severity (1 = slight; 2 = moderate; 3 = severe).
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153
Followup
Quality score max. 27
Outcome
Effect
18 months from admission 90% followed up
22
No improvement in alcohol habits over time; no difference between the groups No differences concerning housing and work
1=2
12 months; 73.7% followup
19
Number of drinking days out of past 30: 1 2 3 Baseline 17.8 16.9 16.4 12 months 4.8 4.3 6.8
1=2>3
2 years after initiation of treatment (1, 3, 6, 12, 18, 24) Followup: 1. 63/73, 86% 2. 73/83, 88% 3. 64/71, 90%
23
Sobriety during the entire outcome year: 1>2, 3 1. 23/63 = 37% 2. 12/73 = 16% 3. 11/64 = 17% Analysis also of share of never intoxicated 1>2, 1>3, 2=3 Inpatient care outcome year: 1. 23%, 2. 63%, 3. 38% Frequent followup
1>2 1>3 2=3
3 months 1. 88, 70% 2. 40, 74%
20
No difference sobriety 1. 33% 2. 30% Social adaptation: 10 of 25 questions 1>2
Sobr: 1=2 Adap. 1>2
7 of 14 studies differences: 5 studies IP > OP (of these here: Wanberg [178] 1974, Chick [32] 1988, Walsh [177] 1991) 2 studies day care > IP Studies where IP better, OP did not have abstinence treatment, social instability not as inclusion criteria and less often randomized
154
2 Psychosocial Treatment for Alcohol Dependence Table 2.19b. Studies comparing the intensity and aftercare of treatment. Treatment duration, inpatient care. Study
Population
PS1
Treatment
Duration
Mosher [122] 1975
N=200 160 men 40 women
2
1. 9 days IP (detoxification/ advice, ind. = 105 2. 21 days IP (advice etc.) = 95
9 days 21 days
Stein [168] 1975
N=58 All men
2
1. Detoxification IP 9 days, ind. assessment aftercare 2. Detoxification + IP 30 days (eclect., extensive content)
9 days 30 days
Stinson [169] 1979
N=466 391 men 75 women
2
Four comparisons 1. IP high staff ratio + OP extensive resources 2. IP high staff ratio + OP inform less resources 3. IP low staff ratio + OP extensive resources 4. IP low staff ratio + OP inform less resources
4–6 w IP OP not stated
Walker [176] 1983
N=245 All men
2
1. 2 w 2. 7 w
2 and 7 w
Willems [179] 1973
N=69 All men
2
1. IP (hospital) brief, max 4 w 2. IP (hospital) long, 8–26 w
1. 20 days 2. 82 days
1)
PS: Problem severity (1 = slight; 2 = moderate; 3 = severe).
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155
Followup
Quality score max. 27
Outcome
3 months, 91% 6 months, 82%
17
Sober 1. 2.
2, 4, 7, 10 and 13 months after admission 1. 26/29 2. 27/29
20
Control baseline data no differences Sober 7 months 13 months 1. 11/26 11/26 2. 8/27 10/27 Frequent followup
1=2
3, 6, 12, 18 months, 86%
21
Consumption level, drinking behavior only (scale) 3 and 4>1 and 2
3, 4>1, 2
3 months 35% 32%
Effect
6 months 23% 18%
1=2
No differences social function, need of care, accomplish goals Close followup
9 months
2 years after discharge, (90%)
23
No difference neuropsychological function in relation to duration of inpatient care Study (non-rand.) found that patients who participated in aftercare 1/w for 9 months were sober more often than others
1=2
Status at 12 months (%): 1 Recovered 28.9 Improved 42.1 Unchanged 28.9 Close followup
1=2 2 44.8 13.8 41.4
156
2 Psychosocial Treatment for Alcohol Dependence Table 2.19c. Studies comparing the intensity and aftercare of treatment. Duration of treatment, outpatient care. Study
Population
PS1
Treatment
Duration
Bennie [16] 1998
N=95
2
1. Home detoxification (8 visits) 2. Mini-intervention 1 visit, no medication, advice
1. 5 days 2. once + once after 4 w
Chapman [31] 1988
N=121 98 men 23 women
2
1. IP (medication/therapy/AA) 6 w 2. OP (unspecified + partner) 6 w 3. 1 confrontative conversation with partner
6w
Chick [32] 1988
N=153
2
1. Extended advice/support 1988 (IP/OP) 2. One session advice/support 3. 5 minute advice
2–4 w
Edwards [47] 1977
N=100 All men (married)
2
1. More extensive treatment 2. One counseling interview
1. 12 months
Orford [135] 1976
N=100 All men (married)
2
1. More extensive treatment 2. One counseling interview (Followup partner once/month first year
1. 12 months
Sannibale [154] N=96 1988 All men
1
1. Group treatment/indiv. standard 2. Group/ind. cognitive therapy 3. Mini-intervention 1 conversation
7w
Zweben [181] 1988
2
1. Systemic marital therapy (8 sessions) Max. 2. One couple conversation 2 months
1)
N=218 Couples
PS: Problem severity (1 = slight; 2 = moderate; 3 = severe).
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157
Followup
Quality score max. 27
Outcome
Effect
6 months 76/95 80% (1=40; 2=36)
22
1. (Detoxification house call) sober twice as long (number of weeks) as 2. mini-interv. 1. 16.3±6.8 2. 9.6±8.1 p<.001
1>2
6, 18 months after initiation, 84/113, 86% 1. 32/36 2. 23/35 3. 29/34
21
No difference at 6 months and 18 months: sobriety, moderate consumption, drinks/drinking day
1=2=3
2 years Followup family member every third month
25
Sobriety: no difference Increased advice less negative consequences of drinking
Sobriety: 1=2=3 Alcohol related problems: 1>2=3
1 year (94%) Followup every month through partner
21
No differences in outcome concerning drinking pattern and consequences
1=2
2 years, 84%
20
No differences at a group level Matching results: Physical dependence 1>2 No physical dependence: 1<2
1=2
15 months N=80 (83%)
20
No difference treatment groups
1=2=3
12 months: dropout treatment or followup 116=47%
22
Close followup No differences abuse days or other outcome measures 1>2 satisfaction treatment (no influence outcome) close followup, group 2 = 5 followup
1=2
158
2 Psychosocial Treatment for Alcohol Dependence Table 2.19d. Studies comparing the intensity and aftercare of treatment. Different number of hours in treatment. Study
Population
PS1
Treatment
Duration
Kamara [81] 1998
N=230 182 men 48 women
3
1. Standard OP 3 months 2. Standard OP 6 months
3 and 6 months respectively
Maisto [97] 1985
N=48 All men
2
1. Time-limited treatment Max 9 months + personal followup 2. Time-limited treatment + data followup 3. Unlimited treatment + personal followup 4. Unlimited treatment + data followup
O’Farrell [129] 1993
N=59 2 Couples, husband alcohol problems
1. After marital therapy addition relapse prevention couple 2. 0 additional relapse prevention sessions
Initial treatment = 5–6 months + relapse prevention = 12 months
O’Farrell [130] 1998
N=59 2 Couples, husband alcohol problems
1. After marital therapy addition of relapse prevention couple 2. 0 addition relapse prevention sessions
Initial treatment = 5–6 months + relapse prevention = 12 months
1. Supportive measures, Antabuse, 100 hours 2. Antabuse + medication prescription once/month 3. Somatic followup, no medication once/month
1 year
Behavioral therapy couple, thereafter with or without addition of relapse prevention Powell [142]
1)
N=174
2
PS: Problem severity (1 = slight; 2 = moderate; 3 = severe).
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159
Followup
Quality score max. 27
Outcome
Effect
3, 6 months after IP
19
2 somewhat better than 1: more often medical, visits, homemaker, fewer arrests
1=2
Once/months until 1.5 year 42/48, 87.5%
19
1. In treatment several weeks, but not more times (ns) Followup once/month of patient and family member 1. 35.3 w 2. 22.0
1=2=3=4
Followup once/month of patient and family member 12 months
24
% sober days 1 6 months 96.8 12 months 94.0
2 87.6 81.9
1>2
18, 24, 30 months after completed BMT, i.e., 18 months after completion of relapse prevention
23
Relapse prevention better outcome until 6 months after relapse prevention. For all who received relapse prevention better relationship until 30 months
1>2
For patients with more severe marital and abuse problems better outcome until 30 months than if they were given marital therapy only
6 months, 1 year after completion of detoxification 148/174 = 85%
Share drinking since 6 months/mean value of severity of drinking 1. 39% of 49 / 9.5±7.6 2. 39% of 49 / 10.5±8.2 3. 37% of 50 / 9.5±7.6
Table continues on next page
160
2 Psychosocial Treatment for Alcohol Dependence Table 2.19d. (cont.) Study
Population
PS1
Treatment
Duration
Project MATCH [143, 144] 1997, 1998
OP directly: N=952 685 men 267 women
2
1. 12-step (12 sessions) 2. CBT (12 sessions) 3. Motiv. (4 sessions)
1, 2. 12 sessions 3. 4 sessions 3 months
2
1. Dynamic treatment 2. Multimodal behavioral therapy
1 or 2 years random in both treatments
IP before OP: N=774 619 men 155 women Öjehagen [182] N=72 1992 60 men 12 women
1)
PS: Problem severity (1 = slight; 2 = moderate; 3 = severe).
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161
Followup
Quality score max. 27
Outcome
Effect
15 months after initiation of treatment (90%)
27
Followup 12 months after completion of treatment share of sober (month 4–15) 3. 15% = 2. 15% <1. 24% (OP) No difference IP
1 year: OP 3=2<1
OP only: 36 months after completion of treatment 1 year and 2 years, respectively, after completion of treatment Followed up 1. 29/36 = 81% 2. 34/36 = 94%
3 years OP: 3=2<1
Followup 36 months after completion of treatment: Share of sober (months 37–39) (OP) 3. 27% = 2. 24% <1. 36% 24
No difference between treatment alternative 1 or 2 or between 1 or 2 years of treatment Matching effect: 1. Dynamic therapy: Patient with better mental status better outcome and those with poorer mental status poorer outcome 2. Multimodal therapy: outcome less associated with mental status
1=2
162
2 Psychosocial Treatment for Alcohol Dependence Table 2.19e. Studies comparing the intensity and aftercare of treatment. Aftercare. Study
Population
PS1
Treatment
Duration
Ahles [3] 1983
N=50 Men only
2
1. Aftercare with treatment contract including family members, support calendar 2. Standard aftercare
6 months 8 sessions
Connors [33] 1992
N=80 54 men 26 women
1
1. Aftercare 8 times in group 6 months 2. Aftercare 8 times individual telephone contact 3. No aftercare (C1) 4. No treatment = 17 C2
Initial treatment = 2 months Aftercare = 6 months
Fitzgerald [58] 1985
N=354 All men
2
1. Followup telephone call every second week 2. 0 followup telephone calls No special treatment apart from tel.
1 year after discharge
Foote [59] 1991
N=325
2
1. Special support during followup every other month = 164 times 2. Standard followup when needed = 162
12 months
Gilbert [62] 1988
N=96 All men
2
1. OP as usual after IP treatment 2. 1 + telephone reminder 2–3 days before visit 3. OP by house calls
Active followup (2, 3) 6 months
O’Farrell [129] 1993
N=59 Couples with alcoholic husband
2
1. Behavioral marital therapy (BMT) + thereafter relapse prevention (RP) couple 2. BMT only
5 months BMT + 15 sessions RP 4 months
1)
PS: Problem severity (1 = slight; 2 = moderate; 3 = severe).
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163
Followup
Quality score max. 27
Outcome
Effect
1 year after discharge per telephone, 72% 1. n=18 2. n=18
16
Sober month 3, 6, and 12: 1>2, continuously sober until 6 months, trend at 12 months: 1>2 Sober month 1–6 / 7–12 / at work month 12 1. 77.8% / 38.9% / 46.7% 2. 16.7% / 11.1% / 13.3%
1>2
6 months, 12 months after completion of aftercare (18 months after initial treatment + completion of aftercare
23
18 months: no difference 1–3 or between 1–3 and 4. Sober days per month, 6 months/ 12 months 1–3. 8.23±7.83 / 8.81±9.24 4. 9.13±6.48 / 9.36±10.85
1, 2, 3 = 4
1 year 288 = 81% 1. 123 2. 165
19
Sober since discharge/or drank <4 days 1. 26/123 = 21% / 40/114 = 35% 2. 37/165 = 22% / 52/161 = 32%
1=2
1 year after treatment
20
Share of sober (%) 12 months: 1. 12.7±13.8 2. 11.9±12.2
1=2
Every 3rd month through 1 year
22
Active followup increased attendance in OP treatment, but did not result in better outcome concerning alcohol consumption
1=2=3
12 months
24
% sober days 1 6 months 96.8 12 months 94.0
1>2
2 87.6 81.9
Table continues on next page
164
2 Psychosocial Treatment for Alcohol Dependence Table 2.19e. (cont.) PS1
Study
Population
O’Farrell [130] 1998
N=59 2 Couple, husband with alcohol problems
Treatment
Duration
1. After marital therapy addition thereafter relapse prevention couple 2. 0 addition relapse prevention
Initial marital therapy = 5–6 months? relapse prevention = 12 months
1. Followup interview only 3 12 months 2. 1 + intensive followup spec. pers. once every 14 days for 3 months, once/month through 9 months 3. 1 + diary cons. sent in 4. 1 + intens. + diary
2, 4 = 14 sessions
behavioral therapy couple, thereafter with or without addition of relapse prevention Ogborne [133] 1988
1)
N=144 90 men 54 women
2
PS: Problem severity (1 = slight; 2 = moderate; 3 = severe).
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165
Followup
Quality score max. 27
Outcome
Effect
18, 24, 30 months after completed BMT, i.e., 18 months after completion of relapse prevention
23
Relapse prevention had better outcome through 6 months after relapse prevention All who received relapse prevention had better relationship through 30 months
1>2
3 months, 12 months 101 = 70%
18
Patients with more severe marital and abuse problems had better outcome through 30 months than if they were given BMT alone
No differences followup 1–4 consumption Association accomplishment-treatment and accomplishment-followup Difficult to reach patient for intensive followup, few (38%) kept a diary
1=2=3=4
166
2 Psychosocial Treatment for Alcohol Dependence Table 2.20.
Treatment of mentally disturbed abusers.
Study
Population
PS1
Treatment
Duration
Burnam [26] 1995
N=276 Homeless abusers with severe mental disorder
3
1. Housing including coordinated intervention for abuse, mental disorder, n=67 2. As in 1 but no housing support, more case management (no coordinated treatment) = 144 3. No specific intervention, but free access to municipal service n=65
3 months intensive + 3 months further treatment when needed
Cooney [36] 1991
N=96 63 men 33 women
2
1. Interactional therapy 2. Cognitive behavioral therapy
6 months + 2 sessions until 12 months (total 20 sessions) 3 years
mental disorder Drake, McHugo [43] 1998
N=223 2 Schizophrenia, bipolar disorder, schizoaffective disorder
1. Integrated treatment in special teams (assertive community treatment) 2. Standard case management
Fals-Stewart [53] 1992
N=60 Co-morbidity: compulsive syndrome
3
1. Treatment compulsion + abuse = 19 1. 3 times/w 2. Treatment abuse + relaxation = 18 6w 3. Treatment of abuse only = 20
Fisher [57] 1996
N=44 Co-morbid Personality disorder (Cluster B and C)
3
1. IP (CBT vs AA vs standard treatment) = 19 2. OP (CBT vs AA vs standard) treatment = 19
12 w, 3 times/w
Jerrell [78] 1995
N=132
2
1. CBT 2. Intensive case management (including education drugs) 3. AA groups within teams
18 months
Lehman [90] 1993
N=54 2 Severely mentally disturbed (schiz. affective disorder)
1. Traditional psychiatric treatment (no treatment abuse) 2. 1 + intensive case management (= few representatives/pat.) including group treatment with sobriety as a goal
1 year
1)
PS: Problem severity (1 = slight; 2 = moderate; 3 = severe).
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167
Followup
Quality score max. 27
Outcome
Effect
3, 4, 9 months: 79, 76, 70%
23
Alcohol abuse: Treatment groups 1, 2>3 at 3 months, but not at 6 months
1=2>3
0.5 and 1.5 year after completion of treatment (1 year and 2 years after initiation of aftercare)
22
No difference between treatments. In mental disorder, cognitive dysfunction 2>1 See matching report
2>1 mental disorder
3 years
23
1>2 dropout (3.7% vs 14%). Tend 1>2 quality of life and certain abuse measures, otherwise the same outcome
1=2
12 months, 95%
20
1. More often sober, stayed longer in treatment, higher reduction of compulsive symptoms Complete sobriety: 1. 58% 2. 27% 3. 30%
1>2=3
After completed treatment 86%
23
In inpatient care CBT, AA > standard treatment In outpatient care CBT > AA and standard treatment, respectively, concerning alcohol, social, and family situation and psychological problems
IP: 1=2>3 OP: 1>2=3
6, 12, 18 months after initiation of study
20
Positive change psychosocial functioning, mental symptoms, abuse. CBT > AA. Case management > AA. Change greater 12–18 months compared to 6–12 months
1>3 2>3
6, 12 months
22
No differences. Problems involving patient in treatment for abuse (few received treatment for abuse)
1=2
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168
2 Psychosocial Treatment for Alcohol Dependence Table 2.20.
(cont.)
Study
Population
PS1
Treatment
Duration
Longabaugh [94] 1994
N=139 96 men 43 women Antisocial personality disorder
2
1. Cognitive behavioral therapy patient only = 53 2. Relation enhancement cogn. = 86 (family members participate 4–8 sessions)
4–6 months + some booster sessions until 12 months = total 20 sessions
Teague [172] 1995
Focus severely mentally disturbed within 7 distr.
2
1. Team-specific working way including abuse fewer pat. (12/pers) 2. Traditional case management more patients (25/person)
27 months
1)
PS: Problem severity (1 = slight; 2 = moderate; 3 = severe).
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169
Followup
Quality score max. 27
Outcome
Effect
6 months after completion of treatment (18 months after initiation of treatment)
22
No difference between treatments. Matching results: 1> 2 in antisocial personality disorder
1>2 pers. disorder
27 months
24
Team with special working method for severely mentally disturbed and who included abuse treatment better than traditional case management
170
2 Psychosocial Treatment for Alcohol Dependence Table 2.21.
Treatment of homeless abusers.
Study
Population
PS1
Treatment
Duration
Annis [7] 1979
N=70 Homeless men
3
1. Halfway house 2. Not halfway house
1. 4–8 months 2. Not in treatment
Braucht [22] 1995
N=323 15% women
3
1. Special unit for homeless abusers 2. Case management + 1
4 months
Burnam [26] 1995
N=276 84% men
3
1. Housing including intervention for abuse, mental disorder, n=67 2. As 1 but no housing support, more case management, n=144 3. No treatment
3 months intensive + 3 months further treatment when needed
Conrad [35] 1998
N=358 All men
3
1. Social model treatment home with CBT orientation + AA/NA + OP 2. Standard treatment: 3 w inpatient care + referral to different treatment units
1. 3, 4 months IP + 9 months OP 2. 2–3 w IP + 1 year OP
Cox [38] 1998
N=298 Homeless; 9% women
3
1. Intensive case management 2. Standard treatment
No time limit
Lapham [89] 1995
N=469 13% women
1. Intensive case management + 4 months sheltered housing (N=161) 2. Regular counseling + 4 months sheltered housing (N=164) 3. 4 months sheltered housing, no counseling (N=92) 4. Control group, no intervention
1–3: 67 days
Miller [108] 1975
N=20 All men
3
1. Behavioral therapy, contingency management 2. Standard treatment for homeless abusers
2 months
Ogborne [131] 1979
N=40 Homeless men
3
1. Counseling = 20 2. No treatment = 20 3. Ind. contact
Max. 6 months
1)
PS: Problem severity (1 = slight; 2 = moderate; 3 = severe).
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171
Followup
Quality score max. 27
Outcome
Effect
3 months
14
Documented relapse to drinking 1. 51% 2. 46%
1=2
6 months
16
No difference concerning drinking pattern or use of services.
1=2
3, 4, 9 months: 79, 76, 70%
23
Alcohol abuse: Treatment groups 1, 2 >3 at 3 months, but not at 6 months
1=2>3
3, 6, 9, 12, 18 and 24 months 1. 60–77% 2. 47–54%
19
Trend to better outcome the first year, thereafter levelling out Alcohol consumption: days in past 30: Baseline 1. 19.0 2. 18.4 12 months 1. 5.7 2. 5.6 24 months 1. 7.3 2. 7.7
1=2
18 months; 82%
22
Small, but significant improvement in both drinking and social function 6 months: days with drinking (in past 30): 1. 14.6 (12.0) 2. 17.8 (11.1) (ES = 0.29)
1>2
10 months: 78%
19
Days with drinking in past 30 (10 months): (SD) 1. 5.3 (1.1) 2. 7.4 (1.1) 3. 7.1 (1.3) 4. 3.8 (1.9)
1=2=3=4
2 months; 100%
22
Alcohol-related arrests: median (SD) 1 2 Baseline 1.70 (1.15) 1.40 (1.07) 2 months followup 0.30 (0.48) 1.30 (0.81)
1>2
3 months 1. 16/20 = 80% 2. 12/20 = 60%
14
Only 10 in the intervention group had regular contact Numbers showing improvement not reported Improved situation tot. 3 patients
1=2
Table continues on next page
172
2 Psychosocial Treatment for Alcohol Dependence Table 2.21.
(cont.)
Study
Population
PS1
Treatment
Duration
Smith [161] 1995
N=149 All women
3
1. Environmental therapeutic community with supportive housing the first 3 months + 12-step treatment 2. Same as 1, but no supportive housing the first 3 months
3 months intensive treatment + 9 months low intensive
Smith [162] 1998
N=106, whereof 15 women
3
1. CRA 2. Standard treatment (12-step + work support, housing + psych
3 months
Sosin [165] 1995
N=418 26% women
3
1. Case management only (as aftercare after detoxification in IP) 2. CM + supportive housing 3. No aftercare
1. 3 months 2. 6 months
1)
PS: Problem severity (1 = slight; 2 = moderate; 3 = severe).
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Followup
Quality score max. 27
Outcome
Effect
18 months from admission 90% followed up
22
No improvement in alcohol habits over time; no difference between groups No differences concerning housing and work
1=2
12 months
24
Alcohol consumption (drinks per week) median + SD at 12 months 1 2 35.59 (22.4) 46.67 (22.8)
1>2
12 months; 73.7%
19
Number of drinking days of past 30: 1 2 3 Baseline 17.8 16.9 16.4 12 months 4.8 4.3 6.8
1=2>3
174
2 Psychosocial Treatment for Alcohol Dependence Table 2.22.
Studies on therapeutic approach.
Study
Population
PS1
Treatment
Duration
Annis [8] 1983
N=150 Interns
2
1. Confrontation group = 100 2. No confrontation, traditional institutional care = 50
1=8 w
Kashner [82] 1992
N=137 Men
2
1. Rehabilitation increase selfconfidence, respect, tolerance, support = 72 2. Traditional confrontative program = 65 3. After IP, 1 year of aftercare
3–4 w IP 1 year aftercare
Miller [110] 1980
N=41 21 men 20 women
1
1. Bibliotherapy 2. Behavioral therapy, self control 3. 2 + relaxation training + social skills training 4. 2 + CBT broad spectrum
2–4: 6 w + 12 w
Miller [116] 1993
N=42 24 men 18 women Problemdrinkers
1
Therapist-style feedback on alcohol habit inventory 1. Confrontative 2. Client-centered 3. Waiting list
1 session
Project MATCH [144] 1998
OP directly: N=952 685 men 267 women
2
1. Cognitive behavioral therapy, CBT 2. 12-step 3. Motivation enhancement therapy, MET
3 months 1, 2 = 12 sessions 3 = 4 sessions
2
Eight therapists were assessed: 1. Good interpersonal skill = (pat = 31) 2. Medium interpersonal skill = (pat = 47) 3. Low interpersonal skill = (pat = 47)
12 days
2
1. Multimodal behavioral therapy (MBT) 2. Dynamic structured (PT)
1 and 2 years respectively
IP before OP: N=774 619 men 155 women Valle [174] 1981
N=247 Majority men
Öjehagen [183] N=72 1997 60 men 12 women
1)
PS: Problem severity (1 = slight; 2 = moderate; 3 = severe).
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175
Followup
Quality score max. 27
Outcome
Effect
12 months
19
No difference relapse between 1 and 2 1<2 interns with low self-esteem 1>2 interns with high self-esteem
1=2
6, 12 months after completion of IP Accomplishment IP 1. 90% 2. 95%
19
Outcome share of sober 6, 12 months: At 6 months: 1. 2.9 times more often sober than 2 At 12 months: 1. 2.1 times more often sober than 2
1>2
8 months assessment
21
Degree of empathetic ability was assessed according to empathy scale and was related to positive outcome for each therapist. 67 % of the variance of positive outcome was explained by good empathetic ability
1=2=3=4
12 months, 83%
26
Those who received client-centered feedback and saw abuse as a habit drank less than those who viewed abuse as an illness The more confrontation, the more resistance, more abuse. Followup
1=2>3
Through 1 year after completion of treatment In-between every 3rd month
27
In direct OP: Early alliance (therapist and patient) predicted participation in treatment, consumption during treatment and 12 months thereafter, after control other factors regardless of treatment After IP therapeutic alliance predicted share of sober days
6, 12, 18, 24 months
16
The higher interpersonal function in the therapist, the fewer number of relapses and days with less probability for use of alcohol at followup
Until 3 years after initiation of treatment
24
Early therapeutic alliance was better in MBT than in PT. Patient alliance positive association with different mood dimensions in MBT after 6 months, but not with course of abuse during treatment or 3rd year
1>2>3
176
2 Psychosocial Treatment for Alcohol Dependence Table 2.23.
Studies illustrating gender-related effects.
Study
Population
PS1
Treatment
Duration
Dahlgren [40] 1989
N=200 All women
1
1. Conversational treatment psychodynamic basis for women only IP + OP 2. Standard treatment IP + OP
Max. 8 months
Lapham [89] 1995
N=469 408 men 61 women
1. Intensive case management + 4 months sheltered housing (N=161) 2. Regular counseling + 4 months sheltered housing (N=164) 3. 4 months sheltered housing, no counseling (N=92) 4. Control group, no intervention (N=52)
1–3: 67 days
Robertson [147] N=37 1986 30 men 7 women
1
1. Motivation enhancing therapy 2. Cognitive behavioral therapy, control training
1. 3–4 sessions 2. 9 sessions 10 w OP
SanchezCraig [151] 1989
N=90 52 men 38 women
1
1. Brief counseling + brochure 2 pages 2. Brief counseling + manual 40 pages 3. Therapist + manual 40 pages
1. 3 sessions 2. 3 sessions 3. 6 sessions 3–6 w
SanchezCraig [152] 1991
N=96 61 men 35 women
1
Replication of S–C 89: 1. Brief counseling + brochure 2 pages 2. Brief counseling + manual 40 pages 3. Therapist + manual 40 pages
1. 3 sessions 2. 3 sessions 3. 6 sessions 3–6 w
1)
PS: Problem severity (1 = slight; 2 = moderate; 3 = severe).
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177
Followup
Quality score max. 27
Outcome
Effect
Followup approx. 1 year after completed treatment (2 years from treatment start) 1. 75/100 = 75% 2. 68/100 = 68%
18
Improved drinking pattern: Year 1: 1 = 50/75 (67%), 2 = 31/68 (45%) Year 2: 1 = 44/75 (59%), 2 = 32/68 (48%)
Year 1: 1>2 Year 2: 1>2
10 months: 78% followup
19
Days with drinking in past 30 (10 months): (SD) 1: 5.3 (1.1) 2: 7.4 (1.1) 3: 7.1 (1.3) 4: 3.8 (1.9)
1=2=3=4
15.5 months, 89.2%
23
Alcohol consumption/month in units 1 2 Baseline 354.4 (53.4) 385.9 (65.6) Followup 268.9 (252.0) 129.4 (86.0)
2>1 Women better outcome than men
3 months (84%) 6 months (80%) 12 months (71%)
23
Days with heavy drinking: men 1 2 3 Admission 43 38 50 12 months 34 23 28 Days with heavy drinking: women 1 2 3 Admission 44 40 42 12 months 8 9 13
1=2=3
3 months (83%) 6 months (77%) 12 months (72%)
23
Days with moderate drinking: men 1 2 3 3 months 24 33 53 12 months 10 38 47 Days with moderate drinking: women 1 2 3 3 months 77 75 50 12 months 69 75 60
Women better outcome than men
1=2=3 Women better outcome than men
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2 Psychosocial Treatment for Alcohol Dependence
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1 Kolumnentitel
3
Pharmacotherapy for Alcohol Withdrawal Syndrome Johan Franck
3.1
Introduction
Withdrawal syndrome after discontinued consumption of alcohol is one of the criteria for the diagnosis of alcohol dependence. The condition is often without complications, but may progress to become a serious, and in some cases life-threatening, condition. Alcohol withdrawal symptoms can be classified into specific symptoms (withdrawal hallucination, delirium tremens or alcohol-conditioned psychotic syndrome, and generalized tonic-clonic seizures) and several unspecific symptoms (high pulse, elevated blood pressure, perspiration, tremor, agitation, anxiety, depression, etc.). The unspecific symptoms occur as early as a few hours after the blood alcohol level has started to decrease. The risk of seizures is greatest during the first few days after the cessation of alcohol intake, while delirium tremens usually develops after 3 to 5 days. Known risk factors for severe withdrawal syndromes and delirium tremens include concurrent physical illness, long-term intake of large amounts of alcohol, and a previous history of delirium or severe withdrawal syndromes. Hallucinations in association with alcohol intoxication and withdrawal usually pass spontaneously and will not be addressed further here, but they are a risk factor for developing delirium tremens. In treatment of withdrawal it is important to reduce the patient’s unspecific symptoms and subjective suffering, but the most important goal is to prevent seizures, delirium tremens, and death. Many studies have been published on the pharmacological treatment of alcohol withdrawal and delirium tremens. Most are studies of benzodiazepines, but other kinds of drugs have also been studied, e.g., anti-epileptics, alpha-2-agonists, beta-receptor antagonists, calcium antagonists, magnesium, antipsychotic drugs, and thiamine. The aim of this chapter is to present an overview of published clinical drug trials on withdrawal treatment for the respective groups of agents. Furthermore, recent meta-analyses in the area are summarized to compare the effectiveness of different agents in alleviating the symptoms of alcohol withdrawal and reducing the risk of withdrawal seizures and delirium.
Treating Alcohol and Drug Abuse. Edited by M. Berglund, S. Thelander, E. Jonsson Copyright c 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 3-527-30682-X
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3.2
Methods 3.2.1
Selection Criteria
A search was conducted for all prospective, randomized, double-blind trials with placebo control or comparison drugs. The effectiveness of antipsychotic drugs in alcohol withdrawal has been reported previously and is mentioned here only when other types of drugs are presented in the same study [104]. A few older studies which do not fulfill the selection criteria have been included in cases where recent documentation is deficient. 3.2.2
Diagnostic Criteria and Outcome Measures
Older studies often lack the diagnostic inclusion criteria presented in the DSM or ICD classifications. Nevertheless, such studies have been included. The most common outcome measure in the selected studies is the reduction of withdrawal symptoms, usually measured by a rating scale. The scale most often used is the Clinical Institute Withdrawal Assessment-Alcohol-revised (CIWA-Ar), a successor to the Gross Rating Scale for Alcohol Withdrawal [49, 118]. Other scales are presented in Table 3.1. Other outcome measures reported in some studies are the number of deaths and the number of cases of withdrawal seizures and delirium that occur during treatment. 3.2.3
Search Strategy
The search terms, “substance withdrawal syndrome/ethyl alcohol”, “alcohol withdrawal”, “psychosis, alcoholic”, and “substance withdrawal delirium” have been combined with “controlled trial” or “randomized controlled trial”. A specific search was made of “nitrous oxide” and “alcohol withdrawal”. The studies are divided below into two groups: treatment of alcohol withdrawal and delirium tremens, respectively. Quality scores are shown in Tables 3.1 and 3.2. The MEDLINE search covers the period from 1966 until 2000. Other databases searched were the Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effectiveness, the Cochrane Controlled Trials Register, PsychInfo, and SweMed. The reference lists from selected published reviews and primary studies were searched manually. No search was performed for unpublished studies.
3.3 Included Studies
3.2.4
Results
Eighty-two randomized controlled trials were found on drug treatment of alcohol withdrawal in clinical patient groups, i.e., patients who presented for care in hospitals or other health care facilities. The corresponding number of studies of delirium tremens was 13. Two of the studies fell within both of these categories and are therefore presented twice. Conclusions are presented for three meta-analyses of pharmacotherapy in alcohol withdrawal published since 1983. No meta-analyses addressing the treatment of delirium tremens were found.
3.3
Included Studies 3.3.1
Treatment of Alcohol Withdrawal
The neurophysiological background to withdrawal reactions after alcohol and drugs is largely known. Tolerance for, and physical dependence on, alcohol causes changes in the central nervous system which compensate for the suppressing effect of the alcohol on the excitability of the nerve cells, the conduction of nerve impulses, and the activity of neurotransmitters in the brain. When the intake of alcohol ceases, these changes cause a condition of increased excitability in the nerve cells, leading to the physical and mental symptoms which represent the withdrawal syndrome. Numerous medications and drugs have been tested for treatment of withdrawal syndrome (see Table 3.1). Clinical trials of the different groups of agents are summarized below. 3.3.1.1 Benzodiazepines (see Table 3.2a) Benzodiazepines compared to placebo Treatment with benactyzine is associated with fewer cases of delirium tremens than are other agents. Rosenfeld and Bizzoco reported that chlordiazepoxide yielded significantly more improved cases than placebo did [97]. The study by Wegner and Fink had deficiencies and was difficult to evaluate [123]. Oxazepam, chlordiazepoxide, and promethazine were all found equally effective for withdrawal symptoms and significantly better than placebo [20]. This finding was in contrast to Hekimian, who did not find any significant differences, but the number of patients was small [53]. Sereny and Kalant found chlordiazepoxide and promazine basically equally effective for tremor, perspiration, and sleep disorders [111]. Five cases of delirium tremens or withdrawal seizures occurred among those treated with promazine, but none in the group that received chlordiazepoxide. A study using an experimental design showed that chlordiazepoxide was superior to placebo for symptomatic treatment [109]. Lepola reported that patients subjectively experienced chlordiazepoxide to be more effective than tiapride, but no
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3 Pharmacotherapy for Alcohol Withdrawal Syndrome Table 3.1. Drugs tested for alcohol withdrawal, delirium tremens, and withdrawal seizures. Group of chemical agents
Indications
Generic name
Commercial names1
Benzodiazepines
Anxiety; agitation; alcohol withdrawal; status epilepticus
alprazolam
Alprazolam, Xanor
diazepam
Apozepam, Stesolid, Valium Librium Temesta Oxascand, Sobril
chlordiazepoxide lorazepam oxazepam Beta-carbolins Beta-receptor blockers
Calcium antagonists
abecarnil Hypertension; angina pectoris; myocardial infarction; migraine; tremor, etc.
Hypertension; vasospasm after subarachnoid hemorrhage
atenolol
Atenolol, Selinol, Tenormin, Uniloc
propranolol pindolol
Inderal, Propranolol Viskén
nimodipine
Nimotop
caroverine Diphenyl methylpiperazine derivatives
Urticaria; itch, agitation; alcoholism; senile agitation conditions
hydroxyzine
Atarax, Vistaril
Imidazoline receptor agonists
Hypertension; opiate withdrawal
clonidine
Catapressan
lofexidine Carboxamide derivatives
Epilepsy; alcohol withdrawal; neuralgia
chlormethiazole
Hermolepsin, Tegretol, Trimonil
Barbituric acid derivatives
Epilepsy; status epilepticus
phenobarbital
Fenemal
diemal
Veronal
Fatty acid derivatives
Epilepsy
valproic acid
Absenor, Ergenyl, Orfiril
Hydantoin derivatives
Epilepsy; status epilepticus
phenytoin
Epanutin, Fenantoin, Lehydan
3.3 Included Studies Table 3.1. (cont.) Group of chemical agents
Indications
Generic name
Commercial names in Sweden1
Proteinase inhibitors
Homeostasis in bleeding that is difficult to control or leakage of spinal fluid
aprotinin
Tisseel Duo Quick, Trasylol
Vitamin B
Conditions of deficiencies, e.g., anorexia, malabsorption, alcoholism
thiamine (vitamin B1)
Betabion, Benerva
Others
Delirium tremens; pre-delirium; alcohol withdrawal
chlormethiazole
Heminevrin
meprobamate tetrabramate caroverine metadoxine lithium
Litarex
Bipolar affective disorder Parkinson’s disease Anesthesia
1
bromocriptine lucidril propofol paraldehyde
Pravidel Diprivan
list not complete.
objective differences could be confirmed [70]. An attempt to simplify drug treatment of alcohol withdrawal has been described by Sellers: diazepam was administered in tablet form (20 mg) every hour until the patient’s symptoms had subsided (CIWA-A<10), and then no further dose was given [110]. Four patients in the placebo group experienced seizures, but no seizures were reported in the diazepam group. Diazepam relieved symptoms more rapidly. The method is not more effective than regular dosage, but involves a simplified method of care. For patients with reduced liver function, or for older patients, this type of “diazepam loading dose therapy” may involve risks, since diazepam is metabolized in the liver and therefore may accumulate or may negatively influence liver function. Manikant found that a high single dose of diazepam (“diazepam loading dose therapy”) yielded symptom relief that was equivalent to one week of daily dosage and suggested that the former method allowed the total dose to be considerably decreased without negative consequences [75]. A similar study of chlordiazepoxide compared symptom-driven dosage and a fixed dosing schedule [101]. Symptom-driven dosage was associated with both a considerably lower total dose and shorter duration of medical care.
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Gamma-hydroxybutyric acid (GHB) uses a mode of action which is similar to that of benzodiazepines and can therefore be expected to have a similar clinical effect. In an early study by Gallimberti, a significant effect on withdrawal symptoms was observed after a single dose of GHB [41]. A significantly larger study in which GHB was compared to diazepam showed only marginal differences in symptom relief [1]. Lenzenhuber, also, did not find any differences in effect between GHB and flunitrazepam in patients who were admitted to the intensive care unit after surgical procedures and then developed severe alcohol withdrawal [69]. GHB has a narrow therapeutic interval, and overdose may cause hallucinations, confusion, hypotension, and unconsciousness. Short-acting compared to long-acting benzodiazepines Lorazepam, a short-acting benzodiazepine, yielded a significant reduction in unspecific withdrawal symptoms even after the first dose [85]. Lorazepam was compared to diazepam, where all subjects in the respective treatment groups received the same dose on a tapering schedule [80]. No differences in reduction of symptoms were shown. Three patients in the lorazepam group, but none in the diazepam group, developed delirium tremens. Another comparison between lorazepam and diazepam showed a tendency toward more rapid symptom relief for diazepam and significantly lower levels in rating of depression and anxiety [94]. There was also a small significant difference in cognitive function in favor of diazepam on the last treatment day. One study found that lorazepam yielded the same symptom relief as chlordiazepoxide [114]. The randomization method, statistical analysis, and outcome analysis were insufficient in this study. In a recently published study, patients who were admitted to hospital after a witnessed generalized seizure were treated intravenously with lorazepam and were observed for 6 hours. In the placebo group, 24% developed a new seizure during the observation period versus 3% in the lorazepam group [34]. This study was perhaps the best executed of the randomized trials found, not least because it used seizures as the primary outcome variable and not only unspecific withdrawal symptoms. Alprazolam (short-acting) was compared to chlordiazepoxide, but no differences in effects could be shown [126]. Alprazolam was also compared to diazepam in a 3-week study with patients who had already abstained from alcohol for 5 days when treatment was initiated [61]. No significant differences could be shown in this study either. A study which randomized patients to alprazolam, diazepam, clonidine, and placebo showed that alprazolam significantly reduced the total number of withdrawal symptoms (measured by the CIWA-Ar-scale) compared to clonidine and placebo [3]. Diazepam yielded a significant reduction in certain symptoms compared to clonidine and placebo. The only significant effect from clonidine compared to placebo was a reduction in diastolic blood pressure. The study should be viewed as a pilot study and has a low statistical power. Clobazam and halazepam were compared to chlordiazepoxide and were found to have equal effect, except that clobazam had a marginally better effect on anxiety and sleep disorders [79, 83]. Abecarnil is a beta-carbolin with a partial agonistic effect on the benzodiazepine receptor. Abecarnil was compared to diazepam for 5 days [6].
3.3 Included Studies
The agents were equal for unspecific withdrawal symptoms. One patient in the abecarnil group developed delirium. Abecarnil was suggested to yield advantages such as a low abuse potential and fewer side effects. Metadoxine is a pyrrolidone derivative with qualities similar to those of benzodiazepines. The withdrawal symptoms decreased significantly faster in patients receiving metadoxine (1800 mg daily) intravenously compared to the equivalent amount of sodium chloride for 10 days [18]. Benzoctamine was compared to oxazepam and was reported to have a better effect on unspecific symptoms, but the study had major deficiencies [45]. Benzodiazepines compared to antipsychotic drugs, vitamin B, hydroxyzine, and promazine One of the largest randomized trials performed in this field compared chlordiazepoxide with chlorpromazine, thiamine, and hydroxyzine in 537 patients [59]. The findings showed that the incidence rates for delirium tremens were 1% for chlordiazepoxide, 4% for thiamine, 4% for hydroxyzine, 7% for chlorpromazine, and 8% in the placebo group. The incidence rates for withdrawal seizures in this study were 1% for chlordiazepoxide, 7% for thiamine, 8% for hydroxyzine, 9% for placebo, and 12% in the chlorpromazine group. A statistical analysis was not presented in this material. Wegner and Fink studied the effect of chlordiazepoxide and promazine on unspecific withdrawal symptoms by allowing the patients themselves to rate their symptoms on a 3-grade scale [123]. The study had methodological problems, e.g., because a large number of psychotropic drugs were given concurrently. Benzodiazepines compared to chlormethiazole/barbiturates Chlordiazepoxide has been compared to chlormethiazole [78]. Out of 50 patients in the chlormethiazole group, none developed delirium tremens, while 4 patients in the former group did. In total, the treatment was discontinued in 14 cases in the chlordiazepoxide group because of “insufficient effect”. In the chlormethiazole group, 7 patients discontinued the treatment for this reason. The study had major deficiencies in reporting of the patient population and was lacking in statistical analysis. In a later study, chlordiazepoxide was found to be equal to chlormethiazole [67]. Another comparison between chlormethiazole and chlordiazepoxide showed equivalent effects [23]. For patients in intensive care, chlormethiazole/haloperidol caused significantly more cases of tracheobronchitis and pneumonia compared to flunitrazepam/haloperidol [115]. Several patients in the chlormethiazole group dropped out because of increased secretion in the airways. Tetrabamate, a pyrimidinetrion derivative, had equal effect on unspecific symptoms compared to chlordiazepoxide [91]. Benzodiazepine compared to haloperidol Palestine and Alatorre studied the effect of haloperidol and chlordiazepoxide [88]. Haloperidol had a more rapid effect on mental symptoms. The test lasted only 4 hours, and no conclusions could be drawn concerning the effect on seizures and delirium.
195
196
3 Pharmacotherapy for Alcohol Withdrawal Syndrome Table 3.2a-f. Treatment of alcohol withdrawal. Randomized controlled trials, meta-analyses, and selected retrospective studies. Table 3.2a. Benzodiazepines Study
Drugs compared
No. randomized (No. who completed)
Treatment time (days)
Ewing [35] 1960
1. benactyzine 2. paraldehyde 3. pyridoxine
1. 29 2. 26 3. 25
7
Rosenfeld & Bizzoco [97] 1961
1. chlordiazepoxide 2. placebo
1. 30 2. 30
5
Sereny & Kalant [111] 1965
1. 2. 3. 4. 5.
58
3
Wegner & Fink [123] 1965
1. chlordiazepoxide 2. promazine (+ meprobamate) 3. placebo
1. 32 (28) 2. 33 (29) 3. ? (13)
4
Bowman & Thimann [20] 1966
1. 2. 3. 4.
6. 26 7. 25 8. 23 9. 25
42
Hekimian et al. [53] 1966
1. methaminodiazepoxide 2. nicotinamide dinucleotide 3. placebo
1. 10 2. 10 3. 10
3
Gillmer [45] 1973
1. oxazepam 2. benzoctamine
1. 19 2. 15 Concerns no. who completed trial; no. randomized not reported
28
McGrath et al. [78] 1975
1. chlormethiazole 2. chlordiazepoxide
1. 50 (43) 2. 50 (36)
8
Legend see page 202.
chlordiazepoxide 200 mg chlordiazepoxide 400 mg promethazine 400 mg promethazine 800 mg placebo
chlordiazepoxide oxazepam promazine placebo
3.3 Included Studies
197
Outcome measure
No. who developed seizure/DT
Quality score
Comments
DT/seizure; unspecific symptoms
1. 1 (DT) 2. 4 (DT), 1 (seizure) 3. 4 (DT), 1 (seizure) Concerns DT or hallucinosis
27/33
Pioneer with appropriate methodology. 1. and 2. more effective for unspecific symptoms than 3.
“Improved” on a 0–4 scale
1. 2 (DT) 2. 2 (DT)
19/33
Significantly more improved by 1.
Unspecific symptoms; seizures; DT
1. 0 2. 0 3. 2 (seizure), 1 (DT) 4. 2 (seizure) 5. 1 (DT)
20/33
Inclusion in order of priority; no randomization; dropout rate not reported.
Self-rating
1. 1 (DT) 2. 2 (seizure) 3. 2 (seizure)
16/33
Several different sedatives and hydantoin given “when required”. Early study with weak methodology.
Unspecific symptoms
Data missing
23/33
Significant symptom relief with 1, 2, and 3 compared to placebo.
Unspecific symptoms
Data missing
24/33
No differences. Short followup time.
Unspecific symptoms
1. 0 2. 1 (seizure)
17/33
Insufficient statistical analysis, probably no difference between the groups.
↓ unspecific symptoms; seizure; DT
1. 0 2. 4 (DT)
15/33
Doubled dropout rate in group 2.
Table continues on next page
198
3 Pharmacotherapy for Alcohol Withdrawal Syndrome Table 3.2a. (cont.) Study
Drugs compared
No. randomized (No. who completed)
Treatment time (days)
Palestine et al. [88] 1976
1. chlordiazepoxide 2. haloperidol
1. 24 (24) 2. 25 (25)
4h
Kramp & Rafaelsen [63] 1978
1. phenobarbital, oral 2. diazepam i.m.
1. 47 2. 44
Data missing
Runion & Fowler [100] 1978
3. chlordiazepoxide 4. hydroxyzine
3. 25 (20) 4. 25 (21)
7
Kolin & Linet [61] 1981
1. alprazolam 2. diazepam
1. 24 (21) 2. 25 (23)
21
Lapierre et al. [67] 1983
1. chlormethiazole 2. chlordiazepoxide
1. 40 (20) 2. 40 (20)
7
Mukherjee [83] 1983
1. clobazam 2. chlordiazepoxide
A total of 40 were included (26)
14
Sellers et al. [110] 1983
1. diazepam 2. placebo + supportive therapy (counseling)
1. 25 2. 25
1+ followup
Solomon et al. [114] 1983
1. lorazepam 2. chlordiazepoxide
1. 25 (19) 2. 25 (23)
5
Lepola et al. [70] 1984
1. chlordiazepoxide 2. tiapride
1. (26) 2. (24)
5
Miller & McCurdy [80] 1984
1. lorazepam 2. diazepam
1. 27 (23) 2. 28 (24)
5
Legend see page 202.
3.3 Included Studies
199
Outcome measure
No. who developed seizure/DT
Quality score
Comments
↓ Unspecific symptoms
1. 0 2. 0
22/33
Haldol had a more rapid effect on mental symptoms. Very short followup time.
Sedation time, number of doses, etc.
1. 1 (seizure) 2. 1 (seizure)
30/33
Tremor measured by objective methodology (EMG)
Data missing
22/33
Serious deficiency in the study was that drugs were administered in different ways. Tendency of greater effect from diazepam on milder withdrawal problems (also see Table 3.3). Tremor decreased most in group 1.
HARS; Scales for unspecific symptoms
1. 0 2. 0
27/33
Patients were included 5 days after the most recent intake of alcohol. Equivalent effect on anxiety and unspecific symptoms.
TSAS
1. 0 2. 0
28/33
Equivalent effect on unspecific symptoms.
HAS, LSEQ
1. 0 2. 0
25/33
Marginal differences in anxiety level and quality of sleep.
CIWA-A
1. 0 2. 4 (seizure)
32/33
Repeated doses of diazepam were given until no symptoms. Complications occurred only in the placebo group, despite “supportive therapy”.
TSAS
1. 2 (seizure) 2. 0
25/33
Equivalent effect on unspecific symptoms.
Unspecific symptoms
1. 0 2. 0
19/33
Dropout rate not reported for respective groups. Total of 60 included.
TSAS
1. 2 (DT) 2. 0
27/33
Equivalent effect on unspecific symptoms.
Table continues on next page
200
3 Pharmacotherapy for Alcohol Withdrawal Syndrome Table 3.2a. (cont.) Study
Drugs compared
No. randomized (No. who completed)
Treatment time (days)
Wilson & Vulcano [126] 1985
1. alprazolam 2. chlordiazepoxide
1. 50 (46) 2. 50 (47)
6
Mendels et al. [79] 1985
1. halazepam 2. chlordiazepoxide
1. 44 (41) 2. 48 (39)
5
Ritson & Chick [95] 1986
1. lorazepam 2. diazepam
1. 20 (1) 2. 20 (20)
6
Gallimberti et al. [41] 1989
1. Gamma-hydroxybutyric acid (GHB) 2. placebo
1. 11 (11) 2. 12 (12)
7h after single dose
Radouco-Thomas et al. [91] 1989
1. tetrabamate 2. chlordiazepoxide
1. 34 (30) 2. 33 (30)
6
Bono et al. [18] 1991
1. metadoxine 2. pyridoxine
1. 20 (20) 2. 20 (20)
10
Manikant et al. [75] 1993
1. diazepam (daily dose) 2. diazepam (loading dose)
1. (21) 2. (20) Total of 44 included
7
Saitz et al. [101] 1994
1. chlordiazepoxide (fixed dose) 2. chlordiazepoxide (symptom-directed dose)
1. 50 2. 51
Treatment time was the primary outcome variable
Spies et al. [115] 1995
1. 2. 3. 4.
1. 55 (48) 2. 55 (49) 3. 55 (50) 4. 55 (50)
Varying (until CIWAAr <20)
Legend see page 202.
flunitrazepam/clonidine chlormethiazole/haloperidol flunitrazepam/haloperidol ethanol
3.3 Included Studies
201
Outcome measure
No. who developed seizure/DT
Quality score
Comments
↓ Unspecific symptoms; Beck index
1. 3 (DT) 2. 3 (DT)
27/33
No differences in effect.
TSAS
1. 0 2. 0
23/33
No differences in effect.
GRSAW
Data missing
30/33
More rapid symptom alleviation with diazepam.
Unspecific symptoms
1. 0
28/33
Significant difference in withdrawal symptoms in favor of GHB despite small number of patients.
2. 0
CIWA-A + SSAS
1. 0 2. 0
28/33
Equivalent effect.
↓ Unspecific symptoms. More rapid reduction in group 1.
1. 0 2. 0
22/33
Bromazepam was given concurrently each day.
CIWA-A
1. 0 2. 0
26/33
Equally rapid symptom relief in both groups. Lower total dose was required in group 2.
CIWA-Ar
1. 3 (DT) 2. 1 (DT)
29/33
Significantly shorter treatment time and total dose in group 2. The difference in occurrence of DT was not significant.
CIWA-Ar
1. 3 (DT) 2. 0 3. 0 4. 2 (DT)
31/33
More cases of tracheobronchitis in group 2. Four patients dropped out from this group due to bronchial hypersecretion. Table continues on next page
202
3 Pharmacotherapy for Alcohol Withdrawal Syndrome Table 3.2a. (cont.) Study
Drugs compared
No. randomized (No. who completed)
Treatment time (days)
Spies et al. [116] 1996
1. flunitrazepam/clonidine
1. 60 (54)
2. chlormethiazole/haloperidol 3. flunitrazepam/haloperidol
2. 60 (50) 3. 60 (55)
Varying (until CIWAAr <20)
Anton [6] 1997
1. abecarnil 2. diazepam
1. 24 (24) 2. 24 (20)
5
Addolorato et al. [1] 1999
1. gamma-hydroxybutyric acid (GHB) 2. diazepam
1. 30 (26)
10
Lenzenhuber et al. [69] 1999
1. gamma-hydroxybutyric acid (GHB) 2. flunitrazepam
1. 21 (21)
D’Onofrio et al. [34] 1999
1. lorazepam 2. placebo
1. 100 (93) 2. 88 (77)
2. 30 (22) Varying
2. 21 (21)
6h
AWAS = Alcohol Withdrawal Assessment Scale [112]; AWS = Alcohol Withdrawal Scale [30]; ASQ = Abstinence Symtoms Questionnaire [105]; CIWA = Clinical Institute Withdrawal Assessment–Alcohol; CPRS: Comprehensive Psychiatric Rating Scale; GRSAW = Gross Rating Scale for Alcohol Withdrawal; BPRS = Brief Psychiatric Rating Scale; HAS = Hamilton Anxiety Scale; LSEQ = Leeds Sleep Evaluation Questionnaire; MAWS = Mainz Alcohol Withdrawal Scale [12]; TSAS = Total Severity Assessment Scale [50]; SSAS = Selected Severity Assessment Scale [51]; HARS = Hamilton Anxiety Rating Scale; WSR = Withdrawal Symtom Rating [112]; DT = delirium tremens.
3.3 Included Studies
203
Outcome measure
No. who developed seizure/DT
Quality score
Comments
CIWA-Ar
1. 4 (hallucinations; possibly DT) 2. 0 3. 0
31/33
Chlormethiazole/haloperidol was associated with significantly more cases of pneumonia. Ten patients dropped out from this group due to bronchial hypersecretion.
CIWA-Ar
1. 1 (DT) 2. 0
25/33
Equivalent effect on unspecific symptoms.
CIWA-Ar
1. 0
28/33
No differences in effect.
29/33
Patients who required intensive care. Most of the patients in both groups also received haloperidol and clonidine. GHB-treated patients had more psychotic symptoms and required more haloperidol.
34/36
Lorazepam reduced the risk of developing a second seizure.
2. 0 CIWA
1. 1 (seizure) 2. 0 (1 died )
Seizures
1. 3 (seizure) 2. 21 (seizure)
204
3 Pharmacotherapy for Alcohol Withdrawal Syndrome
Summary The studies consistently showed that benzodiazepines reduced symptoms of autonomous hyperactivity (perspiration, tremor, palpitation, etc.). The large number of clinical trials of this group of medications made it possible to show a statistically confirmed effect on withdrawal seizures and delirium tremens by meta-analyses (see below). 3.3.1.2 Chlormethiazole and Anti-Epileptics (see Table 3.2b) Chlormethiazole compared to placebo Chlormethiazole has been compared to placebo in a design where all subjects received phenytoin as seizure prophylaxis. The chlormethiazole group reported faster reduction of unspecific symptoms [46]. The effect from chlormethiazole was also compared to amobarbital and placebo [52]. The placebo group had significantly shorter sleep times than the others; however, no difference was found in the effect on perspiration, heart rate, and blood pressure.
Chlormethiazole compared to others Madden found no appreciable differences in symptom relief between chlormethiazole and trifluoperazine [72]. Murphy compared chlormethiazole, tiapride, and placebo [84]. The placebo group was closed after 3 out of 9 patients developed seizures. Two patients in the tiapride group developed delirium tremens. Otherwise, a similar symptomatic effect from tiapride and chlormethiazole was observed. Borg and Weinholt found that bromocriptine had a significant effect on agitation, restlessness, depression, perspiration, and tremor in a placebo-controlled study [19]. Interpretation was difficult since all patients also received benzodiazepines or carbamazepine in varying doses. Bromocriptine had no significant effect compared to placebo and less effect than chlormethiazole and chlordiazepoxide [23]. Piracetam, which is chemically related to GABA, was tested against chlormethiazole, and no significant differences in effect were observed [32]. Retrospective studies indicated that early initiation of treatment with chlormethiazole in high-risk patients (severe unspecific withdrawal symptoms, previous history of delirium, long-term intake of large amounts of alcohol, high age, concurrent somatic illness, or poor general condition) could reduce the risk for developing delirium or considerably ameliorate the severity [89, 90]. Carbamazepine compared to placebo The effect from carbamazepine on withdrawal symptoms was investigated in two randomized trials and was found to be superior to placebo [17, 56]. Carbamazepine yielded a more rapid reduction in agitation, anxiety, nightmares, and sleeplessness than placebo. Furthermore, the patients’ ability to work was restored significantly more rapidly. A large dropout rate lowered the quality of the study, which otherwise used an acceptable methodology.
3.3 Included Studies
Carbamazepine compared to benzodiazepines The effects of carbamazepine and oxazepam were found to be similar [73, 117]. The latter study reported side effects from carbamazepine such as vomiting, severe itching, and ataxia. Two patients in the oxazepam group developed delirium, and one had an epileptic seizure. Both groups concurrently received chlormethiazole or other sedatives, which rendered interpretation difficult. Carbamazepine compared to chlormethiazole Carbamazepine and chlormethiazole had equivalent effects on unspecific withdrawal symptoms [94, 106]. Carbamazepine compared to tiapride Compared to tiapride, a dopamine antagonist, carbamazepine yielded more rapid reduction in anxiety, agitation, and hallucinosis [4]. Carbamazepine compared to phenobarbital Carbamazepine was compared to phenobarbital in a study from Denmark where, at the time, barbiturates were considered to be first-line drugs [37]. Treatment times and dosage varied. The outcome was equivalent, and no differences in side effects were reported. Valproic acid compared to phenobarbital Equivalent effects on unspecific withdrawal symptoms [98]. No patients developed seizures or delirium. Carbamazepine compared to valproic acid In an open, randomized (but not placebo-controlled) study of valproic acid as adjunct treatment, 5 patients in the control group, but none in the valproic acid group, developed seizures [66]. Four of these patients had concurrent medication with chlormethiazole and one with phenytoin, the latter because of previous episodes with withdrawal seizures. Hillbom compared carbamazepine, valproic acid, and placebo [56]. Among the 138 randomized patients who received 4 days of treatment with the respective substance, 3 patients in the placebo group developed seizures, 2 in the carbamazepine group, and 1 in the valproic acid group. One case of delirium occurred in the placebo group and 2 in the valproic acid group. The authors concluded that treatment should be initiated even under alcohol influence since most seizures occur within 24 hours after the patient has become sober. A rapid increase of the drug concentration in plasma was therefore desirable. Carbamazepine syrup compared to tablets A nonrandomized cohort study compared carbamazepine syrup to carbamazepine tablets (each containing 400 mg carbamazepine) when the drug was first administered [116]. The risk of developing withdrawal seizures in 2–10 hours after the first dose was significantly reduced in the group receiving syrup. No replication study has been found. Hydantoin The addition of diphenylhydantoin as prophylaxis against withdrawal seizures for patients who concurrently received chlordiazepoxide and thiamine did not yield any significant differences – no patients in the treatment or control group
205
206
3 Pharmacotherapy for Alcohol Withdrawal Syndrome Table 3.2b. Chlormethiazole and anti-epileptics. Study
Drugs compared
No. randomized (No. who completed)
Treatment time (days)
Glatt [46] 1965
1. chlormethiazole 2. placebo
1. 51 (49) 2. 49 (48)
7
Harfst [52] 1967
1. amobarbital 2. chlormethiazole 3. placebo
1. 10 (10) 2. 10 (10) 3. 10 (10)
6
Madden et al. [72] 1969
1. chlormethiazole 2. trifluoperazine
Total of 100; no. completing not reported
7
Rothstein [99] 1973
1. hydantoin 2. control
1. 100 (100) 2. 100 (100)
Not reported
Sampliner [102] 1974
1. hydantoin 2. placebo
Total of 157 (155)
5
Björkqvist et al. [17] 1976
1. carbamazepine 2. placebo
1. 52 (34) 2. 53 (35)
7
Dencker et al. [32] 1978
1. piracetam
1. (32)
7
2. chlormethiazole Dropout rate not reported
2. (28)
1. valproic acid 2. control
1. 22 2. 27
Lambie et al. [66] 1980 Legend see page 212.
7
3.3 Included Studies
207
Outcome measure
No. who developed seizure/DT
Quality score
Comments
Unspecific symptoms
1. 0 2. 1 (suspected DT)
22/33
More rapid symptom relief with chlormethiazole. All received phenytoin concurrently.
Heart rate, blood pressure, perspiration, sleep time.
1. 0 2. 0 3. 1 (seizure)
22/33
1. and 2. had significantly longer sleep time than placebo did.
↓ Unspecific symptoms
1. (2 seizure) 2. 2 (seizure, 1 DT)
16/33
Group 2 also received phenytoin. The effect was judged as equivalent.
Seizure
1. 0 2. 0
24/33
All received chlordiazepoxide and thiamine.
Seizure
1. 0 2.11 (seizure)
28/33
Patients with previous seizures. All received chlordiazepoxide. Hydantoin significantly reduced the risk of developing seizures.
Unspecific symptoms
1. 0 2. 0
26/36
More rapid symptom relief with carbamazepine. Sleeping agent was given concurrently.
CPRS
1. 2 (pre-delirium), 1 (seizure) 2. 1 (pre-delirium)
27/33
One patient dropped out due to seizures (not reported in which group).
Unspecific symptoms
1. 0 2. 5 (seizure)
17/33
Clouded consciousness occurred in 4 patients (not reported in which group). Table continues on next page
208
3 Pharmacotherapy for Alcohol Withdrawal Syndrome Table 3.2b. (cont.) Study
Drugs compared
No. randomized (No. who completed)
Pålsson & Eberhard [89] 1981
chlormethiazole
359 (not randomized)
Ritola & Malinen [94] 1981
1. carbamazepine 2. chlormethiazole
1. 34 (33) 2. 34 (29)
7
Agricola et al. [4] 1982
1. carbamazepine 2. tiapride
1. 30 (27) 2. 30 (28)
7
Borg & Weinholdt [19] 1982
1. bromocriptine 2. placebo
Murphy et al. [84] 1983
1. chlormethiazole 2. tiapride 3. placebo
1. 29 (25) 2. 30 (25) 3. 9 (7)
5
Sternebring et al. [116] 1983
1. carbamazepine (tablet) 2. carbamazepine (syrup)
1. 19/19 2. 13/13
10 h
Flygenring et al. [37] 1984
1. carbamazepine 2. phenobarbital
1. 37 (31) 2. 35 (29)
6
Legend see page 212.
Treatment time (days)
3.3 Included Studies
209
Outcome measure
No. who developed seizure/DT
Quality score
Comments
No. of cases of DT
Retrospective study
Early initiation of chlormethiazole as a consequence of changed routines coincided with a decrease >50% in the number of DT cases in Helsingborg
Unspecific symptoms
1. 0 2. 0
23/33
Equivalent effect.
Unspecific symptoms
1. 0 2. 0
24/33
Carbamazepine had a greater effect on anxiety.
Other sedatives were given concurrently in varying doses.
SSAS
1. 1 (seizure) 2. 1 (seizure), 2 (DT) 3. 3 (seizure), 1 (DT)
Seizure
Unspecific symptoms
1. 1 (seizure) 2. 1 (DT)
22/33
Phenytoin was given to patients with previous seizures.
Not applicable
Significantly more seizures in group 1.
23/33
No differences between the agents. Individual dosage, varying treatment time. Table continues on next page
210
3 Pharmacotherapy for Alcohol Withdrawal Syndrome Table 3.2b. (cont.) Study
Drugs compared
No. randomized (No. who completed)
Treatment time (days)
Burroughs [23] 1985
1. chlordiazepoxide 2. chlormethiazole 3. 4. placebo
1. 20 2. 20 3. 20 4. 11
5
Baumgartner & Rowen [13] 1987
1. clonidine 2. chlordiazepoxide
1. (26) 2. (21) Total of 61 randomized
4
Schulte [106] 1987
1. carbamazepine 2. chlormethiazole
1. 19 2. 19
7
Alldredge et al. [5] 1989
1. phenytoin intravenously 2. sodium chloride intravenously
1. 45 2. 45
Single dose of infusion/ 12 h observation
Hillbom et al. [56] 1989
1. placebo 2. carbamazepine 3. valproic acid
1. 49 2. 43 3. 46
4
Malcolm [73] et al. 1989
1. carbamazepine 2. oxazepam
1. 43 (32) 2. 43 (34)
7
Chance [26] 1991
1. phenytoin 2. placebo
1. 28 (28) 2. 27 (27)
6h
Stuppaeck et al. [117] 1992
1. oxazepam 2. carbamazepine
60 (52)
7
Legend see page 212.
3.3 Included Studies
211
Outcome measure
No. who developed seizure/DT
Quality score
Comments
GRSAW
1. 0 2. 0 3. 0 4. 0
23/33
1. and 2. equivalent 3. effect lacking.
AWS
1. 0 2. 0
28/33
Significantly lower blood pressure from clonidine.
Unspecific symptoms
1. 0 2. 0
22/33
Chlorprothixene and other sedatives were given “when required”.
New seizure or free from seizures 12 h after treatment
1. 6 (seizure) 2. 6 (seizure)
31/33
Patients were included within 6 h after a seizure.
Withdrawal seizures/ delirium tremens
1. 3/1 2. 2/0 3. 1/2
29/33
Side effects from carbamazepine and valproic acid caused premature interruption of the study.
CIWA No difference between 1. and 2.
1. 0 2. 0
30/33
Seizure
1. 6 (seizure) 2. 5 (seizure)
31/33
Seizure patients were randomized and monitored for 6 h. No significant difference.
CIWA
1. 3 (2 DT, 1 seizure) 2. 0
29/33
Significantly lower CIWA score for carbamazepine day 6–7. Well executed study with fixed dosage. Table continues on next page
212
3 Pharmacotherapy for Alcohol Withdrawal Syndrome Table 3.2b. (cont.) Study
Drugs compared
No. randomized (No. who completed)
Treatment time (days)
Rathlev et al. [93] 1994
1. phenytoin 2. sodium chloride
1. 49 (49) 2. 51 (51)
6h
Rosenthal et al. [98] 1998
1. phenobarbital 2. valproic acid
Total of 41 included (32)
5
AWAS = Alcohol Withdrawal Assessment Scale [112]; AWS = Alcohol Withdrawal Scale [30]; ASQ = Abstinence Symtoms Questionnaire [105]; CIWA = Clinical Institute Withdrawal Assessment–Alcohol; CPRS: Comprehensive Psychiatric Rating Scale; GRSAW = Gross Rating Scale for Alcohol Withdrawal; BPRS = Brief Psychiatric Rating Scale; HAS = Hamilton Anxiety Scale; LSEQ = Leeds Sleep Evaluation Questionnaire; MAWS = Mainz Alcohol Withdrawal Scale [12]; TSAS = Total Severity Assessment Scale [50]; SSAS = Selected Severity Assessment Scale [51]; HARS = Hamilton Anxiety Rating Scale; WSR = Withdrawal Symtom Rating [112]; DT = delirium tremens.
3.3 Included Studies
213
Outcome measure
No. who developed seizure/DT
Quality score
Comments
New seizure within 6 h.
1. 10 (seizure) 2. 12 (seizure)
30/33
No significant difference.
ASQ
1. 0 2. 0
25/33
Equivalent effect on unspecific symptoms.
214
3 Pharmacotherapy for Alcohol Withdrawal Syndrome
developed seizures [99]. The study had a low statistical power. In a concurrent study, diphenylhydantoin or placebo was given to patients who had a previous history of seizures as adults regardless of the cause [102]. All patients received chlordiazepoxide. None in the hydantoin group developed seizures; however, 11 patients in the placebo group did. The results indicated that combination treatment with hydantoin and a benzodiazepine agent could significantly lower the risk of seizures in patients who had previously developed seizures. Intravenous infusion of phenytoin was given as patients who had experienced a documented seizure became sober. This did not influence the risk for developing a new seizure within a 6 hours period compared to placebo [5, 26, 93]. These 3 studies had a specific design since all patients had experienced a seizure during the withdrawal period. Therefore, the results could not be automatically compared with the study by Sampliner and Ibers, which is the only one where selection is based on previous seizures and where obvious effects could be reported [102]. Summary To a limited extent, carbamazepine and chlormethiazole have been compared with placebo, but evidence is not available to assess the effects on seizures and delirium. For example, the frequent use of carbamazepine in alcohol withdrawal is based on only 2 randomized studies where 77 patients in total received an active drug. In studies which compared carbamazepine and benzodiazepines, only 58 patients in the carbamazepine groups completed the treatment. This number is too low to make any statistically confirmed conclusions regarding differences in effects and side effects. One study indicated that the addition of hydantoin (to patients treated with benzodiazepines) could reduce the risk of developing seizures. 3.3.1.3 Imidazoline Agonists (see Table 3.2c) Clonidine compared to placebo Clonidine 0.15 mg given 3 times daily for 4 days accelerated the recovery in patients with moderate withdrawal by 24 hours [16]. All 60 participants in the study received sleeping agents in the form of 250 mg methaqualone and 25 mg diphenhydramine. In the placebo group, 15 patients received diphenylhydantoin because of previous epileptic seizures. The corresponding number in the clonidine group was 6. Chlorpromazine was also given concurrently. The rating scales used were poorly defined. An open randomized study of 24 patients compared clonidine with carbamazepine without placebo control and without blinding by rating the patients’ unspecific symptoms by CPRS [128]. The carbamazepine group also received dixyrazine or chlorprothixene daily. Furthermore, benzodiazepines were given at night in both groups. No differences between the groups were shown. A single-blind study of clonidine with a crossover design was conducted in 11 patients [124]. Clonidine reduced the heart rate, blood pressure, and withdrawal symptoms significantly compared to placebo. In the study by Adinoff, clonidine was not more effective than placebo [3]. Clonidine/placebo was given to patients who reported a daily intake of 150 g of ethanol and who were admitted to hospital for other reasons [81]. Nine percent in the clonidine group developed mild
3.3 Included Studies
withdrawal symptoms versus 50% in the placebo group, of which 14% were found to be pre-delirium. Lofexidine compared to placebo Lofexidine, which is closely related to clonidine, was compared to placebo [30]. The withdrawal symptoms decreased somewhat more rapidly in the lofexidine group, but the results were not significant. The most obvious difference was that lofexidine lowered the blood pressure. One patient in this group had to drop out because of hallucinations. Six patients in the placebo group dropped out because of insufficient effect. Two of these patients developed seizures. The most common side effect was low blood pressure. In an open study without any control group, one case of withdrawal seizure among 28 patients treated with lofexidine was reported [22]. Cushman later repeated his study of lofexidine and found a significant reduction in pulse, blood pressure, and tremor, but no effect on perspiration, restlessness, respiration rate, or subjective well-being [31]. In this study as well, hallucinosis occurred in the lofexidine group. Clonidine compared to benzodiazepines A comparison of clonidine 200 mg and chlordiazepoxide 50 mg every 8 hours during 60 h of treatment (7 doses in total) showed that clonidine decreased heart rate and systolic blood pressure more rapidly [13]. Anxiety and agitation decreased equally rapidly in both groups. The same research group later published a study of clonidine given transdermally compared to chlordiazepoxide orally for 4 days with fixed doses [14]. Clonidine reduced the withdrawal symptoms more rapidly during the first 40 hours. The anxiety level decreased significantly more rapidly in this group compared to chlordiazepoxide, as did heart rate and blood pressure. Clonidine compared to chlormethiazole A study compared clonidine with chlormethiazole [74]. All patients received concurrent treatment with carbamazepine. The trial drugs had an equal effect on withdrawal symptoms, except for systolic and diastolic blood pressure and heart rate, which decreased more rapidly and to a greater extent in the clonidine group. Clonidine was compared to chlormethiazole in yet another study [96]. The results indicated that clonidine was less effective than chlormethiazole. Everyone in the chlormethiazole group had an uncomplicated course. Eight patients out of 16 in the clonidine group had to discontinue because of orthostatic hypotension (3 patients), hallucinations (2 patients), seizures (2 patients), or drowsiness (1 patients). Another 7 patients in the clonidine group had orthostatic hypotension on at least one occasion, but did not discontinue the study. The strength of this trial was that no other psychotropic drugs were given concurrently. Clonidine compared to chlorprothixene/carbamazepine Balldin and Bokström reported a study of clonidine compared to chlorprothixene/carbamazepine [10]. There was no significant differences in unspecific symptoms. One patient in each group developed psychotic symptoms.
215
216
3 Pharmacotherapy for Alcohol Withdrawal Syndrome Table 3.2c. Imidazoline agonists. Study
Drugs compared
No. randomized (No. who completed)
Treatment time (days)
Björkqvist [16] 1975
1. clonidine 2. placebo
1. 30 (29) 2. 30 (28)
4
Wålinder et al. [128] 1981
1. clonidine 2. carbamazepine + neuroleptic
1. 11 (10) 2. 15 (9)
7
Wilkins [124] 1983
1. clonidine 2. placebo
11 (11) cross design
4h
Cushman et al. [30] 1985
1. placebo 2. lofexidine
1. 32 (26) 2. 31 (28)
2
Manhem et al. [74] 1985
1. clonidine 2. chlormethiazole
1. 10 (9) 2. 10 (8)
4
Balldin & Bokström [10] 1986
1. clonidine 2. chlorprothixene + carbamazepine
1. 19 (15) 2. 19 (17)
7
Cushman & Sowers [31] 1989
1. lofexidine 2. placebo
1. 13 (10) 2. 10 (7)
4
Mondavio & Ghiazza [81] 1989 Robinson et al. [96] 1989
1. clonidine 2. placebo
1. 22 (22) 2. 22 (22)
10
3. clonidine 4. chlormethiazole
3. 16 (8) 4. 16 (16)
4
Legend see page 218.
3.3 Included Studies
217
Outcome measure
No. who developed seizure/DT
Quality score
Comments
↓ Unspecific symptoms
1. 0 2. 0
25/33
Chlorpromazine and hydantoin given concurrently.
CPRS
1. 1 (DT) 2. 1 (DT)
23/33
Equivalent effect on CPRS (“inner tension”).
GRSAW
Data missing
26/33
Significantly better effect from clonidine.
AWS
1. 2 (seizure) 2. 0
24/33
Significantly lower blood pressure from lofexidine.
Heart rate, blood pressure, hormones
1. 1 (DT) 2. 1 (DT)
28/33
Lower blood pressure and heart rate from clonidine. Carbamazepine given concurrently.
CPRS
1. 1 (DT) 2. 1 (DT)
26/33
Equivalent effect. Nitrazepam and oxazepam given to both groups.
AWS
1. 0 2. 0
25/33
2 in the lofexidine group and 1 in the placebo group interrupted due to hallucinations.
Unspecific symptoms
1. 0 2. 3 (pre-delirium)
23/33
Withdrawal syndrome not defined.
WSR
3. 2 (seizure), 2 (DT) 4. 0
30/33
Large dropout in the clonidine group. No differences in outcome in those who completed trial. No other psychotropic drugs given. Table continues on next page
218
3 Pharmacotherapy for Alcohol Withdrawal Syndrome Table 3.2c. (cont.) Study
Drugs compared
No. randomized (No. who completed)
Treatment time (days)
Baumgartner [14] 1991
1. clonidine transdermally 2. chlordiazepoxide
1. 25 (23) 2. 25 (20)
4
Adinoff [3] 1994
1. 2. 3. 4.
1. 6 (6) 2. 6 (6) 3. 7 (7) 4. 6 (6)
Duration until CIWA <5
alprazolam diazepam clonidine placebo
AWAS = Alcohol Withdrawal Assessment Scale [112]; AWS = Alcohol Withdrawal Scale [30]; ASQ = Abstinence Symtoms Questionnaire [105]; CIWA = Clinical Institute Withdrawal Assessment–Alcohol; CPRS: Comprehensive Psychiatric Rating Scale; GRSAW = Gross Rating Scale for Alcohol Withdrawal; BPRS = Brief Psychiatric Rating Scale; HAS = Hamilton Anxiety Scale; LSEQ = Leeds Sleep Evaluation Questionnaire; MAWS = Mainz Alcohol Withdrawal Scale [12]; TSAS = Total Severity Assessment Scale [50]; SSAS = Selected Severity Assessment Scale [51]; HARS = Hamilton Anxiety Rating Scale; WSR = Withdrawal Symtom Rating [112]; DT = delirium tremens.
3.3 Included Studies
219
Outcome measure
No. who developed seizure/DT
Quality score
Comments
AWAS
1. 0 2. 0
33/33
Clonidine more effective in decreasing heart rate and blood pressure.
CIWA
Ingo
30/33
Previous seizures = exclusion criteria. Small number of patients.
220
3 Pharmacotherapy for Alcohol Withdrawal Syndrome
Summary The above studies show that clonidine reduces unspecific withdrawal symptoms, mainly palpitation and elevated blood pressure, but nothing indicates that clonidine has any protective effect against withdrawal seizures or delirium tremens. 3.3.1.4 Beta-Receptor Antagonists (see Table 3.2d) Beta-receptor antagonist compared to placebo or benzodiazepines Propranolol was compared to chlordiazepoxide in an experimental study where 30 alcohol-dependent individuals were given alcohol at the hospital for 5 days and were then assigned to 5 groups for withdrawal treatment with dosage every 6 hours (placebo, 10 mg propranolol, 40 mg propranolol, 10 mg propranolol + 25 mg chlordiazepoxide, or 25 mg chlordiazepoxide only) [109]. The higher dose of propranolol had a somewhat better effect on tremor, but the effect on other withdrawal symptoms was equivalent to other alternatives. The authors concluded that propranolol could be used in selected patients without any contraindications, e.g., chronic obstructive pulmonary disease or cardiomyopathy. Propranolol was also suggested for use as an adjunct to benzodiazepines in tachyarrythmias or severe tremor. The study was performed in patients with relatively mild withdrawal and does not answer questions such as effect on withdrawal epilepsy, development of delirium, or the risk of severe side effects. Furthermore, the number of patients was small. In the study by Digrane, blood pressure and heart rate were reduced more effectively by pindolol than by placebo when given in addition to other pharmacological treatment [33]. The effect from propranolol on tremor caused by withdrawal was studied by objective methodology [120]. Ten patients dropped out and were replaced by new recruits. No significant differences between placebo and propranolol were found. Insufficient diagnostics and description of patient characteristics and concurrent medication with diazepam or chlormethiazole in some patients made interpretation difficult. Propranolol was associated with a high risk of hallucinations and delirium tremens when given as the only drug [130]. In one study, either atenolol or placebo was given in addition to oxazepam [64]. With the addition of atenolol, the number of patients requiring extra oxazepam decreased significantly. Also the doses of oxazepam were lower. The mean duration in medical care was significantly shorter in the atenolol group. Only 4 randomized patients dropped out, and this occurred before they were given the first dose of the test drug. In another study, either atenolol or placebo was given for 2 weeks of treatment in outpatient care [58]. All patients received concurrent treatment with oxazepam. Atenolol yielded a significantly more rapid reduction in withdrawal symptoms. Also, the craving for alcohol decreased significantly. A comparison of propranolol and diazepam for 15 days showed no differences in effect [9]. All patients in the respective treatment group received the same dose of the drug. The study included only 28 patients. A similar study in which treatment was given for 7 days did not show any differences in effect on withdrawal symptoms between propranolol and diazepam [127]. However, one patient in the propranolol group developed an epileptic seizure and another patient dropped out because of
3.3 Included Studies
delirium tremens. Eleven patients dropped out because they required no medication. Summary As expected, beta-receptor antagonists have a good effect on elevated blood pressure, palpitations, and tremors. No other effects have been confirmed. Nitrous Oxide (see Table 3.2e) Initially, medical air or oxygen was administered by nasal mask in a study of 60 male alcoholics [71]. Patients whose symptom rating dropped by more than half from this treatment were excluded. The remaining 48 patients received nitrous oxide for 20 min. Of these, 42 responded with symptom ratings that dropped by more than half. Oxazepam was used as adjunct treatment in several open studies of nitrous oxide treatment, making the results difficult to interpret [44]. The outcome measure was consistently a reduction in unspecific symptoms. A prospective study showed reduced need of sedatives (benzodiazepines etc.) after treatment with nitrous oxide [43]. There were no studies on the risk of developing seizures/delirium after nitrous oxide treatment. Treatment with nitrous oxide was developed in South Africa and remains controversial there [39]. The method has been criticized for not having sufficient scientific basis, e.g., because the studies have not been repeated by independent researchers. 3.3.1.5
Thiamine (see Table 3.2f) Wernicke’s encephalopathy is a condition with high mortality and risk of permanent brain damage after long-term intake of large volumes of alcohol. Typical signs are gait disorder, eye muscle paralysis, nystagmus, and confusion, but the clinical profile can often be unclear and may appear to be an unspecific state of confusion. The cause is thiamine deficiency, but a direct toxic effect from alcohol on the brain is also considered to contribute. Persistent short-term memory disorder is often observed after the acute phase and is then called Korsakoff’s psychosis. The condition is characterized as “alcohol-conditioned persistent memory disorder” according to DSM-IV. Treatment consists of injecting high doses of thiamine. An epidemiological association between thiamine prescription and the occurrence of Wernicke’s encephalopathy was recently described [92]. In Great Britain, several cases of hypersensitivity to Parentrovite, a thiamine preparation, were registered. This led to the withdrawal of the substance in 1991. Despite the introduction of other substances, the consumption of thiamine as an injection solution decreased considerably. Concurrently, a marked increase in the number of alcohol psychosis cases was noted. 3.3.1.6
221
222
3 Pharmacotherapy for Alcohol Withdrawal Syndrome Table 3.2d. Beta – receptor antagonists. Study
Drugs compared
No. randomized (No. who completed)
Treatment time (days)
Digranes [33] 1976
1. pindolol 2. placebo
1. (55) 2. (56) Total of 120 included
3w
Teräväinen & Larsen [120] 1976
1. propranolol 2. placebo
1. 14 (14) 2. 14 (14) Crossover design
3
Sellers et al. [109] 1977
1. 2. 3. 4. 5.
placebo chlordiazepoxide 25 mg propranolol 40 mg propranolol 10 mg propranolol 10 mg + chlordiazepoxide 25 mg
1. 6 (6) 2. 6 (6) 3. 6 (6) 4. 6 (6) 5. 6 (6)
6
Zilm et al. [130] 1980
1. 2. 3. 4.
chlordiazepoxide propranolol 1. + 2. placebo
60 (47) Not reported per group
2
Kraus et al. [64] 1985
1. atenolol 2. placebo
1. 61 2. 59
9
Horwitz et al. [58] 1989
1. atenolol 2. placebo
1. 88 (55) 2. 92 (44)
14
Bailly et al. [9] 1992
1. diazepam 2. propranolol
1. 14 (13) 2. 14 (14)
15
Worner [127] 1994
1. propranolol 2. diazepam
1. 19 (17) 2. 18 (18)
7
AWAS = Alcohol Withdrawal Assessment Scale [112]; AWS = Alcohol Withdrawal Scale [30]; ASQ = Abstinence Symtoms Questionnaire [105]; CIWA = Clinical Institute Withdrawal Assessment–Alcohol; CPRS: Comprehensive Psychiatric Rating Scale; GRSAW = Gross Rating Scale for Alcohol Withdrawal; BPRS = Brief Psychiatric Rating Scale; HAS = Hamilton Anxiety Scale; LSEQ = Leeds Sleep Evaluation Questionnaire; MAWS = Mainz Alcohol Withdrawal Scale [12]; TSAS = Total Severity Assessment Scale [50]; SSAS = Selected Severity Assessment Scale [51]; HARS = Hamilton Anxiety Rating Scale; WSR = Withdrawal Symtom Rating [112]; DT = delirium tremens.
3.3 Included Studies
223
Outcome measure
No. who developed seizure/DT
Quality score
Comments
Unspecific symptoms
Not reported
25/33
Apart from pindolol/placebo, “standard treatment” with Fenemal or opipramol chloride was given.
Degree of tremor. No difference between 1. and 2.
Not reported
17/33
All received chlormethiazole, several received diazepam.
Unspecific symptoms
None
27/33
2–5 significantly better than placebo.
Reduction in arrythmias
1. 0 2. 4 (DT) 3. 1 (DT) 4. 2 (seizure)
24/33
27% in group 2 developed hallucinations/DT.
Clinically improved or discharged
1. 0 2. 0
27/33
All received oxazepam concurrently.
↓ Unspecific symptoms; treatment failed
1. 1 (seizure) 2. 0
29/33
Outpatient study. All received oxazepam concurrently.
GRSAW
1. 0 2. 1 (seizure)
23/33
Five in group 2 received diazepam as adjunct.
↓ Unspecific
1. 1 (DT), 1 (seizure) 2. 0
19/33
Decreased tremor by propranolol.
symptoms
224
3 Pharmacotherapy for Alcohol Withdrawal Syndrome Table 3.2e. Nitrous oxide. Study
Drugs compared
No. randomized (No. who completed)
Treatment time (days)
Santo-DomingoCarrasco et al. [103] (1985)
1. tetrabamate 2. tiapride
1. 18 (15) 2. 20 (17)
14
Gillman & Lichtigfeld [43] 1989
1. nitrous oxide + diazepam 2. diazepam
78 (56)
7
Lichtigfeld & Gillman [71] 1989
nitrous oxide/air/oxygen
60/12
Gillman & Lichtigfeld [44] 1991
nitrous oxide
AWAS = Alcohol Withdrawal Assessment Scale [112]; AWS = Alcohol Withdrawal Scale [30]; ASQ = Abstinence Symtoms Questionnaire [105]; CIWA = Clinical Institute Withdrawal Assessment–Alcohol; CPRS: Comprehensive Psychiatric Rating Scale; GRSAW = Gross Rating Scale for Alcohol Withdrawal; BPRS = Brief Psychiatric Rating Scale; HAS = Hamilton Anxiety Scale; LSEQ = Leeds Sleep Evaluation Questionnaire; MAWS = Mainz Alcohol Withdrawal Scale [12]; TSAS = Total Severity Assessment Scale [50]; SSAS = Selected Severity Assessment Scale [51]; HARS = Hamilton Anxiety Rating Scale; WSR = Withdrawal Symtom Rating [112]; DT = delirium tremens.
3.3 Included Studies
Outcome measure
No. who developed seizure/DT
Quality score
Unspecific symptoms
1. 6 (DT) 2. 6 (DT)
22/33
Consumption of sedatives
Data missing
19/33
225
Comments
A number of other drugs were given concurrently: hydantoin, oxazepam, chlormethiazole, phenobarbital, which makes interpretation difficult.
17/33
Oxazepam was given concurrently.
226
3 Pharmacotherapy for Alcohol Withdrawal Syndrome Table 3.2f. Thiamine, psychological treatment, other treatment. Study
Drugs compared
No. randomized (No. who completed)
Treatment time (days)
Kaim et al. [59] 1969
1. chlordiazepoxide 2. chlorpromazine
1. 103 (89) 2. 98 (73)
10
3. hydroxyzine
3. 103 (86)
4. thiamine 5. placebo
4. 103 (79) 5. 130 (104)
Sellers et al. [108] 1976
1. lithium before and during withdrawal 2. lithium during withdrawal 3. placebo
1. 6
Naranjo et al. [85] 1983
1. lorazepam + psychological support 2. placebo + psychological support
1. 21
Koppi et al. [62] 1987
1. caroverine 2. meprobamate
1. 10 (9) 2. 10 (10)
15
Banger et al. [11] 1992
1. nimodipine 2. placebo
1. 16 (13) 2. 16 (15)
4
2. 6 3. 6
2. 20
3 (pretreatment) 6 (treatment) 3 doses day 1 + followup 5 days
AWAS = Alcohol Withdrawal Assessment Scale [112]; AWS = Alcohol Withdrawal Scale [30]; ASQ = Abstinence Symtoms Questionnaire [105]; CIWA = Clinical Institute Withdrawal Assessment–Alcohol; CPRS: Comprehensive Psychiatric Rating Scale; GRSAW = Gross Rating Scale for Alcohol Withdrawal; BPRS = Brief Psychiatric Rating Scale; HAS = Hamilton Anxiety Scale; LSEQ = Leeds Sleep Evaluation Questionnaire; MAWS = Mainz Alcohol Withdrawal Scale [12]; TSAS = Total Severity Assessment Scale [50]; SSAS = Selected Severity Assessment Scale [51]; HARS = Hamilton Anxiety Rating Scale; WSR = Withdrawal Symtom Rating [112]; DT = delirium tremens.
3.3 Included Studies
227
Outcome measure
No. who developed seizure/DT
Quality score
Comments
DT and withdrawal seizure
1. 1 (seizure) 1 (DT) 2. 4 (DT), 9 (seizure), 3 (seizure + DT) 3. 2 (DT), 6 (seizure), 2 (seizure + DT) 4. 4 (DT), 7 (seizure) 5. 7 (DT), 8 (seizure), 1 (seizure + DT)
29/36
Early, well designed study. Statistical analysis lacking.
↓ Unspecific symptoms
Data missing
28/33
Fewer withdrawal symptoms in group 1. and 2.
CIWA
1. 1 (DT)
30/33
More rapid symptom relief from lorazepam after the first dose, then equivalent effect on unspecific symptoms.
2. 1 (seizure)
↓ Unspecific symptoms
1. 0 2. 0
27/33
No differences in effect.
MAWS
2 (seizure), 1 (DT). Not stated in which group.
28/33
All received chlormethiazole concurrently.
228
3 Pharmacotherapy for Alcohol Withdrawal Syndrome
Thiamine showed no prophylactic effect on seizures or delirium in a large study (see above) [59]. The basis of facts for dosage and duration of thiamine treatment is limited [28]. Psychological Treatment (see Table 3.2f) There is no evidence that psychological treatment alone reduces the risk of seizures or delirium in association with alcohol withdrawal. Concerning unspecific withdrawal symptoms, the difference in effect between placebo treatment and active drug is insignificant in some studies [85]. This may indicate that it is possible to treat milder withdrawal conditions without drugs and yet acceptably alleviate unspecific symptoms. Shaw et al. monitored the course of withdrawal in 38 hospitalized patients by means of their own CIWA scale (see above) [112]. There was no randomization, and the selection represented only 20% of current patients with alcohol withdrawal. Of the investigated patients, 28 experienced symptom relief from nursing care alone, but one of these later developed a seizure and one experienced hallucinations [112]. Basic neurobiological research has shown that repeated withdrawals may cause a kindling condition in the nervous system, which in the long run further increases the risk of seizures and delirium. Data, mainly from animal experiments, indicate that intensive pharmacological treatment, mainly with benzodiazepines, can counteract the harmful effect on the brain which a withdrawal condition involves. 3.3.1.7
Other Treatment (see Table 3.2f) Nimodipine is a calcium antagonist used for subarachnoid hemorrhage and is administered parenterally. A study compared nimodipine 60 mg x 4 and placebo for 4 days [11]. All patients had chlormethiazole as basic medication, and the consumption of this was equal in both groups. No difference in effect was shown. Four patients dropped out, 2 of whom had epileptic seizures and 1 developed delirium. It is not evident to which groups these patients had been randomized. Caroverine, a calcium antagonist, was compared to meprobamate for 15 days [62]. No differences were shown concerning the effect on withdrawal symptoms. Tetrabamate (barbiturate) was found equal to tiapride (a dopamine antagonist) [103]. A randomized study of lithium for alcohol withdrawal has been found [108]. Lithium reduced subjective symptoms, e.g., agitation and restlessness, but had no effects on heart rate or blood pressure. Ethyl alcohol (ethanol) alleviates withdrawal symptoms per definition (cross-tolerance), and several case studies have been published in which ethanol was given for this purpose, usually to intoxicated patients who had undergone acute surgical procedures in association with accidents, and the aim was to prevent withdrawal during ongoing surgery. No randomized studies have compared ethanol to any other treatment. Optimal dosage, treatment time, administration route, and tapering time are insufficiently studied. Ethanol does not appear to prevent delirium tremens in patients who had already developed symptoms of alcohol withdrawal [48]. Ethanol involves many potentially serious harmful effects on different organ systems. None of the above agents has any documented effect as prophylaxis for 3.3.1.8
3.3 Included Studies
seizures or delirium. In one of the earliest studies with modern methodology, Ewing randomized his patients to benactyzine, paraldehyde, and pyridoxine and found that pyridoxine was less effective than the others for unspecific withdrawal symptoms [35]. Studies of antipsychotic drugs for withdrawal were reported in a previous SBU report and are not addressed here [104]. Meta-analyses and Reviews An analysis of 5 early randomized trials of benzodiazepines compared to placebo for mild to moderate alcohol withdrawal concluded that benzodiazepines are more effective than placebo for preventing delirium and withdrawal seizures (see Table 3.1) [35, 46, 53, 82, 97, 123]. A more recent meta-analysis based on 6 studies also showed a significantly reduced risk for developing delirium or withdrawal seizures in those treated with benzodiazepines [3, 20, 76, 85, 109, 110]. However, no difference in effectiveness between different benzodiazepines could be shown. A similar conclusion has been reported recently by a working group within the Canadian Medical Association [57]. Their meta-analysis was based on 3 studies where a benzodiazepine is compared to placebo. It showed that benzodiazepines were more effective than placebo in treating unspecific symptoms [23, 85, 110]. The effect on delirium and seizures was not analyzed. Williams and McBride noted after their review of the literature that the effect from benzodiazepines in alcohol withdrawal had stronger support than any other type of drug [125]. 3.3.1.9
3.3.2
Treatment of Delirium Tremens
Many older studies are plagued by a poorly delineated patient data, which include many different conditions related to alcohol abuse. Milder withdrawal reactions are not always distinguished from delirium, and the latter term is poorly defined. In most cases the studies are not blinded. Apart from pharmacological treatment of mental and neurologic symptoms, administration of nutrition, control of fluid balance, intensive treatment of concurrent somatic disorders, rest, and sleep is required. Barbiturates (see Table 3.3a) The literature on barbiturates is fragmentary. No comparison between different barbiturates has been found. A retrospective study showed that chlordiazepoxide yielded a more rapid effect on confusion and hallucinations than barbital did [27]. Kramp and Rafaelsen reported a better effect from phenobarbital than diazepam in patients with fully developed delirium tremens and that phenobarbital seemed to counteract progress from milder to more severe symptoms of delirium [63]. No deaths occurred. In patients with milder/fewer symptoms, the agents were equivalent. The authors recommended diazepam before phenobarbital for its anti-epileptic qualities. Diazepam was given as an intramuscular injection, barbital orally. One problem in this study was that several patients in both 3.3.2.1
229
230
3 Pharmacotherapy for Alcohol Withdrawal Syndrome Table 3.3a-d. Treatment of delirium tremens. Randomized controlled trials, meta-analyses, and selected retrospective studies. Table 3.3a. Barbiturates. Study
Drugs compared
No. randomized (No. who completed)
Benuzzi & Muller [15] 1967
1. chlordiazepoxide 2. lucidril 3. chlormethiazole
1. 63 2. 39 3. 29
Christensen & Strandbygaard [27] 1968
1. diemal 2. chlordiazepoxide
1. 51 of whom 12 DT 2. 49 of whom 15 DT
4 and 5 DT patients, respectively, required > 3 days treatment
Athen et al. [7] 1976
1. aprotinin 2. placebo
1. 15 (15) 2. 15 (15)
Varying
Athen et al. [8] 1977 Kramp & Rafaelsen [63] 1978
chlormethiazole
178
1. diazepam 2. barbital
1. 44 (of whom 13 DT) 2. 47 (of whom 17 DT)
Not stated
Palestine [87] 1973
1. haloperidol i.m. 2. mesoridazine i.m. 3. hydroxyzine i.m.
1. 42 2. 14 3. 25
Until no symptoms (maximum of 5 injections)
i.m. = intramuscular injection; DT = delirium tremens.
Treatment time (days)
3.3 Included Studies
231
Outcome measure
Quality score
Comments
Mortality
Retrospective study
Number of deaths within 10 days after treatment initiation was 8 in group 1., 3 in group 2., and 0 in group 3.
Absence of hallucinations and disorientation; essential reduction of unspecific symptoms
Retrospective study
Ten patients in group 2. clearly improved the first day versus 3 in group 1.
Self-rating scale for level of orientation and hallucinations
20/33
All were also treated with chlormethiazole intravenously. Aprotinin did not give a lower consumption of chlormethiazole and did not shorten the delirium.
Sedation time; number of doses etc.
30/33
“Better effect from barbital in patients with manifest DT”.
Global rating on a 5-grade scale was made by the author of the article
23/33
Significantly most “markedly improved” in the haloperidol group.
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3 Pharmacotherapy for Alcohol Withdrawal Syndrome Table 3.3b. Benzodiazepines. Study
Drugs compared
No. randomized (No. who completed)
Treatment time (days)
Brown et al. [21] 1972
1. diazepam intravenously 2. chlordiazepoxide intravenously
1. 7 (7) 2. 11 (7)
3
Kaim & Klett [60] 1972
1. 2. 3. 4.
1. 46 2. 55 3. 46 4. 41
10
Thompson et al. [121] 1975
1. diazepam i.m. 2. paraldehyde rectally
1. 17 (17) 2. 17 (17)
Until no symptoms
Wasilewski et al. [122] 1996
1. diazepam in a loading dose 2. diazepam with daily dose
1. 51 (51)
Varying
chlordiazepoxide paraldehyde perphenazine pentobarbital (concerns no. completing trial; no. randomized not reported)
2. 45 (45)
i.m. = intramuscular injection; DT = delirium tremens.
3.3 Included Studies
233
Outcome measure
Quality score
Comments
“Recovered”, “improved”, or “no change”
20/33
No difference in effect. Diazepam acted more rapidly.
Duration of DT; severity of symptoms
29/33
No significant differences between groups.
Occurrence of agitation, hallucinations, incontinence, disorientation etc
26/33
Diazepam had a more rapid effect. Paraldehyde caused significantly more side effects.
CIWA-Ar
27/33
Deficient randomization. Several different drugs were used in the control group (haloperidol, promazine, chlormethiazole, oxazepam, chlorpromazine, perphenazine).
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groups had measurable levels of benzodiazepines in their blood at the time of admission. The use of barbiturates in withdrawal syndrome and delirium has declined because of the risk of respiratory arrest in association with overdose and in practice are often limited to intensive care for these indications. 3.3.2.2 Benzodiazepines (see Table 3.3b)
Brown gave diazepam or chlordiazepoxide intravenously to delirious patients and did not find any difference in effects, apart from the fact that the effect was somewhat more rapid with diazepam [21]. A multicenter study of 4 agents (chlordiazepoxide, paraldehyde, perphenazine, and chlorpromazine) did not show any difference in effect between the treatment groups [60]. In another study, diazepam brought on sedation twice as rapidly as paraldehyde did [121]. Diazepam was given intravenously (10 mg as a loading dose, then 5 mg every 5 min until sedation). Paraldehyde was given rectally (10 mg every 30 min until sedation). Paraldehyde caused significant side effects and patients with concurrent somatic complications required twice as high a dose of this agent for sedation. Hence, diazepam appears superior to paraldehyde in delirium tremens and has the advantage of being less toxic. Wasilewski attempted to give diazepam in a loading dose (repeated doses until CIWAAr<10), which reduced both the duration of the delirium and the total dose significantly compared to daily dosage according to a schedule [122]. Benzodiazepines were recommended in several reviews as treatment for delirium tremens [36]. 3.3.2.3 Chlormethiazole (see Table 3.3c)
No randomized studies of the effect on fully developed delirium tremens have been found. In an open study, chlormethiazole or clorazepate was given to patients with fully developed delirium tremens [25]. Chlormethiazole was given as an intravenous infusion and clorazepate as repeated intravenous injections. Clorazepate gave a significantly reduced heart rate compared to chlormethiazole, but otherwise no differences were found. The effect from chlormethiazole on the cases of delirium tremens appearing in clinical trials in alcohol withdrawal has generally been reported to be good. In some studies, mortality from delirium tremens has decreased to zero after treatment with chlormethiazole [8, 15, 24]. Snel et al. tried adjunct treatment with piracetam in patients who were given chlormethiazole as the primary agent [113]. Adding piracetam gave more rapid symptom relief and shortened the treatment time from 7 to 3 days compared to placebo. 3.3.2.4 Imidazoline Agonists (see Table 3.3d)
In one of the few randomized studies of pharmacological treatment in fully developed delirium tremens, the effect from clonidine was studied compared to chlormethiazole [107]. Both substances were judged to have acceptable clinical effects. Monotherapy with clonidine was insufficient in four fifths of the patients. In the chlormethiazole group, additional medication was required in half of the patients. Chlormethiazole affected respiration in 44% of the patients versus 19% in the clonidine group.
3.4 Discussion
3.3.2.5 Other Treatment (see Table 3.3d)
The peptidase inhibitor aprotinin (Trasylol) was tested against placebo as intravenous therapy for delirium tremens (200 000 IE every 6 h) [7, 119]. The outcome measure consisted of the total dose of chlormethiazole required for symptom relief. No difference could be found between aprotinin and placebo. Propofol is an anesthetic used in anesthesiology and intensive care. Intravenous infusion of propofol may cause a drop in blood pressure, and continuous monitoring is therefore required [36]. The documentation of propofol in delirium is insufficient, and randomized studies are lacking completely. A case study of delirium tremens exists, but has been criticized for not having the correct diagnosis [29, 68]. In a doubleblind study, 100 g fructose was given intravenously during 6 h. The control group received glucose. No differences could be shown [38]. Electroconvulsive treatment (ECT) is used routinely for different types of delirium. No published randomized trials of ECT in delirium tremens have been found. Meta-analyses No meta-analyses of pharmacological treatment in delirium tremens were found. 3.3.2.6
3.4
Discussion
The ideal drug for alcohol withdrawal should be cross-tolerant against alcohol, prevent seizures and delirium, reduce anxiety and agitation, be non-toxic, have an immediate and long-term effect, preferably not be metabolized in the liver, and not be addictive in short-term treatment. Benzodiazepines fulfill several of these criteria and are recommended internationally as first-line drugs in uncomplicated alcohol withdrawal [57, 77, 86]. A sufficient number of studies show that benzodiazepines significantly reduce the unspecific symptoms of alcohol withdrawal and more effectively than placebo does. Meta-analyses have also shown that benzodiazepines significantly reduce the risk of developing delirium tremens and withdrawal seizures compared to placebo. It is estimated that if 100 patients are treated, withdrawal seizures are avoided in nearly 8 of these cases and nearly 5 cases of delirium are avoided. There is a tendency for benzodiazepines with a long half-life to prevent delirium and seizures more effectively than those with a short half-life, but the difference is not statistically significant [6, 54, 76, 80, 95, 114]. Chlordiazepoxide (for many years the recommended treatment, particularly in American clinics) has no advantages compared to other benzodiazepines with a long half-life. In summary, there is no evidence to show that any particular agent in the group of benzodiazepines is superior in treating alcohol withdrawal. The dosage may need to be reduced in the elderly and in patients with reduced liver function. The risk of developing dependency in treatment with benzodiazepines may be greater in individuals who are already alcohol dependent, but the specific and immediate beneficial effect against severe complications must be considered in treating withdrawal [2]. Short-term treatment probably minimizes the risk of dependency. Alcohol with-
235
236
3 Pharmacotherapy for Alcohol Withdrawal Syndrome Table 3.3c. Chlormethiazole. Study
Drugs compared
No. randomized (No. who completed)
Treatment time (days)
Caspari et al. [25] 1992
1. chlormethiazole intravenously 2. clorazepate intravenously
1. 21
3–10
1. chlormethiazole 2. chlormethiazole + piracetam Selection/dropouts not described
1. 12 2. 12
7
No. randomized (No. who completed)
Treatment time (days)
Snel et al. [113] 1983
2. 20
i.m. = intramuscular injection.
Table 3.3d. Imidazoline agonists, other treatment. Study
Drugs compared
Sehnert et al. [107] 1998
1. clonidine intravenously 1. 48 2. chlormethiazole 2. 48 intravenously
5
Friend et al. [38] 1971
1. fructose 2. dextrose
1
Tacke & Kempf [119] 1975
1. placebo 2. aprotinin
1. 15 (13) 2. 15 (11)
i.m. = intramuscular injection; DT = delirium tremens.
3.4 Discussion
237
Outcome measure
Quality score
Comments
Heart rate and blood pressure
20/33
Clorazepate reduced palpitation more effectively; otherwise no differences. Addition of haloperidol was necessary in 7 in group 1, and 12 in group 2. Two in each group had a prolonged course of DT.
Several symptom scales
25/33
Piracetam shortened the treatment time.
Outcome measure
Quality score
Comments
≤5 points on 25-grade scale
24/33
84% in group 1 and 60% in group 2 improved within 5 days. The clonidine group needed more benzodiazepines.
“Improved”, “no difference”, “deteriorated”
25/33
No significant differences between groups.
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drawal in individuals who also abuse benzodiazepines may involve a higher risk of withdrawal seizures, which is why the use of cross-tolerant benzodiazepine agents in such cases is particularly motivated. Beta-receptor antagonists reduce unspecific withdrawal symptoms more effectively than placebo does. High doses of beta-receptor antagonists, in particular those with a high penetration to the central nervous system, have been reported to cause delirium [65]. Beta-receptor antagonists suppress the hyperactivity in the autonomous nervous system and can hence mask a developing delirium [129]. Published studies do not offer any support in judging whether beta-receptor blockers can prevent withdrawal seizures or delirium. Beta-receptor blockers have no known preventive effect on seizures. All reviewed studies show that clonidine has a significantly better effect on withdrawal symptoms compared to placebo and a better effect than the compared drugs in treating palpitation and elevated blood pressure. These effects are due to a direct inhibition of nerve cells in the sympathetic nervous system. Clonidine is consistently reported to have a poor effect on sleep disorders. There is no evidence that clonidine prevents seizures or delirium. A large problem in several of the clonidine trials is that other psychotropic drugs have been given concurrently, which reduces the value of the conclusions to a considerable degree. There is no support that clonidine alone is better than placebo in alcohol withdrawal. Most reviews advise against using clonidine as monotherapy in alcohol withdrawal. Published randomized trials show that chlormethiazole consistently has a significantly better effect on withdrawal symptoms than placebo and clonidine, and it has an equivalent effect to benzodiazepines, barbiturates, and antipsychotic drugs. Most studies of barbiturates are descriptive, lack a control group, and have other methodological deficiencies. The number of patients included in randomized studies of chlormethiazole and barbiturates is too small to estimate the possible preventive effect on withdrawal seizures and delirium. The overall beneficial effect from chlormethiazole is reduced by side effects, mainly increased secretion in the respiratory tract, which may constitute a risk in somnolent patients. There is insufficient evidence to assess whether the preventive effect of carbamazepine or other anti-epileptic drugs such as phenytoin or valproic acid against delirium and withdrawal seizures is significantly greater than that of placebo. However, carbamazepine reduces unspecific withdrawal symptoms more effectively than placebo does. There is no significant difference between carbamazepine and oxazepam concerning the effect on unspecific withdrawal symptoms. An advantage of carbamazepine is the low abuse potential. Furthermore, carbamazepine is less sedative than oxazepam, which enables the patient to start rehabilitation sooner. Since carbamazepine does not enhance the effect of alcohol, drug treatment could be initiated even if the patient is still influenced by alcohol, which could possibly prevent severe withdrawal [40]. However, this is not studied in any randomized trial, and therefore the use of carbamazepine in treating alcohol withdrawal lacks scientific support as regards both the effects against seizures and delirium and the risks of side effects and giving pharmacological treatment to intoxicated patients.
3.5 Summary
The side effects from valproic acid and carbamazepine reduce the overall beneficial effect of these drugs. For example, carbamazepine causes a skin rash in 2% of the patients. Other well-known side effects from carbamazepine are ataxia, accommodation disorder, and nausea. There are no severe hematological side effects from carbamazepine reported in the reviewed literature in a treatment time of less than one week.
3.5
Summary
Strong evidence from placebo controlled studies shows that benzodiazepines, betareceptor antagonists, calcium antagonists, carbamazepine, and clonidine reduce unspecific withdrawal symptoms more effectively than placebo does. Only the benzodiazepine group has a documented effect as a preventive treatment against withdrawal seizures or delirium tremens. Hence, evidence is lacking to support the recommendation of other drugs as monotherapy in alcohol withdrawal. The studies of nitrous oxide treatment are difficult to interpret because of several methodological problems, but nitrous oxide appears to reduce unspecific withdrawal symptoms. There is insufficient evidence to show that nitrous oxide could prevent the origin of seizures or delirium. Few randomized controlled clinical trials have investigated pharmacological treatment in fully developed delirium tremens. Published studies have consistently small patient databases. The state of knowledge is insufficient. On the basis of proven clinical experience, most textbooks recommend benzodiazepines and chlormethiazole as first-line agents for treating delirium tremens. Chlormethiazole has more potentially serious side effects than benzodiazepines, mainly respiratory depression and increased airway secretion.
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dence of Korsakoff’s psychosis in the East End of Glasgow. Alcohol Alcohol 1997; 32:281–285. Rathlev NK, D’Onofrio G, Fish SS, et al. The lack of efficacy of phenytoin in the prevention of recurrent alcoholrelated seizures. Ann Emerg Med 1994; 23:513–518. Ritola E, Malinen L. A double-blind comparison of carbamazepine and clomethiazole in the treatment of alcohol withdrawal syndrome. Acta Psychiatr Scand 1981; 64:254–259. Ritson B, Chick J. Comparison of two benzodiazepines in the treatment of alcohol withdrawal: effects on symptoms and cognitive recovery. Drug Alcohol Depend 1986; 18:329–334. Robinson BJ, Robinson GM, Maling TJ, Johnson RH. Is clonidine useful in the treatment of alcohol withdrawal? Alcohol Clin Exp Res 1989; 13:95–98. Rosenfeld JE, Bizzoco DH. A controlled study of alcohol withdrawal. Q J Stud Alcohol Suppl 1961; 1:77–84. Rosenthal RN, Perkel C, Singh P, Anand O, Miner CR. A pilot open randomized trial of valproate and phenobarbital in the treatment of acute alcohol withdrawal. Am J Addict 1998; 7:189–197. Rothstein E. Prevention of Alcohol Withdrawal Seizures: The Roles of diphenylhydantoin and chlordiazepoxide. Am J Psychiatry 1973; 130:1381–1382. Runion HI, Fowler FN. A double blind study of chlordiazepoxide and hydroxyzine HCI therapy in acute alcohol withdrawal utilizing chronic electromyography for tremor. Proceedings of the Western Pharmacology Society 1978; 21:303–309. Saitz R, Mayo-Smith MF, Roberts MS, Redmond HA, Bernard DR, Calkins DR. Individualized treatment for alcohol withdrawal. A randomized doubleblind controlled trial. JAMA 1994; 272:519–523. Sampliner R, Iber F. Diphenylhydantoin control of alcohol withdrawal seizures. Results of a controlled study. JAMA 1974; 230:1430–1432.
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Ortiz MF, Barroso Canizares A, Caballero Martin L. Double-blind study of the efficacy of tetrabamate and tiapride in the treatment of alcohol deprivation syndrome. Med Clin Barc 1985; 85:533–536. SBU. [Treatment with neuroleptics] [Swedish]. SBU report no. 133/1, 1997.105. Schmauss C, Apelt S, Emrich HM. Characterization of benzodiazepine withdrawal in high- and lowdose dependent psychiatric inpatients. Brain Res Bull 1987; 19:393–400. Schulte RM. [Therapy of pre-delirium alcohol withdrawal syndrome. Results of a comparative study of carbamazepine and clomethiazole] [German]. Fortschr Med 1987; 105: 493–496. Sehnert W, Brecht HM, Nowak FG. Hochdosierte i.v. Clonidintherapie. Intesivmedizin und Notfallsmedizin [German]. 1998; 4:270–280. Sellers EM, Cooper SD, Zilm DH, Shanks C. Lithium treatment during alcoholic withdrawal. Clin Pharmacol Ther 1976; 20:199–206. Sellers EM, Zilm DH, Degani NC. Comparative efficacy of propranolol and chlordiazepoxide in alcohol withdrawal. J Stud Alcohol 1977; 38:2096–2108. Sellers EM, Naranjo CA, Harrison M, Devenyi P, Sykora K. Diazepam loading: Simplified treatment of alcohol withdrawal. Clin Pharmacol Ther 1983; 34:822–826. Sereny G, Kalant H. Comparative clinical evaluation of chlordiazepoxide and promazine in treatment of alcoholwithdrawal syndrome. BMJ 1965; 1:92–97. Shaw JM, Kolesar GS, Sellers EM, Kaplan HL, Sandor P. Development of optimal treatment tactics for alcohol withdrawal. I. Assessment and effectivness of supportive care. J Clin Psychoparmacol 1981; 1:382–387. Snel H, Lehmann E, Velikonja M. [Piracetam in the treatment of alcoholinduced delirium.] [German] MMW Munch Med Wochenschr 1983; 125:947–949.
114 Solomon J, Rouck LA, Koepke HH.
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Double-blind comparison of lorazepam and chlordiazepoxide in the treatment of the acute alcohol abstinence syndrome. Clin Ther 1983; 6:52–58. Spies CD, Dubisz N, Funk W, Blum S, Muller C, Rommelspacher H, Brummer G, Specht M, Hanneman L, Striebel HW, et al. Prophylaxis of alcohol withdrawal syndrome in alcoholdependent patients admitted to the intensive care unit after tumour resection. Br J Anaesth 1995; 75:734–739. Spies C, Dubisz N, Neumann T, Blum S, Muller C, Rommelspacher H, Brummer G, Specht M, et al. Therapy of alcolhol withdrawal syndrome in intensive care unit patients following trauma: results of a prospective, randomized trial. Crit Care Med 1996; 24:414–422. Sternebring B, Holm R, Wadstein J. Reduction in early alcohol abstinence fits by administration of carbamazepine syrup instead of tablets. Eur J Clin Pharmacol 1983; 24:611–613. Stuppaeck CH, Pycha R, Miller C, Whitworth AB, Oberbauer H, Fleischhacker WW. Carbamazepine versus oxazepam in the treatment of alcohol withdrawal: a double-blind study. Alcohol Alcohol 1992; 27:153–158. Sullivan JT, Sykora K, Schneiderman J, Naranjo CA, Sellers EM. Assessment of alcohol withdrawal: The revised Clinical Institute Withdrawal Assessment for Alcohol scale (CIWA-AR). Br J Addict 1989; 84:1353–1357. Tacke B, Kempf H. [Double-blind study of Aprotininum (Trasylol) in the management of alcoholic delirium.] [German] Int Pharmacopsychiatry 1975; 10:37–41. Teräväinen H, Larsen A. Effect of propranolol on acute withdrawal tremor in alcoholic patients. J Neurol Neurosurg Psychiatry 1976; 39:607–612. Thompson WL, Johnson AD, Maddrey WL. Diazepam and paraldehyde for treatment of severe delirium tremens. A controlled trial. Ann Intern Med 1975; 82:175–180.
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1 Kolumnentitel
4
Pharmacotherapy for Alcohol Dependence Mats Berglund
4.1
Introduction
Many types of psychopharmacological drugs have been used in the long-term treatment of alcohol dependence. Certain primary agents, e.g., disulfiram and acamprosate, have been used. Other agents that have effects on other psychiatric conditions have also been tested on patients with alcohol dependence. Aversive agents, mainly disulfiram, came into general use in the 1950s. Benzodiazepines, tricyclic antidepressants, antipsychotic drugs, and lithium were introduced during the 1950s, 1960s, and 1970s. During the 1980s, SSRI agents and buspirone were tested, and during the 1990s the specific “anticraving” agents naltrexone and acamprosate were introduced. All of these agents have been tested in the long-term treatment of alcohol dependence. Not until recent years have specific psychopharmacological drugs been developed for dependence conditions, with the exception of aversive agents. Also, psychosocial treatment methods have been developed and refined during the past decades. A good outcome requires the integration of modern pharmacological treatment and effective psychosocial treatment. Randomized controlled trials with placebo or other active agents have increased since the 1960s. The methodology during the earlier decades was relatively undeveloped, and the outcome criteria were generally global in nature, e.g., improved or not, relapse or not, etc. Diagnostics were also undeveloped, and only in the mid 1980s was a common operationally based diagnostic system established, i.e., the DSM system. During the past 10 years, clinical studies have maintained a good scientific standard. However, only the most recent agents have been studied by such methods. Less advanced studies must be used to evaluate the older agents, and the conclusions can be less certain. An earlier SBU report on antipsychotic drugs and abuse found that many studies had been performed during the 1960s and 1970s and that antipsychotic drugs had an effect on the long-term treatment of alcohol dependence [146]. These studies were not found in modern reviews of treatment with psy-
Treating Alcohol and Drug Abuse. Edited by M. Berglund, S. Thelander, E. Jonsson Copyright c 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 3-527-30682-X
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chopharmacological agents for alcohol dependence. One reason is that many of these are not classified as randomized controlled studies in databases, e.g., MEDLINE.
4.2
Methods 4.2.1
Search Strategies
The keywords “alcoholism” and “randomized controlled trials” were used to search MEDLINE. All studies published up to the end of 2000 were included in the original publication in Swedish. Furthermore, all reviews are included, and the reference lists of retrieved articles were also reviewed. A complementary search, performed in May 2002, is included in the English version. The conclusions in the Swedish and English version are the same, as were the principles of analysis. This review includes only the studies classified as psychopharmacological treatment and which meet the following requirements: 1. Psychopharmacological treatment of alcohol dependence with or without concurrent mental illness. 2. At least 4 weeks of treatment and a population of at least 15 individuals. 3. Randomized controlled trials with placebo, other drugs, or no pharmacological treatment. Consequently, pharmacological treatment of other abuse (including nicotine), organic syndromes, and somatic morbidity were not included. Initially, 104 studies were identified from MEDLINE and another 18 from the following reference literature: Litten and Allen, 1991 (9 new studies), Litten et al., 1996 (5 new studies), and Schuckit, 1996 (3 new studies) [83, 84, 147]. Another study was added after review of reference lists. Studies added after the MEDLINE search were published in 1981 (× 2), 1984, 1985, 1986 (× 2), 1987 (× 2), 1989 (× 3), 1991, 1992 (× 2), 1993 (× 3), and 1994. After reviewing all criteria and retrieving studies with more than one publication we acquired 71 studies that met the inclusion criteria. The SBU report on substance abuse and antipsychotic drugs identified eight studies published in 1984 or before. Only one of these was identified in the current MEDLINE search and in the review literature. Thus, another seven studies were added. 4.2.2
Complementary Search
A complementary search of reference lists identified the following reviews: Moncrieff and Drummond (1997), Litten and Allen (1998), and Garbutt et al. (1999) [42, 85, 99]. Another 23 studies were added. The Cochrane Controlled Trial Registry was also searched, but no further studies were added from this.
4.3 Analytical Principles
The 2002 search identified an additional 18 published studies, 5 of which were included as unpublished in the Swedish version. Three new unpublished studies were also included. 4.2.3
Unpublished Studies
Some studies performed during the 1990s have not yet been published. Researchers in the field have been interviewed on the results from their unpublished studies, and information has been collected from a large number of conferences where these studies were presented. Unpublished studies are presented at the end of each section on the different agents. Unpublished studies are, however, not quality rated. As regards antipsychotic drugs and buspirone, the results from these studies have some bearing on the conclusions. In other cases, the active substance shows better results than placebo, e.g., studies of naltrexone and possibly acamprosate. Quality Rating Quality rating is based on the SBU model: “Guide for rating quality in the substance abuse project”. The assessed values are presented in the analysis.
4.3
Analytical Principles 4.3.1
Categorization
The groups of agents were analyzed separately. SSRI agents were analyzed separately from other agents which influence serotonin metabolism. The structure of the analyses is based on historic development, with aversive agents first, followed by antipsychotic drugs, dopamine agonists, SSRI agents, other 5-HT agents, acamprosate, naltrexone, and other agents. The analysis concludes by addressing treatment of patient groups who also suffer from depression or anxiety. The lithium section has included all studies, regardless of whether the patients suffered from alcohol dependence alone or also had other disorders. SSRI agents and buspirone were analyzed separately depending on whether or not the patients had multiple disorders. 4.3.2
Target Group and Treatment Goals
In most studies, the patients were alcohol dependent. Many studies in recent years have used systematic diagnostics based on ICD-10 or DSM. Studies from earlier years often lack such diagnostics, and the subjects included are referred to only as alcoholics.
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Some studies describe the groups studied as heavy consumers. This applies mainly in early studies of SSRI agents. In many of these studies, medication is used to reduce alcohol consumption without concurrent psychosocial treatment. The same methodology is used in other SSRI studies, where most of the patients treated are diagnosed as alcohol dependent. This one-sided treatment strategy has not been applied in studies of other agents, which is the reason for analyzing them separately.
4.4
Overview of Tables
The Tables present a small number of variables to help the reader to obtain a comparative overview. Study The main publication of a study is always presented. Other publications with new and relevant data are also reported. Most studies, however, have appeared only in a single publication. If several agents are included in the study, the publication is presented in several Tables. Number of patients The number of patients reflects the number at the time of randomization. Comorbidity for other dependencies, and psychiatric diagnoses are reported in the Tables. Agent The dose per day and whether or not the study is placebo controlled is reported. Study Duration Duration is always reported in weeks (6 months is converted to 26 weeks, etc.). If the study uses a design other than parallel groups, e.g., crossover design, this is also reported here. Treatment If psychosocial treatment is based on therapy manuals, the study is presented under a special heading “manual-based treatment”. Otherwise, the way in which the treatment was carried out is reported in the Tables as described in the respective studies. Attrition The number of patients who left the treatment prior to the planned completion is reported and, where possible, this is divided into treatment and control groups.
4.4 Overview of Tables
ITT (intention to treat) All randomized patients are included in estimates of treatment effect. Such data may be difficult to obtain, especially in older studies. Thus, if data are available but ITT values were not stated, these have been calculated. Interrupted treatment has been viewed as failed treatment if nothing else can be documented in these studies. The ITT analyses can be performed in two ways, to consider all interruptions as failed or to use the last observation carried forward. A followup of all interruptions at the conclusion of the treatment, the most appropriate method, was done in only a few studies. The primary outcome measures, which often vary among studies, have been reported. For acamprosate, the most common outcome measure is total abstinence or the proportion of days of complete sobriety. For naltrexone, usually freedom from abuse or number of abuse-free days has been measured. The primary outcome measures in some studies are unclear. In these cases, the same variables as those used in other studies have been presented to achieve the best possible overview and comparison between studies. When several outcome measures are used, there is a substantial risk that only those which showed significant effects are reported. Completers The analysis only concerns those patients who completed the treatment. The same type of calculation as for the ITT analysis has been applied. Correct identification This addresses the patients’ perception of which agent they received. Although only a few studies included this, these studies have been reported mainly because of the importance of this information in determining the success of blinding. Studies having the goal of reducing the alcohol consumption without using concurrent psychosocial treatment (SSRI studies) are addressed only in the text, as are disulfiram depot studies and studies with other agents and the antipsychotic drug studies reported in a previous SBU report [146].
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4.5
Overview of Included Studies Study Aversive agents Placebo Oral Depot Antabusesupervision Antipsychotic drugs Dopamine agonists SSRI Other 5-HT agents Acamprosate Naltrexone/Nalmefene Lithium Carbamazepine GHB Enalapril Beta blockers Alc + Depression Alc + Anxiety Alc + Social anxiety -----Total
Published
Unpublished
124 126
– –
127 111 126 115 111 118 119 128 121 121 121 121 128 124 121 -----122
– 2 – 2 1 3 6 – – – – 1 – – – -----15
4.6
Results 4.6.1
Aversive Agents Oral administration (see Table 4.1) The search revealed three placebo-controlled studies using disulfiram (Antabuse) and one using calcium carbimide (Dipsan). The study of aversive effects requires a special study design. In the two studies by Fuller et al., the choice was to randomize to three alternatives; placebo (vitamin tablets), disulfiram 1 mg (does not cause any aversive reaction), and disulfiram 250 mg [38, 39, 40]. After the randomization, the patients receiving placebo are informed that they did not receive disulfiram. In the design by Chick et al., the same procedure of giving information after randomization was used with the placebo group [25]. It did not include a 1mg group. The study by Peachey et al. of calcium carbimide used a crossover design where the patients were informed that they were receiving an active substance half of the time and placebo half of the time [124]. Despite this, many experienced that they were on an active substance during the entire period and only 8% of the patients could correctly identify which substances they were receiving.
4.6 Results
Two studies by Fuller found no difference in the rate of total abstinence among the different groups in an ITT analysis. The second study found that “completers” who were on 250 mg disulfiram had a significantly lower number of days with alcohol consumption. Treatment with disulfiram was not under supervision, and patients took the medication, on average, in only 20% of the treatments. In the study by Chick et al., disulfiram was given under supervision [25]. A significant increase in the number of sober days could be noted in the disulfiram group compared with the placebo group. A study of calcium carbimide by Peachey et al. reported no differences in effect between active substance and placebo [124]. Fifty-one percent were completely sober during the entire study, and alcohol was consumed in 22% of the cases treated with calcium carbimide alone and in 13% of the cases treated with placebo alone. Meta-analyses. Aversive drugs versus placebo The effect size was 0.09 (CI –0.04, 0.23) and the heterogeneity test was positive (p = 0.002). Moderator for heterogeneity was supervision/no supervision (p = 0.004). Chick study, supervision (25) d = 0.72 (CI 0.635, 1.08). The others, no supervision, d = –0.00 (CI –0.15, 0.14). Comparison between supervised and unsupervised disulfiram treatment (see Table 4.1) Four studies have compared disulfiram given with and without supervision. All studies reported better results with supervision, although the difference is not significant in all studies. A study by Miller identified an effect only from the 12-step program but not from the CRA method [98]. A study from 1978 by Liebson et al., investigated alcohol-dependent heroin addicts in a methadone program [82]. It found that if methadone administration was combined with disulfiram treatment, police custody was eight times less with supervised than with unsupervised disulfiram treatment. As regards alcohol consumption, the study by Carrol et al. found a significantly better effect with supervised disulfiram treatment than that observed in the control group [24]. Annis and Peachey studied the effects from calcium carbimide given together with regular medical visits or with relapse prevention [5]. No significant differences were seen. Meta-analysis: supervision versus no supervision D = 0.53 (CI 0.26, 0.79). Heterogeneity test negative. Depot medication (no Table) The main problem with this treatment is that therapeutic blood levels of disulfiram are not reached with the agents currently available [59]. A Swedish study showed no differences between active substance and placebo [17, 88]. Several international studies have been performed with negative results [58, 59, 161, 162], while Wilson et al. reported a significant positive effect [163].
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4 Pharmacotherapy for Alcohol Dependence Table 4.1. Aversive agents. Study
Number of patients
Agent
Study duration
Treatment
Fuller [39, 40] (1979, 1983)
128
1. Placebo (not blinded) 2. Disulfiram 1 mg 3. Disulfiram 250 mg (unsupervised)
52 w
Individual counseling
Fuller [38] (1986)
605
1. Placebo (not blinded) 2. Disulfiram 1 mg 3. Disulfiram 250 mg (unsupervised)
52 w
AA, group and individual counseling
Chick [25] (1992)
126
1. Placebo (not blinded) 2. Disulfiram 200 mg (supervised)
24 w
AA, group and individual counseling
Peachey [124] (1989)
109
Calcium carbimide 100 mg
16 w Crossover design
Psychosocial counseling
Placebo studies
Antabuse supervision, non-manual-based Azrin [9] (1982)
43
Disulfiram 250 mg
26 w
1. Traditional group (n=14) 2. Disulfiram contract (n=15) 3. Disulfiram contract + behavioral therapy (n=14)
Keane [64] (1984)
25
Disulfiram 250 mg
13 w
1. No contract (n=9) 2. Antabuse contract (n=8) 3. Antabuse contract + positive reinforcement (n=8)
4.6 Results
255
Attrition
ITT
Completers
Correct identification
Quality score
61%
Completely sober: 1. 12% 2. 35% 3. 21% (ns)
–
–
27 (29)
53%
Completely sober: 1. 16% 2. 22% 3. 19% (ns)
Days with alcohol consumption 1. 87±14 (SD) 2. 75±12 3. 49±8 (p<0.05)
–
32 (34)
1. 47% 2. 44%
Sober days: 1. ∆ + 54±53 2. ∆ + 98±68 (p<0.05)
–
–
30 (33)
37%
CC = Placebo (ns)
Completely sober 51% Alcohol only in: CC 22% Placebo 13%
8% pat ident correct
33
–
Days with alcohol consumption 1. 16 2. 8 3. 1 (p<0.01)
–
–
20
–
Abuse free/ takes antabuse: 1. 78%/55% 2+3. 88%/88% (ns)/(p=0.06)
–
–
21
Table continues on next page
256
4 Pharmacotherapy for Alcohol Dependence Table 4.1. (cont.) Study
Number of patients
Agent
Study duration
Treatment
Antabuse supervision, non-manual-based Liebson [82] (1978)
25 Disulfiram alcoholMethadone dependent heroin addicts
29 w
1. Unsupervised disulfiram 2. Supervised disulfiram
Annis & Peachey [5] (1992)
56
Calcium carbimide 100 mg
17 w
1. Combined with medical visit 2. Combined with relapse prevention
Miller [98] (1992)
62
Disulfiram 250 mg
12 w
12-step program 1. Unsupervised 25/30 2. Supervised 31/32
Miller [98] (1992)
58
Disulfiram 250 mg
12 w
Community Reinforcement Approach 1. Unsupervised 26/29 2. Supervised 27/29
Gerrein [48] (1973)
49
Disulfiram 250 mg
8w
Alcohol counseling 1. Dis unsupervised (n=13) 2. Dis supervised (n=13) 3. No dis (n=23)
4.6 Results
Attrition
ITT
–
Illegal drug: 1. 13% 2. 9% (ns)
23%
257
Completers
Correct identification
Quality score
–
–
16
–
Alcohol consumption 2<1 (p=0.06)
–
31
1. 17% 2. 3%
Days with alcohol consumption 1. 1.35±1.94 2. 0.25±0.59 p=0.004
Days with alcohol consumption 1. 1.00±1.55 2. 0.25±0.60
–
26
1. 10% 2. 7%
Days with alcohol consumption 1. 0.22±0.65 2. 0.20±0.29 ns
Days with alcohol consumption 1. 0.24±0.67 2. 0.19±0.42
–
26
1. 61% 2. 15% 3. 74%
Completely sober: 1. 7% 2. 40% p<0.05 3. 9%
Completely sober: 1. 20% 2. 45% 3. 33% ns
–
26
Police custody: 0.8/100 days 0.1/100 days (p<0.05)
Table continues on next page
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4 Pharmacotherapy for Alcohol Dependence Table 4.1. (cont.) Study
Number of patients
Agent
Study duration
Treatment
12 w
Not Disulfiram 1. CBT 2. TSF Disulfiram 3. CBT 4. TSF 5. Support
Manual-based Carroll [23] (1998)
122 Disulfiram 250 mg cocaineand alcoholdependent
4.6 Results
Attrition
1. 2. 3. 4. 5.
63% 53% 88% 80% 84%
259
ITT
Completers
Correct identification
Quality score
Total abstinence >3 w: 1. 11% 2. 22% 3. 54% 4. 60% 5. 48% 1+2/3+4+5 p<0.001
–
–
31
Cocaine free >3 w: 1. 28% 2. 30% 3. 58% 4. 52% 5. 30% 1+2/3+4+5 p=0.07
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4 Pharmacotherapy for Alcohol Dependence
Conclusion In summary, disulfiram and calcium carbimide, taken without supervision, have no effect in the studies performed. However, positive results are reported from the only placebo-controlled study where treatment was given under supervised conditions. Four smaller studies compared disulfiram with and without supervision and all reported better results when treatment was supervised. Two other studies found that supervised antabuse treatment had better effects than no antabuse treatment. Depot medication has no documented effect. If disulfiram is used, the data indicate that this should take place under supervision. The results are supported by several studies showing that disulfiram treatment under supervision is more effective than that without supervision or than no medication. 4.6.2
Antipsychotic Drugs (no Table)
An SBU report on treatment with antipsychotic drugs summarized the literature on antipsychotic drugs in the treatment of abuse [146]. The analysis included 10 randomized placebo-controlled studies [14, 15, 19, 21, 22, 53, 91, 127, 149, 150, 157]. In total, 316 patients were randomized, and improvement was reported in 67% of patients treated with antipsychotic drugs and in 40% of the placebo-treated patients. In 2001, Wiesback et al. [160] reported a 6-month study comparing 10 mg flupenthixol decanoate or placebo as intramuscular injection in 281 alcoholics. Relapse rates were 85% for flupenthixol and 66% for placebo, which represents a significant difference with a worse outcome for the drug. Two large studies have been performed in central Europe with tiapride. Tiapride showed the same effect as placebo [52]. Conclusion The published studies are of poor quality, and the positive results shown have not been reproducible in new studies. Based on this and the risk for side effects, antipsychotic drugs are not indicated in the treatment of alcohol dependence. Randomized studies on the treatment of alcohol dependent patients with schizophrenia have not been published. 4.6.3
Dopamine Agonists (see Table 4.2)
In this area, bromocriptine has been used in all studies except one. The first study showed a convincing effect on alcohol dependence, but these results have not been reproducible in later studies [18]. Both oral and depot medication have been used. In the studies by Lawford et al., reduced craving was reported in patients treated with bromocriptine with D2 dopamine receptor A1 allele, but not with A2 allele. This is the first randomized study relating the treatment response to molecular genetic variables [80].
4.6 Results
Conclusion Bromocriptine has no effect on alcohol dependence. 4.6.4
SSRI Agents Studies based on pharmacological reduction of alcohol consumption (no Table) These studies included individuals with a high consumption who were not alcohol dependent. No defined psychosocial treatment was given. Zimelidine, citalopram, viqualine, and fluoxetine have been studied [106–109, 111, 113]. Citalopram (40 mg) showed an effect, while citalopram (20 mg) had no effect compared to placebo. Fluoxetine at 60 mg/day had a better effect than at 40 mg per day. Viqualine at 200 mg/day had an effect, but viqualine at 100 mg/day did not. Consistently, the effect remained only for a few weeks. Gorelick and Paredes gave fluoxetine or placebo to hospitalized patients who were allowed to drink alcohol [49]. Here too, a reduction in alcohol consumption was achieved after one week but not later. Balldin et al. gave 40 mg citalopram and placebo, respectively, in a double-blind crossover study with 5 weeks of each treatment, and 30 patients completed the study [10]. In the entire group, no differences were found between citalopram and placebo. Those who drank less than 107 g alcohol/day (median) had a significant reduction in their consumption under treatment with citalopram compared to placebo. Eriksson et al. tried to reproduce these results in a new group of high consumers with equivalent consumption levels [33]. In a study with a parallel group design, including 36 individuals, no differences between citalopram and placebo were found. It is interesting that a temporary reduction could be registered in the citalopram group, and that this appeared only in individuals with a D2 dopamine receptor A2 allele. Studies with concurrent psychosocial treatment (see Table 4.3) Three of these studies reported positive results, but in only one study is this based on ITT analysis [57]. Gerra et al. reported effects only in familial alcoholism and Tiihonen et al. only in reporting from family members [47, 155]. The two studies with the highest quality scores both report negative results [114, 70]. Kranzler et al. report significant deterioration for type B alcoholics with active substance compared to placebo [71]. Naranjo found poorer results with active substance than with placebo, which reached a significant level one week after the completion of treatment [114]. Pettinatti et al. reported that sertraline was more effective than placebo in alcohol-dependent patients without a lifetime diagnosis of depression [130]. Conclusion Treatment with SSRI agents yields only a temporary, and unstable, reduction in consumption. Giving SSRI agents concurrently with psychosocial treatment has no confirmed effect according to the studies with the highest quality scores. Other
261
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4 Pharmacotherapy for Alcohol Dependence Table 4.2. Bromocriptine + psychosocial treatment. Study
Number of patients
Agent
Study duration
Treatment
Borg [18] (1983)
50
Bromocriptine 15 mg
6 months
Not specified
Dongier [31] (1991)
84
Bromocriptine 7.5 mg
8w
No specified treatment
George [43] (1992)
41
5-hydroxytryptophane + Carbidopa 40 mg
52 w
Aftercare
Levodopa + Carbidopa 40 mg Powell [136] (1995)
216 Aff/ anxiety condition = 88 ASP = 65
Nortriptyline ~150 mg Bromocriptine 7.5 mg
6 months
Treatment type not reported
Lawford [80] (1995)
83
Bromocriptine 7.5 mg
6w Inpatient care
Inpatient care
Naranjo [116] (1997)
366
1. Bromocriptine 50 mg/m 2. Bromocriptine 25 mg/m
26 w
Standard psychosocial treatment
Penick [128] (1996)
4.6 Results
263
Attrition
ITT
Completers
Correct identification
Quality score
Bromocr 21% Placebo 12%
–
Sober last months: Bromocr 95% Placebo 35% (p<0.001)
–
24
Bromocr 58% Placebo 51%
–
Consumption days/w: Bromocr 1.7±0.5 Placebo 2.0±0.6 (ns) SCL-90-R: Bromocr 0.33±0.08 Placebo 0.40±0.08 (p<0.05)
–
26
5-HT 80% L-dopa 80% Placebo 87%
–
Completely sober: 5-HT 38% L-dopa 25% Placebo 18% (ns)
–
28
52–55%
–
Completely sober ASP: Nortr 64% (+ concurrent affective disease) Brom 33% Plac 11% (p<0.05) Others no difference
–
26 (28)
Bromocr 33% Placebo 39%
–
Reduced craving: Bromocr 34% Placebo 8% (p=0.27) A1 Allelle 68% A2 Allelle 10% (p=0.001)
–
28
1. 54% 2. 43% Placebo 39%
Completely sober: 1. 24% 2. 29% Placebo 27% (ns)
Abuse free: 1. 62% 2. 58% Placebo 65% (ns)
Completely sober: 20–23% Alcohol consumption but not abuse: 22–27%
31
264
4 Pharmacotherapy for Alcohol Dependence Table 4.3. SSRI + psychosocial treatment. Study
Number of patients
Agent
Study duration
Treatment
Non-manual-based treatment Gerra [47] (1992)
28
Fluoxetine 40 mg
3x4w Crossover design
Group meetings every week
Krantzler [68] (1993)
19
Fluvoxamine 200 mg
12 w
Relapse prevention once a week
Naranjo [114] (1995)
99 Cipramil 40 mg (60 alcohol dependent)
12 w
Controlled drinking Brief intervention
Kabel & Petty [63] (1996)
28
Fluoxetine 60 mg
12 w
Aftercare
Tiihonen [155] 62 (1996)
Cipramil 40 mg
12 w
Visits Physician 2 Nurse 3
Janiri [57] (1996)
Fluoxetine 20 mg
8w
Multimodal treatment
50
4.6 Results
265
Attrition
ITT
Completers
Correct identification
Quality score
Not stated
–
Alcohol consumption days: Fluoxetine from 12.8±1.3 to 6.0±0.8 (p<0.05) Familial alcoholism only
–
20
Fluvoxamine 80% Placebo 11% (p<0.005)
–
–
–
Study was interrupted due to high dropout rate
Cipramil 42% Placebo 23%
–
Reduced alcohol consumption: Cipramil 35%±24% Placebo 38%±17% (ns)
Cipramil 42% Placebo 87%
30
Fluoxetine 40% Placebo 23%
Completely sober: Fluoxetine 53% Placebo 69% (ns)
–
–
25
Cipramil 32% Placebo 58%
Completely sober: Cipramil 19% Placebo 10% (p=0.1)
–
–
24
Fluoxetine 10% Placebo 31%
Completely sober: Fluoxetine 62% Placebo 35% (p<0.05)
–
–
23
Table continues on next page
266
4 Pharmacotherapy for Alcohol Dependence Table 4.3. (cont.) Study
Number of patients
Agent
Study duration
Treatment
Manual-based treatment Krantzler [70, 71] (1995, 1996)
101
Fluoxetine 60 mg
12 w
CBT manual (79% group) (21% individual)
Krantzler [73] (2000)
122
Nefazodone Mean 419 (SD 120)/d
11 w
Coping skill training
Romach [139] (2000)
136
Dexfenfluramine 1. 7.5 mg 2. 15 mg 3. 22.5 mg 4. 30 mg
11 w
Brief behavioral intervention
Pettinati [130] (2001)
100 Sertraline 200 mg Lifetime diagnosis of depression Yes=53 No=47
14 w
12-step facilitation
4.6 Results
267
Attrition
ITT
Completers
Correct identification
Quality score
Length of treatment: Fluo 9.5±3.7 w Plac 10±3.0 w
Completely sober: Fluo 58% (ns) Plac 52% Alcohol consumption days Type A: Fluo 4.4±10.1 Plac 5.0±9.6 Type B: Fluo 15.1±20.7 Plac 5.6±11.3 (p<0.001)
–
Fluo 80% Plac 56%
32
Nefazodone 27% Placebo 21%
Heavy drink days: Nef 11% Placebo 8% (ns)
–
Nefazodone 75% Placebo 41%
Dexfenfluramine 1. 37% 2. 29% 3. 22% 4. 38% Placebo 39%
40% no heavy drinking last 4 w No differences between groups
–
–
–
Sertraline 36% Placebo 48%
Abstinence rate Sertraline 36% Placebo 20%
(Significant effect in those without lifetime depression)
–
–
268
4 Pharmacotherapy for Alcohol Dependence
studies report positive effects. The size and quality of these studies are insufficient to form the basis for positive conclusions about effectiveness. 4.6.5
Other Agents with Effect on the 5-HT System Studies based on pharmacological reduction of alcohol consumption (no Table) Naranjo et al. studied ritanserin, a central 5-HT2 antagonist in high consumers who did not have a DSM-III-R diagnosis on alcohol dependence or alcohol abuse [114]. The treatment lasted for 2 weeks and the results are not conclusive concerning changes in alcohol consumption. Studies with concurrent psychosocial treatment (see Table 4.4) Studies included 5-hydroxytryptophane (pre-stage to serotonin), buspirone (serotonin agonist 5-HT1A), ritanserin (5-HT2-antagonist), ondasetron (5-HT3-antagonist), and tianeptine (tricyclic antidepressant with serotonin influence). In none of the studies were any differences observed between active substance and placebo. The ritanserin studies included 916 patients and the buspirone studies 104. Note that the buspirone studies including patients with comorbid anxiety conditions are analyzed separately in Table 4.9. In one ondasetron study [148], an effect is reported in those with the lowest consumption and only at a low dose. In the other study [62], the ITT analysis is probably nonsignificant. In those with early onset, low doses are related to better outcome than placebo. An unpublished study which compared buspirone and acamprosate, and which was sponsored by the buspirone manufacturer, has not been presented in scientific conferences. Therefore, it is considered to be a negative study as regards a buspirone effect. Conclusion Agents other than the SSRI agents with an effect on the 5-HT system have no documented effect in treating alcohol dependence without psychiatric comorbidity. 4.6.6
Acamprosate (see Table 4.5)
All published studies have been performed in Europe. Similar protocols were used in most of the studies. The outcome measures have been the number of totally abstinent individuals and the number of abstinent days during treatment. The heavy drinking rate (maximum 5 drinks/day) was not reported, with one exception, i.e., Tempesta et al. [154]. The rate of completely sober patients is shown in the table. Sixteen studies, involving 4158 patients, are presented. In 9 studies, significant differences in the ITT analysis are reported, and in all but two studies there are positive tendencies in different variables.
4.6 Results
The study by Chicks et al. differs from the others in that only 64% of the patients are sober on day one (in other studies 100%) [27]. In Gual’s study [51], treatment was initiated without previous detoxification, in contrast to the other studies. A Swedish study of 40 patients by Borg has not been presented at scientific meetings, but shows no difference between active substance and placebo [16]. A large American study by Mason et al. has been presented at scientific meetings [95]. The ITT analysis shows a significant effect from acamprosate. In a Dutch study, patients treated with acamprosate were randomized into three groups: regular medical visits, medical visits + cognitive behavioral therapy, and medical visit + brief intervention [164]. No differences in effect were observed. Meta-analysis (see Figure 4.1) Since most of the studies have a similar design, it is possible to perform a metaanalysis. Lhuitre et al. and Gerra et al. have been excluded because of lack of usable data [47, 87]. Data are also lacking from Borg’s study [13]. The other studies have been included. Figure 4.1 presents the size of the effect, and Figure 4.2 presents odds ratios. These measures basically show the same thing. The effect size is shown so that a direct comparison can be made with other meta-analyses in the SBU report. The odds ratios are shown so that a direct comparison can be made with Cochrane analyses in other areas. The effect size, d, was 0.26 (CI 0.20, 0.32). The heterogeneity test was negative. The overall odds ratio was 1.93 (CI 1.64, 2.28). The heterogeneity test was negative. Conclusion Acamprosate is extensively documented. Confirmed effects exist concerning increased sobriety (presented in the overview) and more abstinent days (not presented in the overview). 4.6.7
Naltrexone and Nalmefene (see Table 4.6)
The table shows the rate of return to heavy drinking and the number of heavy drinking days, but not the number of abstinent individuals. Heavy drinking is defined as more than five drinks for men (four for women) at the same occasion of consumption. The reason for using this outcome is that it has been the primary outcome in most studies. Of the 21 published studies (N=2253) presented in Table 4.6, 13 (N=2021) included more than 50 outpatient alcoholics. Eight of these (N=870) showed positive effects in the ITT analysis, 2 (N=225) only in the completers’ analysis, and 3 (N=926) were negative. The unpublished studies (N=471) included Gastpar (Germany, 151, N=162), Balldin (Sweden, 11, N=120), Rybakowski (Poland, 144, N=80) and Auriacombe (France, 8, N=109). Only Balldin reported a positive effect.
269
270
4 Pharmacotherapy for Alcohol Dependence Table 4.4. Other agents with effects on 5-HT system + psychosocial treatment. Study
Number of patients
Agent
Study duration
Treatment
52 w
Aftercare
Non manual-based treatment George [43] (1992)
41
5-hydroxytryptophane + Carbidopa 40 mg Levodopa + Carbidopa
Malec [90] (1996)
57
Buspirone 40 mg
12 w
Optional different alternatives 37% participated
George [45] (1999)
49
Buspirone 30 mg
52 w
Aftercare
Sellers [148] (1994)
86
Ondansetron 0.25 mg Ondansetron 2.0 mg
6w
Brief intervention once/week
Favre [34] (1997)
342
Tianeptine 37.5 mg
39 w
–
1. Ritanserin 2.5 mg 2. Ritanserin 5.0 mg 3. Ritanserin 10 mg
26 w
Supportive therapy
Wiesbeck [159] 493 (1999)
4.6 Results
271
Attrition
ITT
Completers
Correct identification
Quality score
5-HT 80% L-dopa 80% Placebo 87%
–
Completely sober: 5-HT 38% L-dopa 25% Placebo 18% (ns)
–
28
Buspirone 43% Placebo 31%
No significant differences
Completely sober: Buspirone 13% Placebo 15% (ns)
Buspirone 75% Placebo 41%
30
80%
Completely sober 20% No differences between the groups
No differences between the groups
–
25
Ondansetron 0.25 18% Ondansetron 2.0 14% Placebo 21%
–
Drinks/Drinking day: Ond 0.25 –1.9 Ond 2.0 –1.2 Placebo –1.3 (ns)
–
31
Tianeptine 66% Placebo 55%
Completely sober: Tianeptine 30% Placebo 26% (ns)
Completely sober: Tianeptine 50% Placebo 56% (ns)
–
27 (29)
1. 43% 2. 50% 3. 47% Placebo 42%
Completely sober: 1. 43% 2. 51% 3. 47% Placebo 41% (ns)
–
–
27 (29)
Table continues on next page
272
4 Pharmacotherapy for Alcohol Dependence Table 4.4. (cont.) Study
Number of patients
Agent
Study duration
Treatment
Manual-based treatment Fawcett [37] (2000)
108
Buspirone ~0.4 mg/kg
26 w
Supportive intervention
Johnson [61] (1996)
423
Ritanserin 2.5 mg Ritanserin 5.0 mg
11 w
CBT manual
Johnson [62] (2000)
271
1. Ondansetron 1mg/kg 2. Ondansetron 4 mg/kg 3. Ondansetron 16 mg/kg
11 w
CBT manual
4.6 Results
273
Attrition
ITT
Completers
Correct identification
Quality score
Buspirone 73% Placebo 62%
–
% heavy drinking Buspirone 0.25±0.45 Placebo 0.39±1.0
–
–
Ritanserin 2.5 41% Ritanserin 5.0 38% Placebo 36%
–
∆ Alcohol consumption days/w: Rit 2.5 –0.8±1.2 Rit 5.0 –1.0±1.2 Placebo –0.9±1.3 (ns)
–
30 (32)
1. 48% 2. 39% 3. 44% Placebo 36%
Total no report Early onset 2, 1, 3>placebo Late onset placebo>1
–
–
29
274
4 Pharmacotherapy for Alcohol Dependence Table 4.5. Acamprosate. Study
Number of patients
Agent
Study duration
Treatment
Non manual-based treatment Lhuintre [86] (1985)
85
Acamprosate 1000–2250 mg
12 w
Medical visit once/month
Lhuintre [87] (1990)
569
Acamprosate 1330 mg
12 w
Medical visit once/month Psychotherapy allowed
Gerra [47] (1992)
28
Acamprosate 1333 mg
3x4w crossover design
Group meeting every week
Pelc [125] (1992)
102
Acamprosate 2000 mg
26 w
–
Ladewig [77] (1993)
62
Acamprosate 2000 mg
24 w
Similar psychosocial treatment
Paille [123] (1995)
538
Acamprosate 1333 mg 2000 mg
52 w
Medical visit once/month 0–6 months, once every other month 7–12 months + psychotherapy when required
4.6 Results
275
Attrition
ITT
Completers
Correct identification
Quality score
Acamp 21% Placebo 16%
Completely sober: Acamp 54% Placebo 29% (p<0.05)
Completely sober: Acamp 61% Placebo 32% (p<0.02)
–
24 (26)
Acamp 37% Placebo 36%
–
Improvement (overall score): Acamp 1.35±1.86 Placebo 0.98±1.98 (p<0.1)
–
26 (28)
Not stated
–
Alcohol consumption days: Acamp from 11.1±0.9 to 4.4±0.6 (p<0.05) Placebo not stated Concerns non-familial alcoholism only
–
20
Acamp 34% Placebo 79%
Completely sober: Acamp 24% Placebo 4% (p<0.05)
–
–
24 (26)
35%
Completely sober: Acamp 38% Placebo 17% (ns)
–
–
23 (25)
Acamp 2.0 48% Acamp 1.33 55% Placebo 65%
Completely sober: Acamp 2.0 19.1% Acamp 1.33 18.1% Placebo 11.3% (p<0.1)
–
–
27 (29)
Table continues on next page
276
4 Pharmacotherapy for Alcohol Dependence Table 4.5. (cont.) Study
Number of patients
Agent
Study duration
Treatment
Roussaux [140] (1996)
127
Acamprosate 2000 mg
12 w
Ind. + group + family when required
Whitworth [158] (1996)
448
Acamprosate 2000 mg (adjusted for weight)
52 w
Similar psychosocial treatment
Sass [145] (1996)
272
Acamprosate 2000 mg (adjusted for weight)
48 w
Treatment as usual once/w for 8 w, then group once/2 w
Poldrugo [132] 246 (1997)
Acamprosate 2000 mg (adjusted for weight)
26 w
Group, family, individual counseling
Geerlings [46] (1997)
262
Acamprosate 2000 mg
24 w
Standard treatment
Pelc [126] (1997)
188
Acamprosate 1. 1333 mg 2. 2000 mg
12 w
Supportive therapy
Barrias [12] (1997)
302
Acamprosate 2000 mg
52 w
Supportive therapy
Besson [13] (1998)
118
Acamprosate 2000 mg (adjusted for weight) (stratified for disulfiram)
52 w
Psychosocial treatment
4.6 Results
277
Attrition
ITT
Completers
Correct identification
Quality score
Acamp 30% Placebo 28%
–
Completely sober: Acamp 29% Placebo 33% (ns)
–
25 (27)
Acamp 58% Placebo 62%
Completely sober: Acamp 18% Placebo 7% (p=0.007)
Completely sober: Acamp 44% Placebo 19% (p=0.001)
–
30 (32)
Acamp 41% Placebo 60%
Completely sober: Acamp 45% Placebo 25% (p<0.005)
–
31 (33)
Acamp 47% Placebo 62%
Completely sober: Acamp 41% Placebo 21% (p=0.0004)
Completely sober: Acamp 77% Placebo 54% (p=0.005)
–
30 (32)
Acamp 59% Placebo 69%
Completely sober: Acamp 25% Placebo 13% (p<0.05)
Completely sober: Acamp 62% Placebo 43% (ns)
–
27 (29)
1. Acamp 30% 2. Acamp 32% Placebo 48%
Completely sober: 1. Acamp 44% 2. Acamp 51% Placebo 26% (p<0.05)
Completely sober: 1. Acamp 41% 2. Acamp 41% Placebo 15% (p<0.001)
–
30 (32)
Acamp 43% Placebo 45%
Completely sober: Acamp 39% Placebo 26% (p<0.005)
–
–
26 (28)
Acamp 65% Placebo 65%
Completely sober: Acamp 25% Placebo 5% (p<0.005)
Completely sober: Acamp 74% Placebo 42% (ns)
–
28 (30)
Table continues on next page
278
4 Pharmacotherapy for Alcohol Dependence Table 4.5. (cont.) Study
Number of patients
Agent
Study duration
Treatment
Tempesta [154] (2000)
330
Acamprosate 2000 mg
26 w
Individual behavioral therapy
Chick [27] (2000)
581
Acamprosate 2000 mg
26 w
Supportive therapy
Gual [51] (2001)
288
Acamprosate 2000 mg
26 w
Supportive therapy
4.6 Results
279
Attrition
ITT
Completers
Correct identification
Quality score
Acamp 34% Placebo 36%
Completely sober: Acamp 58% Placebo 45% (p<0.005)
Completely sober: Acamp 77% Placebo 61% (p<0.005)
–
29 (31)
Acamp 65% Placebo 65%
Completely sober: Acamp 12% Placebo 11% (ns)
–
–
27 (29)
Acamp 35% Placebo 39%
Completely sober: Acamp 35% Placebo 26% (ns)
–
–
–
280
4 Pharmacotherapy for Alcohol Dependence
Favors placebo
Favors acamprosate
Figure 4.1. Acamprosate (odds ratio). indicates the 95% confidence interval (CI). A filled square denotes the effect size of an A filled diamond denotes the summary effect individual study. The size of the square is relat- of a meta-analysis. ed to the size of the study. The horizontal line
Meta-analysis At the time of publication of the Swedish version, more than 50% of the studies had not yet been published. There were insufficient data for these studies to be included in a meta-analysis. Three studies, O’Malley et al. [119], Balldin et al. [10], and Heinälä et al. [54] had included a second randomization for psychosocial treatment (cognitive behavior therapy, CBT vs supportive therapy), and all three found a positive effect in the Naltrexone/CBT group, while only O’Malley reported a positive effect in the Naltrexone/supportive therapy group (Table 4.7, Figure 3). Therefore, the other studies were grouped according to type of psychosocial treatment (Table 4.8, Figure 4). The Monti study used the cue-exposure technique, and the Monterosso study used the BRENDA method, which included CBT components. Both were included in the cognitive coping skill method. The Krystal study used 12-step therapy and the Morris study used an education program. They were both included in the supportive group. In the cognitive coping skills group, 6 out of 7 studies (N=652/776) reported effects in ITT or completers’ analysis, while in the supportive group only 2 out of 7 studies (N=218/1371) reported positive effects. Differences between study outcomes were significant (p=0.049, Fisher’s exact test). This possibly indicates that cognitive behavioral therapy ought to be given together with naltrexone/nalmefene to achieve an effect. However, an alternative
4.6 Results
Favors placebo
281
Favors acamprosate
Figure 4.2. Acamprosate (effect size). indicates the 95% confidence interval (CI). A filled square denotes the effect size of an A filled diamond denotes the summary effect individual study. The size of the square is relat- of a meta-analysis. ed to the size of the study. The horizontal line
interpretation is that a well- structured (manual-based) treatment is required, but that alternatives other than CBT are feasible as motivation-enhancing treatment. Combining ondansetrone and naltrexone Johnson et al. [60] studied the combination of ondansetrone and naltrexone versus placebo in 20 alcoholics with better outcome for those with the combined treatment. Aversive agents and naltrexone Two small studies [24, 78] (N=18 and 30), respectively, have compared disulfiram with naltrexone or added naltrexone to aversive drugs. The results are inconclusive. Acamprosate and naltrexone: Meta-analyses Three meta-analyses were published after the release of the Swedish version of the SBU report (Kranzler and van Kirk 2001 [74], Streeton and Whelan 2001 [153], and Srisurapanont and Jarusuraisin 2002 [152]). Kranzler and van Kirk [74] included 8 studies on naltrexone (N=781) and 11 studies on acamprosate (N=3204). The review was positive for both drugs. Differences in abstinence rates between active drug and placebo were +12% (CI, 5%, 20%) for naltrexone and +11% (CI, 8%, 15%) for acamprosate. Differences in relapse rate for naltrexone were –16% (CI, –21%, –8%).
282
4 Pharmacotherapy for Alcohol Dependence Table 4.6. Naltrexone and nalmefene. Study
Number of patients
Agent
Study duration
Treatment
1 month, day patient then twice/w group therapy
Non manual-based treatment Volpicelli [165, 166] (1992, 1995) O’Brien [118] (1996)
70
Naltrexone 50 mg
12 w
Mason [92] (1994)
21
1. Nalmefene 40 mg 2. Nalmefene 10 mg
12 w
Knox & Donovan [67] (1999)
63
Naltrexone 50 mg
3w inpatient care
Inpatient care
Chick [26] (2000)
175
Naltrexone 50 mg
12 w
Treatment as usual
Morris [103] (2001)
121
Naltrexone 50 mg
12 w
Education support group
Latt [79] (2001)
107
Naltrexone 50 mg
12 w
Advice by physician
–
4.6 Results
283
Attrition
ITT
Completers
Correct identification
Quality score
Naltrexone 31% Placebo 40%
Abuse free: Naltrexone 77% Placebo 46% (p<0.01)
–
–
26
1. 57% 2. 57% Placebo 71%
Abuse free: 1. 71% 2. 0% Placebo 33% (p<0.05)
–
–
27
Not reported
Craving no differences Followup no differences
–
–
27
Naltrexone 59% Placebo 58%
No differences
Consumption days: Naltrexone 11.8 Placebo 19.7 (p<0.10)
–
27
Naltrexone 31% Placebo 41%
Time to relapse Naltrexone 6.7 w Placebo 4.2 w (p<0.001)
Relapse rate Naltrexone 19/38 Placebo 26/33
–
–
–
No relapse Naltrexone 66% Placebo 47% (p<0.047)
–
–
–
Table continues on next page
284
4 Pharmacotherapy for Alcohol Dependence Table 4.6. (cont.) Study
Number of patients
Agent
Study duration
Treatment
Naltrexone 50 mg
12 w
Randomized: 1. Coping skill 2. Support
Oslin [122] (1997)
44 Naltrexone 50 mg (>50 years)
12 w
Group therapy once/week Case manager
Volpicelli [168] (1997)
97
Naltrexone 50 mg
12 w
CBT twice/w, then once/w
Kranzler [72] (1998)
20
Naltrexone depot 206 mg (15/20)
4w
Coping skill
Hersh [55] (1998)
64 Naltrexone 50 mg alcoholand cocaine dependent
8w
Relapse prevention
Anton [7] (1999)
131
12 w
CBT
Manual-based treatment O’Malley [119, 121] (1992, 1996)
104
Jaffe [56] (1996)
Naltrexone 50 mg
4.6 Results
285
Attrition
ITT
Completers
Correct identification
Quality score
Naltrexone 1. 34% 2. 22% Placebo 1. 40% 2. 41%
Abuse free: Naltrexone 1. 66% 2. 57% Placebo 1. 20% 2. ~20% (p=0.007)
Drinks/drinking day: Naltrexone 1. 3.5±1.2 (SE) 2. 6.4±1.6 Placebo 1. 8.6±1.3 2. 5.3±1.3 (p<0.005)
–
32
Naltrexone 33% Placebo 43%
Abuse free: Naltrexone 86% Placebo 65% (ns)
–
–
29
Naltrexone 27% Placebo 27%
Abuse free: Naltrexone 65% Placebo 47% (p=0.07)
Abuse free: Naltrexone 74% Placebo 47% (p=0.02)
–
30
0%
Abuse days: Naltr 3.8±10.7% Plac 5.3±8.4% (p=0.03)
–
Naltrexone 47% Placebo 20%
30
Naltrexone 35% Placebo 42%
Time to alcohol abuse: Naltrexone 3.2±2.9 w Placebo 4.0±2.9 w
–
–
30
Naltrexone 13% Placebo 22%
Abuse free: Naltrexone 62% Placebo 40% (p<0.02)
–
–
32
Table continues on next page
286
4 Pharmacotherapy for Alcohol Dependence Table 4.6. (cont.) Study
Number of patients
Agent
Study duration
Treatment
Mason [94] (1999)
105
1. Nalmefene 20 mg 2. Nalmefene 80 mg
12 w
CBT once/w
Heinälä [54] (2001)
121
Naltrexone 50 mg
12 + 20 w (targeted)
Randomized: 1. CBT 2. Support
Kranzler [73] (2001)
124
Naltrexone 50 mg
11 w
Coping skill training
Krystal [76] (2001)
627
1. Naltrexone 50 mg 52 w 2. Naltrexone 50 mg 13 w + Placebo 39 w
52 w
12-step facilitation counseling
Monterosso [100] (2001)
183
Naltrexone 100 mg
(36 w) 12 w report
Psychosocial (BRENDA)
Monti [101] (2001)
128
Naltrexone 50 mg (during aftercare)
12 w
2 w partial hospital Cue exp v Education (randomized) 12 w aftercare
Balldin [11] in press
118
Naltrexone 50 mg
24 w
Randomized: 1. CBT 2. Treatment as usual
4.6 Results
287
Attrition
ITT
Completers
Correct identification
Quality score
Nalmefene 36% Placebo 34%
Abuse free: Nalmefene 63% Placebo 41% (p=0.02)
Abuse free: Nalmefene 62% Placebo 39% (p=0.04)
No significant differences
32
12 w 17% 32 w 31% No differences between the groups
Abuse free: N 1. 27% 2. 7% P 1. 3% 2. 12% (p<0.05)
–
–
–
Naltrexone 41% Placebo 21%
Heavy drinking days: Naltrexone 12% Placebo 8%
–
Naltrexone 60% Placebo 41%
–
27%
Drinking days: 3 m 12 m 1+2 11% 1.15% Plac. 14% 2.19% (ns) Plac. 18% (ns)
–
–
–
18%
Heavy drinking days: Naltrexone 5% Placebo 8.9% p<0.05
–
–
–
Relapse Naltrexone 28% Placebo 33% (ns)
Heavy drinking days: Naltrexone 0.5% Placebo 1.7% p <0.05
Pat.
70%
Naltrexone: 1. 16% 2. 23% Placebo 1. 23% 2. 34%
% abuse days: N 1. 21±25 2. 34±24 P 1. 38±30 2. 39±32 (p<0.05)
N N 44% P 20%
P 13% 18%
Don’t know 44% 63% Not published
288
4 Pharmacotherapy for Alcohol Dependence Table 4.7. Randomized Naltrexone/Placebo + Randomized CBT/ Supportive therapy studies (N=343).
O’Malley 1992 Heinälä 2001 Balldin (in press)
CBT
Supportive
+ + +
+ 0 0 Efficacy: ITT + Completers (+)
Table 4.8. Randomized Naltrexone and Nalmefene vs Placebo (>50 patients) by CBT/similar techniques or supportive/12-step therapy.
CBT/Similar techniques (N=776) Volpicelli Volpicelli Anton Mason Kranzler Monti Monterosso
1992 1997 1997 1999 2000 2001 2001
Supportive/12 step therapy (N=1371) + (+) + + 0 (+) +
Chick Krystal Morris Latt Gastpar Rybakowski Auriacombe
2000 2001 2001 2002 2003 – –
0 0 + + 0 0 0
Efficacy: ITT + Completers (+)
Streeton and Whelan [153] included 7 studies in their analysis. Their conclusions about efficacy were positive, and the results were very similar compared with the previous meta-analysis. Differences in abstinence rates were +10% (CI 4%, 16%) and in the relapse rate –14% (CI –23%, –5%). Srisurapanont and Jarusuraisin [152] were included in a Cochrane review of 19 studies. They concluded that naltrexone was effective in short-term treatment. Figures for the differences in abstinence rates were +8% (RR 0.88, CI 0.80, 0.98). Acamprosate versus naltrexone One published study compared naltrexone to acamprosate in a randomized but nonblinded design. Rubio et al. [143] studied 157 alcoholics and reported that 41% in the naltrexone group versus 17% in the acamprosate group (p<0.001) had reported no relapse after 1 year. Kiefer et al. [65] reported on 160 alcoholics, comparing placebo, acamprosate, naltrexone, and the combination of acamprosate and naltrexone. All groups with active drugs had a significantly better outcome than with placebo. The combination of naltrexone and acamprosate also had a significantly better outcome than the acamprosate only group.
4.6 Results
Conclusions Naltrexone/nalmefene increases the number of nonheavy drinking patients or the proportion of nonheavy drinking days. To be effective, treatment requires a wellstructured, psychosocial treatment like cognitive behavioral therapy. Direct comparisons between naltrexone and acamprosate are still too few to enable valid conclusions on the relative effects of the two drugs. 4.6.8
Other Agents Gamma-hydroxybutyric acid Gallimberti et al. studied the effect of gamma-hydroxybutyric acid (GHB) in 82 alcoholics during 3 months of treatment [41]. Thirteen percent left the treatment and 27% in the GHB group and 5% in the placebo group were abstinent (ITT analysis, p<0.05), and 63% and 20%, respectively, did not return to heavy drinking (ITT analysis p<0.001). Carbamazepine Mueller et al. studied the effect of carbamazepine in 29 patients during 12 months of treatment [104]. Only 1 in 13 patients took carbamazepine during the entire 12-month period, while 8 in 16 took placebo. Nevertheless, the patients treated with carbamazepine had longer times until the first day of abuse than the placebo group (p=0.04).
Enalapril Naranjo et al. studied enalapril (angiotensin-converting enzyme inhibitor) in 42 alcoholics, with negative results [110]. Atenolol Gottlieb et al. studied atenolol (beta blocker) in 100 patients for 1 year [50]. Fifteen patients were completely sober (7 in the atenolol group and 8 in the placebo group). Thus, there were no differences between the groups. Conclusions The study with gamma-hydroxybutyric acid shows good results. The agent, however, is classified as a narcotic in some countries. Carbamazepine shows initially good results, but only one patient completed the treatment. The side effects probably limit the use of the agent. 4.6.9
Lithium (see Table 4.9)
In early studies, lithium was reported to have an effect on patients who also suffered from depression. The studies had high attrition, and the results were based on
289
290
4 Pharmacotherapy for Alcohol Dependence Table 4.9. Lithium. Study
Number of patients
Agent
Study duration
Treatment
Kline [66] (1974)
73 (non-psychotic depression)
Lithium 0.6–1.2 mM/L Cross-over design
48–96 w
–
Merry [97] (1976)
71 (34 depressed according to Becks Inventory for depression)
Lithium 0.8–1.2 mM/L
ca 52 w
Lithium clinic every 6 w
Pond [133] (1981)
47 (9 depressed according to MMPI)
Lithium 0.6–1.2 mEq Cross-over design
26 w
–
Fawcett [35, 36] (1984, 1987) Clark & Fawcett [28] (1989) Pisani [131] (1993)
132 (2/3 major depression)
Lithium 0.7–1.2
78 w
–
de la Fuente [30] (1989)
53 (47% probable depression)
Lithium 0.6–1.2
26 w
–
Dorus [32] (1989)
457 (171 lifetime major depression or dysthymia)
Lithium 0.6–1.2
52 w
Individual and group treatment
Fawcett [37] (2000)
108
Lithium 0.4–1.0
26 w
Supportive intervention
Placebo studies
4.6 Results
291
Attrition
ITT
Completers
Correct identification
Quality score
59%
–
Severe relapses: Lithium 43.5% Placebo 73.5% Depression score: Lithium = Placebo (p<0.01)
–
20
47%
–
Number of heavy drinking days Depression group: Lithium 0.7±0.4 (SE) Placebo 5.1±2.2 (SE) (p<0.05)
–
21
60%
–
Alcoholconsumption: Lithium = Placebo
–
19
Lithium 31% Placebo 24%
Completely sober: Lithium 34% Placebo 27% (ns)
Completely sober: Lithium <0.04 28% (n=18) Placebo 36% (n=42) Lithium >0.4 57% (n=28) (p<0.01 vs. other)
–
29
Lithium 50% Placebo 48%
Completely sober: Lithium 42% Placebo 29% (ns)
Completely sober: Lithium 71% Placebo 54% (ns)
–
26
Lithium 43% Placebo 34%
Completely sober: Lithium 36% Placebo 31% (ns)
Completely sober: Lithium 35% Placebo 29% (ns)
–
32 (34)
Lithium 54% Placebo 62%
% heavy drinking days Lithium 0.64±1.3 Placebo 0.39±1.0 Table continues on next page
292
4 Pharmacotherapy for Alcohol Dependence Table 4.9. (cont.) Study
Number of patients
Agent
Study duration
Treatment
Lithium Chlordiazepoxide 30 mg
26 w
–
Comparison with other agent Powell [135] (1986)
100 (20 major depression, 9 mania)
4.6 Results
293
Attrition
ITT
Completers
Correct identification
Quality score
Lithium 48% Chlordia 56%
Completely sober: Lithium 12% Chlordia 23% (ns)
Completely sober: Lithium 23% Chlordia 55% (p<0.1)
–
26
294
4 Pharmacotherapy for Alcohol Dependence
completer analyses. Later studies have not been able to confirm any effect. Clark and Fawcett, de la Fuente et al., and Dorus et al. found no differences in their ITT analyses [28, 30, 32]. Clark and Fawcett reported that completers with lithium above 0.4 had a better alcohol course than the rest. None of the studies report improvement in depression symptoms. Powell et al. [135] compared lithium with chlordiazepoxide. They found a nonsignificant tendency that patients on chlordiazepoxide improved in a higher frequency. Conclusion There is no evidence that lithium has any effect on alcohol-dependent patients who do not also have concurrent depression.
4.7
Comorbidity
Studies of alcohol-dependent patients having other concurrent mental disorders have been analyzed separately. Three groups will be analyzed; depression, social phobia, and anxiety. 4.7.1
Anti-Depressive Treatment and Psychiatric Comorbidity (Depression) (Table 4.10)
Eight studies are presented in the table. One study was excluded because of technical deficiencies [75]. Six out of seven studies show effects on depression in ITT analyses. The results were not related to whether the depression was primary or secondary or whether classic tricyclic antidepressants or SSRI agents had been used. Only one study reported an observed effect on alcohol consumption. SSRI and social phobia In 2001, Randall et al. [137] described the effect of paroxetine on social phobia in 15 patients, reporting a significant positive effect on the psychiatric symptoms. Buspirone and psychiatric comorbidity (anxiety) (see Table 4.11) Four studies are presented in the table. In three studies, an effect on the anxiety condition is found and in one an effect on the patient’s alcohol dependence. Conclusion Antidepressive treatment for depression in alcohol-dependent patients has an effect on the depressive condition. In the same manner, anxiety treatment has an effect on the anxiety condition. There is no confirmed evidence that these treatments influence the patient’s alcohol dependence.
4.8 Discussion
4.8
Discussion 4.8.1
Acamprosate and Naltrexone
During the past decade, two drugs have been developed for treating alcohol dependence, i.e., acamprosate and naltrexone/nalmefene. Clinical studies are beginning to provide an increasingly clear profile for each of the agents. Treatment with acamprosate yields more total abstinence in patients and more abstinent days, while treatment with naltrexone yields more patients with no return to heavy drinking and fewer days with heavy drinking. The acamprosate studies usually have not presented data on heavy drinking, and hence these differences are not necessarily real. Tempesta et al. report significantly lower levels of consumption during drinking days with acamprosate than with placebo [154]. Modes of action It is unknown how acamprosate yields increased total abstinence rates. Despite the large number of studies, there are surprisingly few observations on how the drug acts. Nor are there many reports on which patients are suitable candidates for treatment. One observation is that types 1 and 2, based on Lesch’s typology, respond better to treatment than types 3 and 4 [81]. Knowledge about naltrexone is better. The experience of intoxication is not as strong, and it is easier to stop after a couple of drinks [121, 167]. Patients with a strong craving and a strong family history of alcoholism (100) respond better [56, 166]. Doses and treatment duration The doses used have usually been 2000 mg/day for acamprosate and 50 mg/day for naltrexone. In later studies, higher doses have been used at times. Treatment time has been 6 or 12 months for acamprosate. After 12 months, the change achieved seems to be constant [123, 145]. Månsson [105] showed that after treatment for 6 months, the effects were stable during the following 6 months in contrast to treatment for 3 months [6, 120]. Krystal [76] reported no effect during 3 and 12 months, respectively, compared with placebo. Unpublished data from the Monterosso [100] study indicate better effects with 9 months than with 3 months of treatment. 4.8.2
Aversive Agents
Only one placebo-controlled study has been conducted of disulfiram under supervision. This study showed positive results. This, together with several studies which showed an improved effect from supervised disulfiram treatment compared to unsupervised treatment, indicates that disulfiram still has an important place in treatment.
295
296
4 Pharmacotherapy for Alcohol Dependence Table 4.10. Study
Antidepressive treatment + psychiatric comorbidity (depression). Number of patients
Agent
Study duration
Treatment
Non-manual-based treatment Altamura [4] (1990)
30 Dysthymia
Viloxazine 400 mg
12 w
4 w inpatient care 8 w outpatient care
Nunes [117] (1993)
26 Primary dep/ dysthymia
Imipramine ~150 mg (after 12 w with Imi with positive effect) Exposure study
26 w
Type of treatment not stated
Powell [136] (1995)
216 Affective/ anxiety condition = 88 ASP = 65
Nortriptyline ~150 mg Bromocriptine 7.5 mg
6 months
Not stated
71 Actual secondary depression = 28
Desipramine ~200 mg
26 w
Encouraged to participate AA/Psychosocial treatment
Penick [128] (1996)
Mason [93] (1996)
4.8 Discussion
297
Attrition
ITT
Completers
Correct identification
Quality score
Viloxazine 7% Placebo 13%
Depression score: Viloxazine
–
–
23
12%
–
Relapse: (Alc + Dep) Imipramine 31% Placebo 70% (p<0.07)
–
25
(52–55% in the different groups)
–
Completely sober ASP: Nortr 64% (++ concurrent aff disorder) Brom 33% Plac 11% (p<0.01) Other diagnostic groups no differences
–
26 (28)
Dep + Des 67% Dep + Plac 85% Not depr + Des 86% Not depr + Plac 71%
Dep Des
(Analysis 51/71) Dep effect: Dep + Des 82% Plac 22% (p<0.02) No relapse: Dep + Des 92% Dep + Plac 60% No depr + Des 86% No depr + Plac 73% (p<0.03)
–
28
Table continues on next page
298
4 Pharmacotherapy for Alcohol Dependence Table 4.10.
(cont.)
Study
Number of patients
Agent
Study duration
Treatment
McGrath [96] (1996)
69 Prim major dep/ dystymia
Imipramine ~300 mg
12 w
CBT once/week
Cornelius [29] (1997)
51 Primary depression
Fluoxetine 20 mg (40 mg)
12 w
Treatment as usual once/week
Roy [141] (1998)
36 Depression
Sertraline 100 mg
6w
–
Roy-Byrne [142] (2000)
64 Major depression
Nefazodone 500 mg
12 w
Cognitive-behavior skills training
4.8 Discussion
299
Attrition
ITT
Completers
Correct identification
Quality score
49%
Improvement Dep + Alc: Imi 42% Plac 18% (p<0.05) dep only (p<0.005) alc only (ns)
(Analysis >4 w) Dep + Alc improvement: Imi 52% Plac 21% Consumption days: Imi 31%±33% Plac 28%±33%
–
32
10%
Time for first high cons: Flu 8.0 w±4.8 Plac 4.7 w±4.2 (p<0.02) Completely sober: Flu 28% Plac 15% (ns) ∆ Ham-D-24: Flu 6.0±9.6 Plac 2.0±13.3 (p<0.05)
–
–
28
Ser 44% Placebo 72%
Dep much improved: Ser 50% Placebo 60% p<0.001 Completely sober: Ser 100% Plac 94% (ns)
–
–
29
Nefazodone 38% Placebo 66%
Alcohol consumption: Nef=Placebo Major depression: HAM-D Nef
–
–
31
300
4 Pharmacotherapy for Alcohol Dependence Table 4.11. Study
Buspirone and psychiatric comorbidity (anxiety). Number of patients
Agent
Study duration
Treatment
Buspirone 20 mg
8w
Outpatient not further specified
Tollefson [156] 51 (1991) GAD
Buspirone 42 mg (mean value max 60 mg)
24 w
Support 11 visits
Malcolm [89] (1992)
Buspirone 45–60 mg
24 w
Aftercare Encouraged AA once/w 12 w once/2 w 12 w
Buspirone 52 mg (mean value max 60 mg)
12 w
CBT once/w
Non-manual-based treatment Bruno [20] (1989)
50 Anxiety state 38
67 GAD
Manual-based treatment Kranzler [69] (1994)
61 Anxiety state
4.8 Discussion
301
Attrition
ITT
Completers
Correct identification
Quality score
Buspirone 20% Placebo 64%
–
Busp 3.9 drinks/day Plac 4.3 drinks/day (ns) Ham-A: Busp –6.2 Plac –2.9 (p<0.006)
–
23
Buspirone 61% Placebo 84%
–
Alc data cannot be interpreted Ham-A <15: Busp 73% Plac 30% (p=0.015)
–
24
Buspirone 70% Placebo 71%
–
Anxiety severe: Busp 62% Plac 56% (ns) Completely sober months: Busp 52% Plac 55% (ns)
–
31
Buspirone 16% Placebo 47%
Time to first high consumption episode: Busp >Plac (p=0.03) Drinking days: Busp 3.6±11.0 Plac 9.6±13.3 (p<0.1)
Ham-A: Busp 5.8±5.4 Plac 8.3±5.9 (p<0.1)
–
31
302
4 Pharmacotherapy for Alcohol Dependence
4.8.3
Other Agents
Although individual studies are positive, the general picture is that no positive effects are achieved with these agents. 4.8.4
Treatment of Comorbid Conditions
The treatment of the comorbid condition and the treatment of the dependence condition are two separate tasks. Both conditions must be treated, often concurrently.
4.9
Conclusions
1. The effects of acamprosate are well documented. There is a confirmed effect concerning the increase in total abstinence (and number of abstinent days). 2. The naltrexone/nalmefene effects are well documented. There is a confirmed effect concerning no relapse to heavy drinking and the number of nonheavy drinking days. The treatment requires well-structured psychosocial treatment, e.g., cognitive behavioral therapy, to be effective. 3. Disulfiram requires supervised treatment to have an effect. The conclusions are based on 1 placebo controlled and 7 randomized studies of the distribution route. 4. In alcohol-dependent patients with concurrent depression/anxiety, antidepressants/buspirone have an effect on their psychiatric condition. There is no confirmed evidence that these treatments also influence alcohol dependence, but specific treatment focused on dependence is required. 5. Other pharmacological treatment principles have no confirmed effect on alcohol dependence. Treatment with SSRI agents has had an effect in some studies. Further studies are required before any confirmed conclusions can be drawn.
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1 Kolumnentitel
5
The Long-Term Course in Alcohol and Drug Dependence Mats Berglund
5.1
Introduction
The character of the long-term course in alcohol and drug dependence determines the design of a long-term treatment strategy. The terms “alcoholic career” or “drug addict career” can be found in some of the literature. With time, the consequences of abuse become increasingly severe and cause the abuser to decide to cease substance abuse. The main goal of treatment is to shorten the course and help the abuser to cease substance abuse as early as possible. Another option is to view dependence as a chronic condition, where the abuser falls in and out of substance abuse over a long period of time. Here, emphasis is placed on the duration of the condition, and the treatment design should aim at preventing relapse and prolonging abuse-free periods. Studies of “career” abuse and the chronic course are often based on those being treated for alcohol dependence. Hence, they are not representative of other persons with alcohol and drug dependence. Comorbidities, mainly in the form of psychiatric conditions and personality disorders, are clearly overrepresented among these individuals compared to those included in epidemiological studies. If epidemiological material based on cross-sectional studies is used as a point of departure, another picture often emerges where the abuser spontaneously ceases substance abuse after a few years. The strategic consequences of these data are different from those presented in clinical studies. The effects of shorter treatment interventions receive greater importance. Treatment studies which involve “milder” cases become more important in defining strategies which correspond to the findings in epidemiological studies. Often, the goal may be complete abstinence after a relatively short treatment intervention. A systematic review of the literature was conducted based on defined search terms and by examining previously published reviews and reference lists in various articles. In contrast to the other sections of the report, the aim in this section is not to present a complete analysis of the large volume of studies published. Rather, a short review based on very strict inclusion criteria is presented to gain
Treating Alcohol and Drug Abuse. Edited by M. Berglund, S. Thelander, E. Jonsson Copyright c 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 3-527-30682-X
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a perspective on the RCT findings presented in the other sections of the book.
5.2
Methods 5.2.1
Search Strategies
MEDLINE was used to search the literature published between 1966 and 1998 concerning longitudinal studies of alcohol and drug abuse. The terms “substance dependence” or “substance abuse” or “substance use disorders” were combined with “longitudinal studies” or “longitudinal” or “followup”. The search identified 349 studies. A complementary search was conducted for material published until April 2000, identifying 202 additional studies. The requirements on followup time were more stringent in the later search. 5.2.2
Inclusion Criteria
The following inclusion criteria were established for the different types of studies: A. Epidemiological studies (cross-sectional studies) (a) a minimum population of 20 000 individuals, (b) diagnosis of alcohol dependence or substance dependence, based on a structured interview technique, according to ICD-8 or more recent versions or DSMIII or more recent versions, and (c) information about previous and current dependence diagnoses. B. Longitudinal epidemiological/clinical studies (a) systematic diagnosis according to the ICD or DSM systems, (b) personal followup, and (c) at least 20 years of followup. 5.2.3
Search Results
No randomized studies that fulfilled the inclusion criteria were identified. The randomized study with the longest followup compares treatment results from behavioral therapy and psychiatric treatment for 1 and 2 years, respectively [19]. The inclusion criteria limited the review to eight published studies. Most of these studies have been reported in several different publications. This review reports only on the publications which can show core data on the issue in question.
5.3 Epidemiological Studies
5.3
Epidemiological Studies (Cross-Sectional Studies – see Table 5.1)
One study reviewed the importance of both the amount of consumed alcohol and the occurrence of current symptoms of alcohol dependence [2]. During 8 years, Dawson monitored 37 682 individuals who were at least 25 years old. Of these, 1733 (4.6%) were alcohol dependent. The prevalence of alcohol dependence was related to increased mortality, while high consumption without alcohol dependence was not. Low and moderate alcohol consumption was associated with reduced mortality compared to nonusers of alcohol. According to the definitions in the study, 49.5% did not drink alcohol during the past year. Less than half of the alcohol dependent subjects reported regular high consumption of alcohol during the past year. This study points to differences between high consumption and alcohol dependence. It is the pattern of drinking, not primarily the amount of alcohol, which predicts harmful consequences. The duration of alcohol dependence can be studied indirectly by interviewing individuals in the general population about the prevalence of current alcohol dependence and alcohol dependence at some point in life. These questions have been asked in large epidemiological studies, i.e., ECA (Epidemiologic Catchment Area study, according to DSM-III), NCS (National Comorbidity Survey, according to DSM-III-R), and NLAES (National Longitudinal Alcohol Epidemiologic Survey, according to DSM-IV) [6, 10, 14]. In total, 18 571, 8098, and 42 862 individuals, respectively, were interviewed. Of those consuming alcohol, 15% to 20% had at some time in life fulfilled the criteria for alcohol dependence (20% in the NLAES study, 15% in the NCS and ECA studies). Current dependence existed in 4.4% of the persons in the NLAES study and 7.2% in the NCS study. Equivalent data do not exist for the ECA study since the DSM-III criteria for alcohol dependence did not allow this comparison. Only the NLAES study will be included here, since it is the only study that interviewed more than 20 000 subjects [6]. In addition, NLAES involved everyone over 18 years of age, while NCS only included those between 18 and 55 years of age. The NLAES study, conducted in the United States during the early 1990s, noted a strong increase of alcohol dependence mainly among younger age groups. In the group aged 18 to 24 years, 44% of those consuming alcohol had at some time fulfilled the criteria for alcohol dependence. The rate decreased with increasing age: 33% in the group 25–34 years, 24% in the group 35–44 years, 22% in the group 45–54 years, and 11% in the group aged above 55 years. In the youngest group, the ratio between men and women was 1.4 while it was 2.3 in the eldest. However, of all who at some time had been alcohol dependent, only 23% of the men and 16% of the women had fulfilled the criteria for alcohol dependence during the past year. In the youngest age group, the figures are 42% and 28%, respectively, while the equivalent numbers among the oldest are 9% and 7%, respectively. Hence, every fourth man and every sixth woman who had previously been alcohol dependent still fulfilled the criteria.
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National Longitudinal Alcohol Epidemiologic Survey N=42 862 (Alcohol-dependent during past year 1877 [4.38 %])
Grant 1997 [6]
* Significant difference from reference group
National Health Interview Survey Alcohol Supplement N=37 682 (Alcohol–dependent during past year 1733 [4.6 %])
Population
Cross-Sectional Studies.
Dawson 2000 [2]
Table 5.1.
Cross-sectional current dependence in those who consumed alcohol and in relation to lifetime dependence
8 years Mortality
Duration
Total
18–24 25–34 35–44 45–54 55–
Age
11
23
Current dependence Men % %/lifetime 25 42 13 27 19 17 17 14 14 19
18
% 17 19 15 15 12
0.78* 0.86* 0.92 1.07
Sporadic (1–2 drinks/week) Moderate (1–2 drinks/day) High ( 3–4 drinks/day) Very high (7–8 drinks/day)
16
Women %/lifetime 28 15 14 10 17
1.20 1.32* 1.42 1.65*
Mortality No dependence Dependence
Completely sober Mortality=1
Results
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5.4 Longitudinal Clinical Trials
The NLAES study did not report the average duration of the dependence condition. However, the duration of the dependence for most subjects was probably less than 5 years. The equivalent data for dependence on narcotic agents at some time during life was 2.8% [7]. Dependence on cannabis is the most common, followed by drugs and cocaine. Numbers concerning ongoing abuse are not shown.
5.4
Longitudinal Clinical Trials 5.4.1
Long-Term Course in Alcohol Dependence
Vaillant has reported the long-term course in alcohol dependence in two epidemiologically defined groups [18]. The first group, Core City Sample, originally consisted of a control group in studies on juvenile delinquency [3, 4]. This group came from central Boston and is characterized by poor social conditions. A first followup study was made at 31 years of age, and the population has since been monitored from the age of 47 by personal followup studies every 5 years and questionnaires every second year until the age of 60 [17]. The second group, College Sample, originally consisted of 268 college students at Harvard University [18]. They were monitored from 17 to 22 years of age in a study of the normal development during these years. This group has also been studied from 47 years of age with personal followup studies every fifth year and with questionnaires every second year until the age of 70. Only men were studied. One third of the Core City group and 21% of the College group developed alcohol dependence at some time during life (alcohol dependence or alcohol abuse according to DSM-III, which is basically equivalent to alcohol dependence according to DSM-IV). The average age for the development of alcohol dependence was 29 years (±9.5 years) for the Core City group and 40 years (±9.9 years) for the College group. Patients with alcohol dependence have been monitored during 30 years in both the studies. The followup at 60 years (Core City group) and 70 years (College group) showed that 43% and 60%, respectively, of the alcoholdependent subjects were chronic abusers. Mortality in the group with alcohol dependence was significantly higher than that in the other members of in the original study group. At 60 years of age, mortality was 25% and 14%, respectively, in the Core City group, and 15% and 5%, respectively, in the College group. The studies by Vaillant are of major importance, since they are based on two well-defined groups of individuals. One was recruited from a metropolitan environment with social problems, the other among students at Harvard University [17]. Nevertheless, the numbers concerning those with chronic abuse are similar: 14% in the Core City group and 12% in the College group compared with the entire population.
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College sample N=55 (100% men) 21% of original population
Core City Sample N=150 (100% men) 33% of original population Lundby N=41 (100% men) Lifetime alcoholism 19% Psychiatric department, Lund (A) Best course N=60 20% (B) Early retirement N=32
Valliant 1996 [17]
Öjesjö 1982, 2000 [19–22]
Nordström, Berglund 1987, 2000 [12, 13]
Population
Longitudinal Studies, Alcohol.
Valliant 1996 [17]
Table 5.2.
40 years
40 years
30 years (mean value)
30 years (mean value)
Duration
15% (at 60 years of age) 40% (at 70 years of age) Others in initial population: 5% and 17%, respectively. General population: 14% and 40%, respectively
Mortality
Quit abuse 20 years (A) 67% (B) 25 %
Quit abuse All: 39% Living: 52%
40 years (A) 76%
Total abstinence, 37% 25% (at 60 years of age) Controlled drinking, 14% Others in initial population, 14% Reclassified to social drinking, 6% Others comparison group, see above Chronic abuse, 43%
Total abstinence: 19% Controlled drinking: 10% Reclassified to social drinking: 11.5% Chronic abuse: 59.5%
Results Course, including deceased
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5.5 Long-Term Course in Heroin Dependence
As part of the Lundby study, Öjesjö reported on the 40-year course in 41 men with alcohol dependence or alcohol abuse according to DSM-III [20–22]. In total, 39% had ceased abusing alcohol. In the surviving subjects, the corresponding figure was 52%. Most ceased abusing alcohol during their 30s or 40s. In a previous study, the lifetime risk for developing alcohol dependence or abuse was calculated in the same population [19]. This risk was 19% (for alcohol dependence alone the figure was 8.6%). Another Swedish study monitored the 20-year course in alcoholics who were initially hospitalized [12]. An interview study was performed with the 20% who demonstrated the best social course. These were compared with a control group consisting of age-matched early retirement pensioners. Ninety percent of those with a good course and equally as many in the control group with early retirement pension were alcohol dependent according to DSM-III, and the others were alcohol abusers. In the study group, 67% were free from abuse at the followup study. The corresponding number for the control group was 25%. A new followup study of the same group after 15 years showed that the positive alcohol patterns were stable. Two thirds of those who were abusers at the first followup had ceased abuse at the second followup [13].
5.5
Long-Term Course in Heroin Dependence
The study by Vaillant of the long-term course in 100 male patients who had been hospitalized at Lexington Hospital for heroin dependence reported stable abstinence after 20 years in 35% of the cases, an uncertain course in 17%, and active abuse in 35% [16]. The remaining 23% had died, usually as a consequence of abuse. In analyzing the causes behind abstinence, the author found that prison followed by supervision had been the most important factors. Only voluntary hospital care or prison, independent of duration, had no association with abstinence. On one or more occasions, 15 of the abusers had received methadone as maintenance treatment. In a study from California, 581 drug addicts were monitored for 24 years [8]. Two followups were performed. The results were similar to those achieved in the previous study. A stable abstinence was found in approximately 29% and an active abuse (including those in prison) in 28%. The authors reported that in the second decade after followup they did not observe any changes toward gradual recovery. Such a process had taken place already during the first decade after initiating treatment. An additional followup was done in the same group of patients after 33 years; the mean age was then 57 years [9]. At that point, a stable abstinence was found in 22% of those without methadone treatment, 6% were involved in methadone programs, 4% were in prison, 7% abused daily, and 2% abused periodically. As many as 48% were deceased, while 12% could not be traced. Another study concerns a 22-year followup of 1019 persons who participated in a methadone program in the United States (New Mexico) [5]. The study had its weak-
319
Patients Lexington N=100 (100% men) California Civil Addict Program N=581 (100% men)
Methadone program Albuquerque N=1019 (86% men)
Hser 1993 [8]
Goldstein, Herrera 1995 [5]
Population
Longitudinal Studies, Heroin.
Valliant 1973 [16]
Table 5.3.
22 years
24 years
20 years
Duration
Stable, abuse free (not methadone) Methadone program Uncertain In prison Deceased Abuse (not methadone)
Stable, abuse free (not methadone) Methadone program Uncertain In prison Periodic narcotic use Daily narcotic use Deceased
Stable, abuse free Uncertain Deceased Active abuse
Results
5 20 23 5 34 13
22.4 6.9 15 11 9.8 7.2 27.7
25 17 23 35
%
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5.6 Alcohol and Drug Abuse as a Chronic Condition
nesses, e.g., a relatively low followup rate and imprecise criteria for abuse and abstinence. It was found that approximately one half of those who could be localized were still active in methadone programs after 22 years. In total, approximately 40% of the original group were traced. Stable abstinence without methadone was only observed in 5%. The percentage of deceased was somewhat higher than in other studies, as was the percentage of those with an uncertain course. It should be noted that many who participate in methadone programs could have concurrently ongoing abuse. These studies show that a large group of heroin-dependent individuals are active abusers more than 20 years after the first contact with health services.
5.6
Alcohol and Drug Abuse as a Chronic Condition
The epidemiological studies mentioned above show that most subjects who on some occasion had reported alcohol dependence did not fulfill the criteria for the condition at the time of the study. At the same time, long-term studies based on epidemiologically defined groups show that a significant share of those who on some occasion in life were alcohol dependent developed a chronic condition of dependence [17, 21, 22]. This group constitutes approximately 10% to 15% of all men. Equivalent data for women are lacking. A chronic condition of dependence is estimated to be 3% to 5% of the female population. Treatment strategies similar in character as those used for chronic physical diseases, e.g., diabetes and asthma, should be applied in cases of chronic dependence. This treatment strategy has been described in many articles during recent decades. The current review by McLellan shows that the effect from the treatment of alcohol dependence is basically as good as the effects from the treatment of other chronic diseases [11]. The studies concerning opiate dependence are not based on epidemiological materials. In the studies with 20 years of followup, it is evident that a large group had a chronic course. Of those surviving, approximately half of the individuals had chronic dependence. One study showed that those who started a methadone program continued with methadone treatment. After 20 years, half of those contacted were participating in continued methadone programs. Hence, opiate dependence should also be viewed as a chronic condition in a large group of individuals. No randomized studies have been performed which illustrate how long-term treatment should be designed. A theoretical possibility, which has not been systematically evaluated in controlled studies, is “stepped” care. In choosing between different treatment methods with well-documented effects, the least intensive is chosen initially. The effect of this intervention is then monitored, and if results are not reached another method with a higher intensity is used. These methods have recently been discussed by Sobell et al. and by Davison [1, 15].
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5.7
Conclusions
1. The long-term effects of treatment for alcohol and drug abuse have not been studied in controlled studies. 2. Epidemiological studies show that most of those who reported signs of alcohol dependence at some time during their life did not fulfill the criteria for this condition during the past year. 3. Studies based on long-term followup of alcohol-dependent individuals (from epidemiological data and clinical populations) showed that a significant group of alcohol-dependent patients developed chronic dependence. This group consisted of 10% to 15% of all men. The numbers for women were considerably lower, but have not been studied as extensively. 4. In opiate dependence, approximately one half of the men developed chronic abuse of heroin and other drugs, including alcohol. The course for women is insufficiently studied. 5. A long-term treatment strategy is necessary for a large group of alcohol-dependent and opiate-dependent individuals with chronic dependence.
References
References 1 Davison GC. Stepped care: Doing
2
3
4
5
6
7
8
9
more with less? J Consult Clin Psychol 2000; 68:580-585. Dawson DA. Alcohol consumption, alcohol dependence, and all-cause mortality. Alc Clin Exp Res 2000; 24:72-81. Glück S, Glück E. Unravelling Juvenile Delinquency. New York, NY: Commonwealth Fund, 1950. Glück S, Glück E. Delinquents and nondelinquents in perspective. Cambridge, Mass: Harvard University Press, 1968. Goldstein A, Herrera J. Heroin addicts and methadone treatment in Albuquerque: a 22-year follow-up. Drug Alcohol Depend 1995; 40:139-150. Grant BF. Prevalence and correlates of alcohol use and DSM-IV alcohol dependence in United States: Results of the National Longitudinal Alcohol Epidemiologic Survey. J Stud Alcohol 1997; 58:464-473. Hanna EZ, Grant BF. Parallels to early onset alcohol use in the relationship of early onset smoking with drug use and DSM-IV drug and depressive disorders: findings from the National Longitudinal Epidemiologic Survey. Alcohol Clin Exp Res 1999; 23:513-22. Hser Y-I, Anglin D, Powers K. A 24year follow-up of California narcotics addicts. Arch Gen Psychiatry 1993; 50:577-584. Hser Y-I, Hoffman V, Grella CE, Anglin D. A 33-year follow-up of narcotics addicts. Arch Gen Psychiatry 2001; 58:503-508.
10 Kessler RC, McGonagle KA, Zhao S,
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12
13
14
15
16
Nelson CB, Hughes M, Eshleman S, Wittchen HU, Kendler KS. Lifetime and 12-month prevalence of DSM-IIIR psychiatric disorders in the United States: Results from the National Comorbidity Study. Arch Gen Psychiatry 1994; 51:8-19. McLellan AT, Lewis DC, O’Brien CP, Kleber HD. Drug dependence, a chronic medical illness: implications for treatment, insurance, and outcomes evaluation. JAMA 2000; 284:1689-1695. Nordström G, Berglund M. A prospective study of successful long-term adjustment in alcohol dependence: Social drinking versus abstinence. J Stud Alcohol 1987; 48:95-103. Nordström G, Berglund M, Frank A. Stability of successful long-term adjustment in alcohol dependence. A follow-up study 15 years after the first long-term follow-up. Presented at the RSA-meeting, Denver, 2000. Robins LN, Locke BZ, Regier DA. An overview of psychiatric disorders in America. In: Robins LN & Regier DA (Eds). Psychiatric Disorders in America. The Epidemiologic Catchment Area Study. New York, Free Press 1991; 328-366. Sobell MB, Sobell LC. Stepped care as a heuristic approach to the treatment of alcohol problems. J Consult Clin Psychol 2000; 68:573-579. Vaillant GE. A 20-year follow-up of New York narcotic addicts. Arch Gen Psychiatry 1973; 29:237-241.
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male alcohol abuse. Arch Gen Psychiatry 1996; 53:243-249. 18 Öjehagen A, Berglund M, Appel CP, Andersson K, Nilsson B, Skjaerris A, Wedlin-Toftenow AM. A randomised study of long-term outpatient treatment in alcoholics. Psychiatric treatment versus multimodal behavioural therapy, during 1 versus 2 years of treatment. Alcohol Alcohol 1992; 27:649-658. 19 Öjesjö L, Hagnell O, Lanke J. Incidence of alcoholism among men in the Lundby community cohort Sweden, 1957-1972. Probabilistic baseline
calculations. J Stud Alcohol 1982; 43:1190-1198. 20 Öjesjö L, Hagnell O, Otterbeck L. Mortality in alcoholism among men in the Lundby community cohort, Sweden: A forty-year follow-up. J Stud Alcohol 1998; 59:140-145. 21 Öjesjö L. The recovery from alcohol problems over the life course. The Lundby longitudinal study, Sweden. Alcohol 2000; 21:1-5. 22 Öjesjö L, Hagnell O, Otterbeck L. The course of alcoholism among men in the Lundby longitudinal study, Sweden. J Stud Alcohol 2000; 61:320-322.
1 Kolumnentitel
6
Psychosocial Treatment for Drug Dependence Mats Fridell
6.1
Introduction
The term psychosocial treatment is of relatively recent origin and has come to include a range of different treatment approaches with varying theoretic backgrounds, treatment sessions, treatment intensity, professional education requirements, and treatment outcome measures. A feature common to all of these treatments is their reliance on some type of interpersonal intervention, which can be carried out individually or in groups and in outpatient or institutional settings. Until the mid 1980s, a residential approach predominated in the treatment of drug abuse (mainly opiate abuse) in the United States and amphetamine abuse in Scandinavia. This movement was known as the therapeutic community. Another organizationally oriented term is institutional milieu therapy. A review from 1996 identified 300 studies, mainly literature published in English or in Scandinavian languages, where acceptable methodology was used to evaluate the results from different forms of residential treatment. Conclusions from this review are discussed and compared with more recent randomized studies later in the text [58]. Clinical trials of specific treatment methods have also been conducted within the scope of organized treatment environments, e.g., in outpatient clinics for abusers or in institutions. Since the mid 1980s, several studies using increasingly sophisticated methodology have been published. These studies compare defined psychosocial or psychotherapeutic treatment modalities with other forms of therapy. In recent years, studies have also investigated combinations with pharmacological treatment. For example, all but one of the psychosocial studies on opiate abuse in this chapter were undertaken during ongoing methadone maintenance treatment. The need for a safe institutional treatment environment in trials investigating the effectiveness of a method is also emphasized in clinical trials of psychopharmacological drugs in drug abuse. Possibly this complicates interpretation of the vitally active components.
Treating Alcohol and Drug Abuse. Edited by M. Berglund, S. Thelander, E. Jonsson Copyright c 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 3-527-30682-X
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The number of randomized controlled trials (RCTs) in different databases has increased exponentially during the past decade. In total, four randomized trials were registered from 1966 to 1974. This number increased by five from 1975 to 1979. Our literature search until June 1999 identified 800 studies, all types included, i.e., psychosocial studies, pharmacological studies, and other interventions for drug abuse. Some studies have been reported in more than one publication, and therefore the number of references cited exceeds the number of studies.
6.2
Psychosocial Methods – a Review
According to Wolberg, psychotherapeutic interventions and methods can be divided into three main types: (a) supportive methods, (b) re-educative methods, and (c) reconstructive or psychodynamically oriented methods [171]. The categories used in our analysis differ from the Wolberg model since we consolidate three different basic models for psychotherapy – cognitive therapy, family therapy, and dynamic therapy – under the heading of psychotherapies. This method of categorization aggregates the groups of interventions according to the complexity of the method, requirements on competence of the caregiver, and general goals to be attained. 6.2.1
Supportive Treatment Methods
The aim of supportive methods is to return the patient to emotional balance after a crisis and breakdown. In substance abuse, becoming drug-free is a goal. Symptom relief and new adequate, adjustment strategies are key objectives. Methods categorized under supportive measures include counseling, relaxation, acupuncture, therapeutic community models, Gestalt therapy, suggestion therapy and case management, and pharmacological and somatic treatment methods. In the meta-analyses later in the text, non-manual-based counseling, which is included under supportive interventions, is distinguished from manual-based counseling, which is included under re-educative methods. The reason for this distinction is that manual-based counseling usually involves a specific treatment intervention directed at the abusive behavior. Hence, the approach is more similar to behavioral therapy and cognitive interventions than would be the case with nonmanual-based interventions. Supportive measures involve several forms of intervention that are mutually quite different from a theoretical standpoint. The common characteristic is that they are rarely a main feature in a treatment design, but are viewed more as a complement to other measures. Wolberg reports 36 variants [171]. Supportive methods are practiced by several categories of professionals with different educational backgrounds. No formal therapist training is required, which supposedly corresponds to the training level of the average caregiver for substance abusers. Presumably, the methods are therefore more easily applied by broad groups of caregivers.
6.2 Psychosocial Methods – a Review
Institutional Treatment Residential forms of treatment, usually involving a milieu therapeutic approach, are programs aimed at supporting individuals through promoting drug abstinence and social stability. It is reasonable to view both compulsory and voluntary environmental treatment programs from this perspective. A review from 1996 included over 300 assessments of milieu therapy [58]. However, the quality of the empirical material in the review varied. For example, at the time of publication only 5 studies were randomized. However, a few studies used cross-validation methodology, which is basically equivalent to an experimental design in treatment research. Methodologically, it is difficult to perform randomized controlled studies in entire institutions or organizations. The main reason is that institutions vary in regard to the conditions that are critical to the results, even when the treatment content may seem to be identical from a strictly ideological standpoint, e.g., common terminology. They differ in the quality of their organizational structure (management, information, level of knowledge, recruitment of personnel, control of quality of the care) and selection (type of patients/clients, occurrence of mental disorder, etc.). To assure external validity in a genuinely randomized study, a representative random sample of institutions would be required (i.e., “cluster-randomization”). This is rarely done. Common to all environmental treatment models is that they use group pressure as a central form of influence. However, experiences from working with psychotic patients in therapeutic community programs during the 1970s and 1980s showed that the need for individualized measures increased along with the level of severity of the patient’s mental disorder. The interplay between group processes and individualization in everyday practical treatment appears to be decisive for the result. Ignoring important characteristics of patients, e.g., gender, mental disorder, etc., results in a higher dropout rate and selectively poorer results [58]. However, data on mental disorders in patients are usually missing, which makes it difficult to assess the influence of selection factors on the results and hence the comparability with other, similar studies. Diagnostic data on personality disorders, clearly the predominant category of mental problems in drug abusers, rarely appear in the studies in this review. This creates problems concerning the generalizability of the results. Fridell, in a review based on organizational theory and empirical studies of milieu therapy, categorizes environmental treatment institutions for drug abusers into four categories based on their organizational perspective [58]. In the area of institutional treatment of drug abuse, the first approach to be distinguished is the classical English model inspired mainly by Maxwell Jones. The second basic approach of American models is completely different. Synanon, Daytop, Phoenix House, etc., all have direct or indirect links to self-help movements such as Alcoholics Anonymous and Narcotics Anonymous, the latter having its roots in religious movements such as the Oxford movement in the 1930s [58]. Certain treatment alternatives are based on life-long participation, not least the selfhelp-oriented variants, while others are considered to be treatment-oriented organizations. History has laid the groundwork for organizational characteristics that include strongly authoritarian and charismatic leadership and a low level of profes6.2.1.1
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sionalization among employees, and in some cases the residential stay is viewed more as an alternative career than as rehabilitation or treatment in the conventional sense. Hence, abuse is viewed as a disease, incurable but one that the patient can learn to live with, and this is reflected in the 12-step approach to treatment. The Hazelden model is a contemporary variant with more deliberate professionalization and an ambition to treat. Continued participation in Alcoholics Anonymous or Narcotics Anonymous is viewed as a necessary complement. These activities are viewed as a form of voluntary aftercare in a community that focuses on group pressure and social support. Psychiatric milieu therapy represents a third organizational model with a high degree of professionalization among caregivers. This approach also emphasizes short-term and acute objectives of symptom relief and habilitation and strongly regulated activities in law and practice [56, 58]. Finally, environmental therapy is found in compulsory care. In the United States and Sweden environmental treatment programs have been developed to treat offenders. The most important target groups are drug and alcohol abusers under extreme psychosocial stress. Structure-Enhancing Interventions Interventions that enhance structure, limit-setting, and motivation have been studied in five randomized trials involving 416 patients [68, 96, 104, 134, 154]. These studies are not included in the meta-analyses since the outcome criteria are not the same as in other studies. 6.2.1.2
Other Supportive Intervention and Treatment Methods Case management has been used increasingly since the 1980s to treat drug addiction in the United States. The method is a way of organizing the network of caregivers and family members around the individual patient to fulfill treatment goals. It is more of an organizational approach rather than a specific treatment method. Within the scope of case management, interventions like counseling may be directed toward problem areas such as work, risk prevention for HIV infection, information about sexual habits and injection habits, or training specific capacities in the abuser. Examples of counseling goals include taking better care of one’s children or developing functional contact networks [171]. Seven studies of case management include 2319 patients [19, 43, 45, 137, 142, 148, 149]. A special cognitively oriented method used in supportive intervention is “nodelink mapping”. This technique involves visual presentation of different goals, objectives, and methods that will lead to goal attainment. The method is of particular interest in treating patients having reading and writing problems, weak verbal skills, and attention deficit, particularly since patients with the latter often have more difficulty in verbal exchange. The methodology is thoroughly described by, e.g., Dansereau [43]. Five studies of 1319 patients address case management with node-link mapping in the experimental condition. Several studies have been conducted on homeless people in major cities in the United States, many using case management methodology. Four studies of 1869 patients where this methodology is applied are included [43, 45, 89, 90, 149]. 6.2.1.3
6.2 Psychosocial Methods – a Review
6.2.2
Re-educative Methods
The second major group of therapeutic methods encompasses types of re-education and therapies based on behavior theory. These are rooted in learning theory and require caregivers to be adequately trained in the method to function well. Certain variants of the method that have been developed are used by caregivers who are not educated as therapists. These are mainly techniques in relapse prevention and are often manual based. Key goals include symptom relief, modification of deviant behavior, and active acquisition of new and more adaptive behaviors. Wolberg lists 70 variants in his review [171]. Most common are individual-directed methods, but group treatment and family treatment with re-educative goals are also described [51, 52]. The review also includes manual-based counseling techniques. Some methods which were developed from cognitive therapy are included in this group. A term like “cognitive treatment” might in clinical practice encompass several modalities of intervention having quite different focus, treatment intensity, and formal training of the therapists. In this review, cognitive behavioral therapy (CBT) represents several variants that focus on the abusive behavior itself and techniques directed toward changing specific drug-related behaviors. Cognitive (behavioral) therapy, however, refers to theoretically similar methods that involve several and more complex interventions with more extensive goals and that are often carried out over longer periods of time. Hence, these are classified under psychotherapeutic methods. “Drug counseling” is used to systematically train the abuser in avoiding situations that may lead to relapse and concurrently create new more adaptive strategies. Counseling methodology is currently the most common complement to other treatment methods in the United States. This is true for both institution-based interventions and outpatient care models, with and without maintenance treatment using methadone, as in the 12-step program and the Hazelden model [58]. Manuals are published. This review includes 11 studies with 5223 patients where drug counseling is included [40, 44, 45, 60, 68, 109, 110, 127, 128, 147, 165, 172, 173, 174]. Some type of counseling is the most common treatment in the control groups. Another treatment approach which should be included under re-educative treatment is the 12-step model. The model, with its roots in self-help movements such as Alcoholics Anonymous and Narcotics Anonymous, has gained an increasingly strong position in both residential care and outpatient care of alcoholics and, during the past decade, also in treating drug addicts. The 12-step program is often used as a control condition for other treatment interventions. In the discussion, results from the meta-analysis are compared with data from the largest naturalistic study to date (a multicenter study from the United States), where 12-step treatment and relapse prevention was given to over 3000, mainly alcohol- and substance-dependent, patients [53, 116, 123, 124, 125]. It should be emphasized that the 12-step program, despite its striking similarities to behavioral therapy interventions, has no actual learning theory base. Rather, the
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program design has been based on personal experiences from ex-addicts and basically lacks any underlying theory. Modern learning theory provides the theoretical and experimental basis for behavior therapy methods. This theory explains the origins of abuse and addiction in different ways. The first group includes theories that view abusive behavior as associative learning with two parallel motivational processes. In a first stage, drug effects are linked by classical conditioning to situational stimuli (“triggers”) in the abusive environment. In a second stage, the positive drug effects are enhanced by the motive to avoid withdrawal [168]. Learning theories in the second group focus on instrumental learning with classically conditioned responses of a motivation-creating nature which serve as discriminative stimuli for the relapse. Drug craving may appear either as a conditioned response in its actual sense or as a type of motivation phenomenon. Several main types of behavioral therapy methods for drug addicts can be distinguished. The first type is based on classic conditioning and counterconditioning of uncomfortable stimuli to eliminate inhibitions in the patient. A second type, aversive counterconditioning, has the opposite goal, i.e., to activate in the patient an aversion to drugs. A third main type includes methods intended to extinguish reactions of discomfort in the user so that situations which previously caused discomfort, and were avoided, become tolerable. Aversion therapy, therefore, attempts to extinguish drug craving by conditioning uncomfortable responses to the exposure to drug stimuli or environmental stimuli associated with the abusive behavior. In this review, only one study with 24 patients uses aversion treatment [79]. During the 1980s and 1990s, methods like cue exposure were developed to extinguish drug craving. This technique aims to extinguish drug-seeking behavior or craving at the stimulus level or subliminal level (involving stimuli of which the abuser is often only peripherally conscious or completely unaware). Under treatment conditions, the abuser is exposed to stimuli which usually activate craving. By gradually increased stimulus intensity under safe conditions, desensitization to the stimuli takes place and deconditioning is achieved. Experiments have shown that longer sessions (60 min) are more effective than brief ones (10–30 min) and that the generalizability of resistance to relapse increases more if the stimuli are specific and realistic for the test person than if they are unspecific and hypothetical [119]. Five studies with 237 patients use this methodology for drug abuse [40, 119, 126]. Contingency management is another method that uses systematic rewards to gradually form the abuser’s behavior. Commonly, becoming drug free (negative urine tests or self-reported data) is linked to rewards in the form of bonuses during the treatment. The rewards are varied over time to optimally modify the behavior. In the study using, e.g., family therapy, the enhancement (bonus system) was linked with attendance at the therapy sessions [150]. Contingency techniques are used in 12 studies with 1492 patients [22, 24, 49, 73, 74, 83, 101, 143, 144, 154, 156, 165]. Seven of these concern treatment of cocaine-dependent patients [49, 73, 74,
6.2 Psychosocial Methods – a Review
101, 143, 144, 165]. A meta-analysis claims that contingency management is a promising modality for different dependence problems [64]. A fourth main type consists of methods based on so-called operant conditioning, i.e., gradually shaping deviant behavior toward becoming acceptable behavior. This takes place via systematic enhancement of desired behavior, often combining negative enhancement (elimination) or aversive counterconditioning of negative or undesired behavior. A fifth type is based on learning by systematic training or identification with a role model (modeling). Four studies, including 342 patients, address modeling in combination with other dependence interventions and social skills training [5, 6, 7, 67, 68]. The sixth, and final, type is based on training of social skills, at times referred to as coping strategies. Relapse prevention is a mixed form of the two types where craving and relapse are linked to cognitive processes and individual expectations of positive drug effects. These, in turn, are influenced by the individual’s expectations, the subjective meaning of these expectations, and the experience of available alternatives for action [100]. Eleven studies with 1412 patients used relapse prevention [26, 27, 28, 29, 30, 31, 32, 50, 103, 109, 115, 136, 152, 153]. Relapse prevention is also used as a control condition. A meta-analysis has been done of relapse prevention for various disorders, e.g., drug abuse [84]. Modern effect studies often combine several parallel approaches, although one main variant is evaluated. A typical multimodal treatment program is the community reinforcement approach (CRA), slightly modified under the headings of matrix treatment or neurobehavioral treatment. The model has been developed for treating alcohol abuse, but in the studies presented here it has been modified mainly for treating cocaine abuse. CRA is characterized by training skills with measures relevant in the patients’ natural social environment and in the areas where patients need help. This may include the behavior of the abuser or family members and deficient capacity of the abuser to resist drugs or handle conflict situations at home. The Hazelden model for alcohol abusers is one of several sources of inspiration [58]. Integrated elements may include relapse prevention, 12-step meetings in groups, family education groups, and using urine and exhalation tests to systematically check narcotic abstinence. Nine studies with 1189 patients use CRA as an experimental condition [1, 15, 73, 74, 77, 78, 128, 129, 141]. One of these includes 180 opiate abusers in methadone maintenance treatment [1]. 6.2.3
More Extensive Psychotherapy
This group includes family therapies, cognitive therapy, cognitive behavioral therapy, and dynamically oriented therapies. What they have in common is that they usually do not aim only at changing behavior, but focus on change in several different but related areas. Another common characteristic among this group of interventions is that they require extensive training, which in some countries is a requirement for licensing.
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Cognitive therapy differs from classic stimulus-response models in that it is supported by empirical research on how thought patterns create mental disorders and symptoms, but also can alleviate or eliminate dysfunctional perceptions. Cognitive therapy techniques attempt to replace deviant thought patterns with those that facilitate normal adaptation and a more positive outlook on life. This group of methods has been shown to be particularly effective in treating depression and anxiety. The common occurrence of depression and anxiety, often in combination with a personality disorder in drug abusers, makes cognitive behavioral therapy a natural treatment option [57]. Approaches to cognitive therapy focus on daily habits and perception patterns where irrational assumptions, self-destructive notions, and self-degrading thoughts trigger and maintain deviations which may manifest themselves in a wide range of mental disorders or diseases. A more realistic and constructive self perception is formed by using this cognitive focus in conjunction with the therapist as a model, concrete objectives, and other activities aimed at changing the way individuals view themselves [111]. The following review includes a study of family therapy with concurrent elements of cognitive therapy [51, 52]. In the meta-analysis, four randomized studies with 679 patients used cognitive behavioral therapy as the treatment method [17, 41, 42, 54, 102]. Cognitive behavioral therapy is also included as a manual-based intervention in large observation studies from the United States [53, 116, 123, 124, 125]. Family therapy comprises a second category of therapies. (Wolberg considered it a re-educative therapy model [171]). Common to all forms of family therapy is that the family is viewed as a system where problems or symptoms demonstrated by the individual are viewed as signs of disorders in the system rather than in the individual family member. In general, the view is that interventions targeted at the symptom-bearer alone do not have an optimal effect and may even counteract constructive problem-solving processes in the family [92, 150]. The systematic work using the family as a focal point or resource therefore distinguishes family therapies from other forms of therapy. Five basic types of family therapy can be distinguished [92, 150]. The first is structural family therapy, where problems in individual family members can be viewed as signs that the adaptive capacity of the family does not permit crises and developmental phases but causes breakdowns in frameworks and limits. Through intervention, the therapist creates a new social system which redefines the balance of the family system and reactivates growth processes [92, 150]. A second type of family therapy is “strategic”, whereby the therapist actively intervenes in the family with instructions, paradoxes, homework, and interventions aimed at preventing the “pathological” family system from being maintained (Haley). A third type is systematic family therapy, where the therapist is assisted by a cotherapist, often with transgenerational family ties (Palazzoli). Interventions with direct action in the therapy room, and on occasion with several therapists present at the same time, come from this school. A fourth type is the transferential-existential school, where therapists mainly use sincerity and empathy in the encounter with family members to open the family system to change [18].
6.2 Psychosocial Methods – a Review
The variants influenced by psychoanalysis include contextual and psychoanalytical family therapies, which place a greater emphasis on a noninterfering approach by the therapist and interpretation of unconscious processes during interaction. The meta-analysis by Stanton and Shadish included 15 randomized studies with 1571 patients and 3500 family members [151]. Two of these studies did not address drug abuse in the original text, and data were lacking concerning effects on the abuse. Hence, these two studies have been excluded from the current metaanalysis. Through personal contacts, Stanton and Shadish acquired data that is not reported in the original articles. Outcomes from these have been used where possible. 6.2.4
Reconstructive Therapy
The third main category of treatment includes dynamic therapy or reconstructive therapy. These represent a broad group of therapies based on elaborations on psychoanalytic theory and wide variations in therapeutic methods. Wolberg lists 79 different types [171]. Most of them have never been tested empirically. A common characteristic of dynamically oriented types of treatment is the focus on interaction between patient and caregiver, where generalization of previous experiences, behaviors, and thought patterns to the current therapy situation (transference) provides the material for work and change. Goals are symptom relief and personality growth. Insight into one’s own reaction patterns and conflicts are viewed as a condition for change. The therapeutic relationship forms the basis for growth and change. It is assumed that in relating to the therapist the individual learns to observe and correct thought patterns and behaviors which may have started in the past, but which to the degree they persist in the present have become dysfunctional and prevent the individual’s continued development. The transference situation, i.e., the reactivation of ingrained thought and behavioral patterns in the treatment relationship, is viewed as the catalyst for therapeutic work. A fundamental hypothesis in psychodynamic thinking is that problems arising in an individual may reflect underlying needs and conflicts. Hence, more conventional psychotherapy has focused less on immediate symptoms than on underlying causes. At times, this neglect may have generated negative results from dynamic therapy in abuse. Viewing drug misuse as a symptom instead of a problem which must be dealt with as a distinct problem in itself. It is difficult to empirically test forms of psychoanalysis and psychodynamic therapy where the treatment time extends over several years. Yet, randomized controlled studies have been reported in recent decades. Research has been facilitated since phenomena that are central, but difficult to capture, e.g., transference, core conflicts, and the therapeutic alliance, have been operationalized and sometimes manualized so that they can be observed with a high degree of reliability and validity [99]. Since the introduction of short-term psychotherapy in the 1960s, this methodology has been used consistently in psychotherapy studies. This is somewhat in contrast to the clinical field, where traditional psychodynamic long-term
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therapies are still common. In psychodynamic short-term therapy, and in other kinds of time-limited therapies, the number of treatment sessions is limited, on average, to 20 times. Treatment is usually given weekly [170]. Concerning the treatment of drug abuse, two research teams have systematically integrated psychodynamically oriented forms of individual therapy into their randomized studies. These research teams are based in New Jersey (Carroll, Rounsaville) and Philadelphia (Luborsky, McLellan, O’Brien, Woody). In New Jersey, a manual was developed for “interpersonal psychotherapy” (IPT) based on principles developed by Klerman for treating, e.g., depression and drug abuse. Its basic structure focuses on (a) symptoms, (b) the patient’s interpersonal difficulties, (c) maintaining a high activity level by the therapist, and (d) using a traditional investigative and supportive approach by the therapist. Therapy focuses on the patient’s acceptance of the need to end abuse, to manage impulsiveness, to recognize the contexts in which abuse is accentuated, and to find strategies to improve both interpersonal functioning and address other problems. Methods involving reflection, clarification, confrontation, support, and assistance are used to help patients develop new skills [131]. Relapse prevention and counseling are common control conditions. In many ways, interpersonal psychotherapy (IPT) is similar to dynamic shortterm psychotherapy, which was designed for the randomized psychotherapy studies in Philadelphia by Luborsky et al.: “Supportive-Expressive Psychotherapy” (SE). In parallel with this form of therapy, a manualized short-term variant of cognitive therapy, “Cognitive-Behavioral Psychotherapy” (CB), designed by Beck, was tested [11]. Drug counseling was used as the control, and methadone was used for stabilization treatment in all three conditions [172, 173, 174]. However, the advocates of IPT hold the opinion that this form of therapy should not be characterized as psychodynamic. Five studies published in 12 articles compared cognitive and dynamic therapy with other conditions; three studies with 936 patients involved cocaine abusers and three studies with 853 patients opiate abusers [27, 29, 41, 42, 91, 112, 119, 131, 132, 172, 173, 174]. One study with 168 patients, which compares group therapy, IPT, and family therapy, was not included in this meta-analysis because of the way in which the data are presented [91]. All three main therapeutic orientations describe both individual and group therapeutic methods [177]. Both the group and the individual therapy studies in the drug abuse field have been short-term, regardless of theoretic orientation. Eight studies with 2003 patients use group intervention as the experimental approach [77, 110, 111, 112, 133, 134, 148, 152–153]. Group treatment is also used in drug counseling and comparable techniques. Methadone treatment has been described in parallel with psychosocial interventions in 24 out of 25 studies on opiate dependence [1, 14, 15, 22, 24, 26, 43– 45, 79, 83, 89, 90, 93, 104, 112, 114, 131, 132, 134, 140, 154, 156, 172–174]. Only one study does not include methadone maintenance treatment (MMT) [156]. The importance of choosing a treatment form on the basis of patient characteristics was illustrated in one study [114]. Two studies were carried out in outpatient settings and with semiprofessional therapists [112, 174].
6.2 Psychosocial Methods – a Review
Finally, some studies are mentioned that compare combinations of pharmacological measures and psychotherapeutic interventions. Unlike the studies mentioned above, these do not use pharmacological treatment as a stabilizing basic intervention. Instead, they directly compare antidepressants and cognitive psychotherapy.
6.3
Research Considerations 6.3.1
Observational Studies
For comparative purposes, the discussion also includes large American multi-center studies where patients are not randomized to treatment alternatives. However, the quality is high as regards description, registration, and followup, and good as regards statistical control of the treatment conditions. This concerns another two multicenter studies with 4623 patients [53, 81, 123–125, 146]. The national NTORS study from England is also included in the discussion as is the Swedish national SWEDATE evaluation [12, 13, 63]. 6.3.2
Questions
1. Does treatment of drug abuse have any effect? 2. Are there differences in the effect size for the three levels of intervention and treatment methods, i.e., do more complex and demanding methods have a greater effect than less sophisticated methods? 3. Among the various intervention and treatment methods, which interventions have the greatest effects as measured by the following criteria: reduced opiate dependence, cocaine dependence, and cannabis abuse? (Effects studied in residential treatment and for specific groups like abusers with mental illness.) 4. How is retention under the experimental conditions in comparison with the control conditions in studies of opiate dependence, cocaine dependence, and institutional treatment? 5. Are there any interaction effects of pharmacological treatment and psychosocial treatment in treatment of drug abusers with depression? 6. What are the effects of institutional treatment? 7. Measured “before-and-after”, what is the general level of improvement in drug abuse treatment? 6.3.3
Theoretical Approach
Articles are grouped independently of technical model according to the three levels described in the text: supportive, re-educative, and psychotherapeutic interventions.
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In the order presented, the methods gradually become more sophisticated, progressing from case management, which is more of a way to organize basic interventions via non-manual based counseling, over to more behavioral therapeutic interventions and manual-based counseling, and finally to three basic forms of psychotherapy. Likewise, the demands on caregiver competence gradually increase, as do the dosage, goals, and costs of treatment.
6.4
Methods 6.4.1
Search Strategies
The databases used are Alconline, MEDLINE, and Cochrane Library. No starting date was specified, which is why the earliest studies are from the late 1970s. Search strategies are (1) substance abuse disorders, (2) substance abuse, (3) substance dependence, (4) narcotic dependence, (5) 1 or 2, 3 or 4, (6) 5 and studies after 1960, and (7) 6 and RCTs. The above search strategies reflect the primary strategies. Additional searches were done to also capture any randomized studies in institutional care. Keywords used were environmental therapy, therapeutic communities, socioenvironmental therapy, and cohort studies. The reference lists in the articles identified have been reviewed. Using these joint strategies, 5880 studies were found in the databases through March of 1999. Of these, 799 were randomized controlled studies. The latest studies included are from June 1999. A meta-analysis from the latest search has also been included in the representativity analysis. 6.4.2
Representativity
Incorrectly registered studies or missing studies were checked during the first search in June 1997, where it was found that nine early studies were missing. Of the 534 studies registered and categorized as “drug abuse”, a smaller number concerned only alcohol treatment, and one additional study was an economic evaluation. The percentage of error (2%) is low. In the initial searches, however, 30% of all psychosocial studies had been registered as randomized studies, without fulfilling the requirements for such a design. These have been excluded. A search in the Cochrane Controlled Trials Register (edition 4, 2000) did not reveal any additional studies. Some studies identified via reference lists have not been traceable in the database searches. These include unpublished dissertation manuscripts and articles published in journals but not included in MEDLINE or other databases. A retrospective search in 2000 showed that 6 studies had been missed. Three additional meta-analyses have been published: one with 11 randomized studies of dynamic therapy in manual-based comparisons, one meta-analysis of
6.4 Methods
family therapy with 15 randomized studies, and one meta-analysis with 69 prediction studies in opiate abuse, several of these without a randomized controlled design [20, 39, 151]. These are commented on only in the discussion. In addition to the meta-analyses covered by the search through June 1999, three additional meta-analyses published later have been included to further define representativity [33, 64, 84]. Most of the studies included in these analyses were nonrandomized. The meta-analysis of cue exposure failed to report that the same study had been published in two articles [33]. The study by Irvin did not reveal any missing studies [84]. Griffith shows two missing randomized studies [64]. The conclusion drawn is that the SBU review contains more studies of drug abuse than any published meta-analysis. 6.4.3
Publication Bias
In Figure 6.1 below, the effect size (Hedges’ d) on the x-axis and the mean error on the y-axis, is stated inversely so that 0 is at the top. A pattern often appearing in a theoretically correct distribution of articles is shown, a so-called “funnel plot”, since it is similar to a common form in funnels, with a broad base that narrows at the top. A line has been drawn for the overall effect size according to the meta-analysis for 24 studies. For the opiate studies, no clear tendency toward publication bias appears. In Figure 6.2 below, the effect size (Hedges’ d) is stated on the x-axis and the mean error on the y-axis, inversely so that 0 is at the top for the 25 studies of treatment in cocaine abuse which have analyzable data. The diagram shows an asymmetric distribution; the lower left field, with negative d-values and se-values higher than 0.2 is basically unmarked, while approximately
Figure 6.1. Publication bias illustrated with funnel plot for standard error and effect size in 24 randomized controlled trials (RCTs) of psychosocial treatment in combination with methadone maintenance treatment for opiate dependence.
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6 Psychosocial Treatment for Drug Dependence Figure 6.2. Publication bias illustrated with funnel plot for standard error and effect size in 25 randomized controlled trials (RCTs) of psychosocial treatment for cocaine dependence.
ten studies appear in the lower right field and have se-values between approximately 0.4 and 0.2 and positive d-values. In analyzing publication bias, it is assumed that the distribution of studies is symmetrical – which in this case would mean that it would contain about ten more studies, mainly in the lower left field – but that some of the studies have not been published for various reasons. 6.4.4
Quality Rating
All initially classified randomized studies were assessed for quality based on a manual developed by SBU. No studies have been excluded because of quality scores. Those with low scores were also included in the cases where basic data could be extracted. 6.4.5
Classifying and Synthesizing the Material
The material has been synthesized to the extent that the reported data have been categorized to group the studies according to similarities in selection, methodology, or treatment modality. The selection of patients is homogenous, classifying groups of abusers with several years of continuous drug dependence or multidrug abuse and a psychosocial burden similar to that found in published cohort studies. Furthermore, treatment results for opiate dependence are distinguished from results for cocaine dependence and cannabis dependence respectively. Apparently, analyses specifying on specific drug type have not been published previously.
6.4 Methods
The outcome measures chosen for this review are drug abstinence and retention in treatment. Mean values and ranges have been calculated and, where parametric data were not available, have been converted from percentages in some cases. Where standardized measures such as the Addiction Severity Index were reported, measures of abuse during the past month have been used, as were outcome measures over longer periods where these were reported. “Composite scores” (parametric data) are used when these also report distribution measures. The meta-analyses registered the intervention level in at least one of the following four periods: (a) 0 to 3 months, (b) 4 to 6 months, (c) 6 to 12 months, and more than 12 months. Few studies report data for all reporting occasions. The three levels are also tabulated for the longest reported followup time in each meta-analysis. Meta-analyses are performed for the three types of treatment methods where supportive, re-educative, and psychotherapeutic techniques are analyzed between and within each level, and for institutional care. Only randomized studies are included in the meta-analyses. The meta-analyses include 24 studies of opiate treatment with 25 comparisons and 5640 patients, and 27 studies of treatment for cocaine dependence with 6303 patients. Thirteen studies with 1205 patients report on outcomes in cannabis abuse. A larger number of studies could have been included if the reporting had contained the required basic data. Studies were not included if the number, mean values and/or distributions were missing. Next, interaction effects between antidepressive treatment and cognitive behavioral therapy in cocaine abuse are shown. Effects on opiate and cocaine abuse, respectively, in institutional care are reported. Four studies of structure-creating interventions, where the outcome measures are not as homogenous as in other studies, are described separately. The section on results concludes by attempting to illustrate the complexity of the studies’ conscious selection of treatment interventions in the experimental group, which are often similar to those in the control group. The difference in effect compared with placebo conditions (if such existed) is underestimated in these comparisons. Therefore, tables showing results from treatment are also presented, comparing outcome measures after treatment or followup to those related to initiated treatment under experimental and control conditions. 6.4.6
Data Analysis
Effect sizes have been calculated according to Hedges, i.e., the mean effect size for each group of studies minus the mean effect size before treatment divided by the common standard deviation [69]. Hence, the effect size can be explained as the difference, in standard deviation units, between the average patient under experimental conditions and the average patient in the control group. An effect level of zero indicates that no difference exists between the conditions, an effect size of d<0.20 indicates no effect. Effect sizes of d=0.20–0.50 are low, d=0.50–0.80 are moderate, and effect sizes above d=0.80 are high [55, 130].
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To the extent possible, effects on patients are calculated according to the “intention-to-treat” definition, i.e., all who were randomized regardless of whether or not they completed treatment. Weighting of the effect size in the different groups of studies was done according to different time intervals and the three levels in the methods. For the studies lacking data on mean values and distribution measures, both at the start of the study and upon completed treatment or followup, differences were calculated by estimating the distribution from which the effect sizes were extracted, e.g., F-values or correlations. Formulas for these types of calculations were obtained from the literature [55, 69, 130, 139]. A general methodology problem in this review is that some studies do not report basic data to allow a before-and-after analysis (usually numbers). Furthermore, some studies lack data to enable a direct comparison of values under the different test conditions. At a late stage, 22 studies were excluded because they did not present data that could be used in the meta-analysis. A calculation of the average quality scores shows that this exclusion does not eliminate studies due to lower quality scores. Even among the studies that presented d-values, e.g., in other meta-analyses, it was necessary to exclude some studies because they did not report distribution measures.
6.5
Results
Tables A-6.3–6.5 in the Appendix present the design, outcome measures, and primary results classified under the respective treatment intervention (experimental condition). The analysis shows outcomes for the longest measured time period and at four different points in time: 1–3 months, 4–6 months, more than 6 months up to 12 months, and 12 months and longer. 6.5.1
Meta-analysis of Treatment for Opiate Dependence
Twenty-three studies with 24 comparisons report values for outcome in opiate abuse and are included in the final meta-analysis. Two studies where only effect size was reported (d) are also included. The design in 38 studies did include measures of opiate abuse, but it has not been possible to estimate odds-ratios or effect sizes based on the available data. Each study is briefly described in Table A-6.3 in the Appendix [1, 14–16, 19, 22, 24, 26, 44, 45, 50, 51, 54, 66, 72, 79, 83, 89, 90, 93, 98, 103, 112, 114, 115, 126, 127, 131, 134, 137, 140, 142, 150, 154, 158, 159, 172, 173, 175]. Published data have been accepted as the basis for the estimates here in the cases where effect sizes had already been estimated in published meta-analyses and where such parameters could not be calculated due to deficient data in the original articles. Here too, the lack of distribution measures did not permit
6.5 Results
inclusion of the following studies: [15, 22, 24, 54, 66, 72, 79, 83, 115, 126, 134, 140, 142, 175, 254]. Reduction of Heroin Abuse All studies were randomized and ranged in size from 30 to 2973 patients. The quality scores in the studies are generally high (m=26.0). Even in the excluded studies, the mean quality is also high (m=24.0). The analysis uses the three levels: supportive methods with 634 patients, re-educative methods with 4234 patients, and psychotherapeutic methods with 772 patients to compare treatment for opiate dependence. Figure 6.3 shows effect sizes aggregated for the respective level of intervention for the longest followup time (Figure 6.3, Table 6.1) and for four points in time for outcome measurement divided according to the three treatment groups (Figure 6.4, 6.5.1.1
pos. opiates
0.13
pos. opiates
0.23
pos. opiates
0.34
Figure 6.3. Weighted effect sizes (Hedges’ d) in 25 randomized controlled trials of psychosocial interventions for opiate dependence: supportive (n=634), re-educative (n=4234), and psychotherapeutic (n=772). Longest outcome measurement.
pos. opiates pos. opiates pos. opiates pos. opiates pos. opiates pos. opiates pos. opiates pos. opiates pos. opiates pos. opiates pos. opiates pos. opiates
0.16 0.16 0.21 0.00 0.37 0.21 0.28 0.27 0.59 0.00 0.06 0.22
Figure 6.4. Weighted effect sizes (Hedge’s d) in 25 randomized controlled trials of psychosocial interventions for opiate dependence: supportive (n=634), re-educative (n=4234), and psychotherapeutic (n=772). Four outcome intervals.
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6 Psychosocial Treatment for Drug Dependence Table 6.1. Effects of psychosocial treatment of opiate dependency combined with methadone maintenance in randomized controlled trials.
Ref. Authors
Treatment vs Control
T
C
TOT
19 43 45 127
Int case MM vs std CMM Nodelink vs std counseling Nodelink + MMT vs std counseling Detox + counseling vs detoxificat
61 151 82 25 319 103 250 77 34 19 150 81 93 15 40 57 919 15 40 12 47 60 45 22 46 19 25 31 37 385
62 155 73 25 315 63 2723 58 35 38 161 99 75 17 19 27 3315 15 40 17 47 32 49 28 72 18 31 31 12 379
123 306 155 50 634 166 2973 135 69 57 311 180 168 32 59 84 4234 30 80 29 95 92 94 50 118 37 56 62 49 772
1 16 26 44 50 89 90 103 135 144 174 14 51 93 98 112 114 131 150 158 173 173 177
Braucht et al. (1995) Dansereau et al. (1995) Dees et al. (1997) Rawson et al. (1983) Weighted summary Abbott et al. (1998) Booth et al. (1996) Catalano et al. (1997) Dawe et al. (1993) Fals-Stewart et al. (1992) Joe et al. (1994) Joe et al. (1997) McAuliffe et al. (1990) Schmitz et al. (1997) Silverman et al. (1998) Woody et al. (1995) Weighted summary Bernal et al. (1997) Fals-Stewart et al. (1996) Krinsley & Bry (1997) Liddle et al. (1993) McLellan et al. (1993) McLellan et al. (1997) Rounsaville et al. (1983) Stanton & Todd (1982) Szapocznik et al. (1983) Woody et al. (1987) Woody et al. (1987) Ziegler-Driscoll (1977) Weighted summary
CRT vs std treatm. + counseling Counseling vs motivational MMT + RPT vs std MMT MMT + cue exp vs Ward. + cue exp Milieu + ind ther – Milieu + relaxatrain Nodelink vs counseling Long nodelink vs short nodelink RPT + selfhelp vs crisis + interv Group-RPT vs ind RPT Contingency vs non contingen Long MMT + couns vs Short do Fam ther vs family education Behavior couples ther- ind therapy Fam ther vs std intervention Fam ther vs Family education Enhanced MMT vs stand MMT Matched behav vs non matched Multimodal – group vs support Fam ther vs standard treatment One person Fam th vs individual Couns + SE vs counseling Couns + CBT vs counseling Fam ther vs peer group
6.5 Results
1–3 months
4–6 months
7–12 months
> 12 months
Longest
d
SE(d)
d
SE(d)
d
d
d
SE(d)
–0.07 0.08 0.52
0.18 0.11 0.16
0.13
0.11
0.38 0.16
0.29 0.11
0.18
0.07
–0.07 0.13 0.21 0.38 0.13 0.31 0.18 0.37 0.21 0.57 0.20 0.12 0.36 0.50 1.50 0.00 0.23 0.00 0.27 0.34 0.92 0.88 0.88 –0.16 0.39 0.09 –0.65 0.00 –0.04 0.34
0.18 0.11 0.16 0.29 0.08 0.16 0.07 0.18 0.24 0.29 0.11 0.15 0.16 0.36 0.31 0.23 0.05 0.00 0.22 0.18 0.24 0.23 0.22 0.30 0.22 0.33 0.28 0.25 0.33 0.08
0.16
0.45 0.36
0.08
0.28 0.11
0.46
0.28
0.12 0.36
0.15 0.16
0.50 2.50
0.36 0.36
1.50
0.31
0.37
0.11
0.21
0.06
0.62
0.23
0.21
0.16
0.21 0.31
0.16 0.16
0.21 0.57 0.20
0.24 0.29 0.11
0.36
0.16
–0.12 0.28 0.36 0.46
0.23 0.07 0.00 0.23
0.88
0.23
0.04
0.30
0.75 0.88 0.88 –0.16
0.14
0.09 0.00 –2.00 –0.04 0.06
0.59
SE(d)
SE(d)
0.37
0.18
0.57
0.29
0.12
0.15
0.00 0.27
0.23 0.11
0.34 0.92 0.23 0.22 0.30 0.33 0.27 0.31 0.33 0.10
0.39
0.22
–0.65 0.00
0.28 0.25
0.22
0.11
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0.66 0.12 0.12 0.01 -0.06 -0.47 0.76 0.60 -0.12
Figure 6.5. Weighted effect sizes (Hedges’ d) in 15 randomized controlled trials of retention in psychosocial intervention for opiate dependence: supportive (n=741), re-educative (n=779), psychotherapeutic (n=572). Three outcome intervals and longest outcome measurement.
Table 6.1). The figures only show the mean value with confidence intervals for weighted effect sizes (W/d) for the three levels of interventions. Retention in Opiate Studies Fifteen studies have sufficient data to allow analysis. Analysis shows that these are the same studies which have significantly higher retention levels in the experimental groups compared to the control groups [112, 114, 127, 134]. One study shows that counseling in association with additional interventions of a psychotherapeutic nature adds to the outcome [112]. The psychotherapies have an effect on retention. Two family therapies show a high effect compared to the control conditions [72, 160] (Figure 6.5, Table 6.2). 6.5.1.2
Conclusions Re-educative interventions and psychotherapies have significant effects on opiate relapse compared to treated control groups. The effect sizes are moderate. Supportive treatment measures have no effect. On retention, supportive and re-educative interventions have no effects, while psychotherapies have significant effects during the first year. Higher retention was observed in the psychotherapy group than in the re-educative and supportive treatment groups. 6.5.1.3
6.5.2
Meta-analysis of Interventions in Cocaine Dependence
The final analysis includes 27 of 47 studies that used change in cocaine abuse as an outcome measure. Calculations of outcome were done in the same manner as in the opiate studies. The following references refer to studies with data on cocaine: [5–7, 16, 26–30, 32, 42, 43, 45, 49, 50–52, 54, 59, 60, 73, 74, 77, 78, 89–91, 101, 102, 109, 112, 115, 119, 128, 129, 135, 137, 141–144, 148–150, 154, 158–160, 165, 173, 174]. Of 47 studies that measured cocaine use, 27 published data that could be ana-
6.5 Results
lyzed in the meta-analysis. The remaining studies [27, 30, 32, 43, 49–52, 54, 59, 60, 77, 78, 85, 91, 101, 115, 119, 129, 137, 141, 142, 148, 149, 154] did not supply the data required for analysis. Some of the studies also report outcome data in their analyses of both opiate dependence and cocaine dependence. Reduction of Cocaine Abuse All studies were randomized, and they varied in size from 12 to 1973 patients. The quality scores in the studies are consistently high (m=26.0). This also applies to the few studies that must be omitted because of deficiencies in data reporting. The analysis compares three levels: supportive methods with 155 patients, re-educative and behavioral therapeutic methods with 5151 patients, and psychotherapeutic methods with 997 patients (total = 6303 patients). Figure 6.6 presents weighted 6.5.2.1
pos. cocaine
0.08
pos. cocaine
0.24
pos. cocaine
0.12
Figure 6.6. Weighted effect sizes (Hedges’ d) in 27 randomized controlled trials of psychosocial interventions for cocaine dependence: supportive (n=155), re-educative (n=5151), and psychotherapeutic (n=997). Longest outcome measurement.
pos. cocaine
-0.18
pos. cocaine
0.22
pos. cocaine
0.08
pos. cocaine
0.00
pos. cocaine
0.36
pos. cocaine
0.30
pos. cocaine
-0.04
pos. cocaine
0.16
pos. cocaine
0.09
pos. cocaine
-0.01
pos. cocaine
0.24
pos. cocaine
0.07
Figure 6.7. Weighted effect sizes (Hedges’ d) in 27 randomized controlled trials of psychosocial interventions for cocaine dependence: supportive (n=155), re-educative (n=5151), and psychotherapeutic (n=997). Four outcome intervals.
345
346
6 Psychosocial Treatment for Drug Dependence Table 6.2. Retention in randomized controlled studies of psychosocial interventions in combination with methadone maintenance treatment for opiate dependence.
Ref. Authors
Treatment vs Control
T
C
TOT
127 Rawson et al. (1983) 140 Shaffer & LaSalvia (1997) 142 Siegal et al. (1996) Weighted summary 26 Catalano et al. (1997) 44 Dawe et al. (1993) 89 Joe et al. (1994) 128 Rawson et al. (1995) 136 Schmitz et al. (1997) 174 Woody et al. (1995) Weighted summary 72 Henggeler et al. (1996) 112 McLellan et al. (1993) 114 McLellan et al. (1997) 131 Rounsaville et al. (1983) 160 Szapocznik et al. (1986) 173 Woody et al. (1987) Weighted summary
Delox + counseling vs detox Couns + yoga vs couns + gr Case man vs stand treatment
25 29 313 367 82 34 150 50 15 82 413 58 60 45 22 56 71 312
25 30 319 374 62 35 161 50 17 41 366 60 32 49 28 52 39 260
50 59 632 741 144 69 311 100 32 123 779 118 92 94 50 108 110 572
MMT + RPT vs std MMT MMT + cue exp vs Ward + cue Nodelink vs counseling CRA vs standard treatment Group-RPT vs ind RPT Long MMT + couns vs short do Multisyst FT vs control Enhan MMT vs stand MMT Matched vs non matched multimodal – group vs Supp One pers fam-ther vs conjo Couns + SE vs counseling
6.5 Results
< 4 months
4–12 months
> 12 months
Max time
d
SE(d)
d
SE(d)
d
SE(d)
d
SE(d)
0.66
0.29 0.12 0.11 0.12
0.26 0.08 0.08
0.12
0.26
0.12
0.26
–0.01 –0.13
0.11 0.20
–0.13
0.20
–0.13 –0.06 1.05 0.81 0.34 –0.05 1.13 0.06 0.60
0.19 0.09 0.20 0.23 0.21 0.28 0.21 0.20 0.09
–0.80 –0.47
0.20 0.14
–0.35
0.29
–0.01 –0.12
0.20 0.16
0.66 0.12 0.11 0.15 –0.01 –0.39 –0.01 –0.13 0.56 –0.80 –0.15 1.05 0.81 0.34 –0.35 1.13 –0.01 0.56
0.29 0.26 0.08 0.07 0.17 0.24 0.11 0.20 0.36 0.20 0.07 0.20 0.23 0.21 0.29 0.21 0.20 0.09
0.66 –0.01 –0.39 0.00 0.17 0.56 0.00 0.01 1.05
0.29 0.17 0.24 0.11 0.20 0.36 0.19 0.07 0.20
–0.45 1.06
0.29 0.21
0.76
0.13
347
348
6 Psychosocial Treatment for Drug Dependence Table 6.3. Effect sizes in 27 randomized controlled trials of psychosocial interventions in cocaine dependence.
Ref. 43 45 137 148 149
Authors
Dansereau et al. (1995) Dees et al. (1997) Schumacher et al. (1995) Sosin et al. (1995) Stahler et al. (1995) Weighted summary 5 Azrin et al. (1994) 16 Booth et al. (1996) 26 Catalano et al. (1997) 28, 29 Carroll et al. (1994a, b) 42 Crits-Christoph et al. (1999) 49 Elk et al. (1998) 50 Fals-Stewart et al. (1992) 73 Higgins et al. (1993) 74 Higgins et al. (1994 89 Joe et al. (1994) 90 Joe et al. (1997 102 Maude-Griffin et al. (1998) 111 McKay et al. (1997) 115 Milby et al. (1996) 128 Rawson et al. (1994) 129 Richard et al. (1995) 135 Schmitz et al. (1997) 143 Silverman et al. (1996) 144 Silverman et al. (1998) 165 Weinstein et al. (1997) 174 Woody et al. (1995) Weighted summary 27 Carrol et al. (1991) 42 Crits-Christoph et al. (1999) 51 False-Stewart et al. (1996) 59 Friedman (1989) 112 McLellan et al. (1993) 150 Stanton & Todd (1982) 160 Szapocznik et al. (1986) 173 Woody et al. (1987) 173 Woody et al. (1987) Weighted summary
Treatment vs Control
T
C
TOT
Nodelink M vs stand copunseling MMT + nodelink vs std couns Enhanced care + hous vs usual care Case-M vs social aftercare Resid treatm vs housing + couns
151 82 69 232 420 954 46 250 77 29 121 6 19 19 20 150 81 59 46 69 50 57 16 19 40 137 57 1368 21 243 40 85 60 46 43 25 31 594
155 73 62 187 302 779 36 2723 58 27 123 6 38 19 20 161 99 69 52 62 50 168 16 18 19 286 27 4077 21 123 40 50 32 53 22 31 31 403
306 155 131 419 722 1733 82 2973 135 56 244 12 57 38 40 311 180 128 98 131 100 225 32 37 59 423 84 5445 42 366 80 135 92 118 65 56 62 997
Behavioral therapy vs supportive Counseling vs motivational interv MMT + RPT – std MMT RPT + desipr – clin manag + placebo SE or CB vs counseling Contingency vs non contingen Milieu + behav vs milieu + relax CRA + conting vs counseling CBT vs 12-step Node-link mapp vs counseling Long node-link M vs short NLM KBT vs 12-step Ind RPT + group vs 12-step Enh day treat vs 12-step + couns CRA vs standard treatment NBT + acupunct vs NBT NMT + contingency vs non conting Contingency vs non conting Increased cont vs fixed conting Int counsel + lectures vs counsel Counsel + therapy vs counsel RPT vs dynamic therapy CBT or SE vs ind + group couns Cogn fam ther vs indiv therapy Functional fam ther vs parent gr Enhanced MMT vs stand MMT Fam ther vs standard treatm One pers fam-ther vs conjoint Couns + SE vs counseling Couns + CBT vs counseling
6.5 Results
1–3 months
4–6 months
7–12 months
> 12 months
Max time
d
SE(d)
d
SE(d)
d
SE(d)
d
d
SE(d)
–0.18
0.16
0.22
0.16
0.08
0.16
0.08
0.16
–0.18 0.51
0.16 0.23
0.22 0.79 0.26
0.16 0.23 0.07
0.08 0.74
0.16 0.23
–0.35
0.27
0.08 0.79 0.26 –0.06 0.35 0.05
0.16 0.23 0.07 0.17 0.27 0.13
0.00 0.28
0.32 0.32
0.00 0.28 0.32 0.13 0.21 –0.14 0.10 0.14
0.32 0.32 0.11 0.15 0.18 0.20 0.18 0.20
1.42 0.79 1.54 –0.05 0.28 0.24 –0.15 –0.06 0.27 –0.01 0.77 0.58 –0.02 –1.00 2.00 0.16
0.40 0.34 0.31 0.25 0.23 0.04 0.44 0.11 0.22 0.18 0.23 0.21 0.26 0.29 0.31 0.07
0.10
0.13
0.28
0.13
1.24 0.97 0.20
0.36 0.34 0.11
0.25 0.15 0.40
0.18 0.20 0.18
0.80 0.49 0.32 0.10 0.21 –0.14
0.34 0.32 0.11 0.15 0.18 0.20
0.51 0.64 4.98
0.36 0.34 0.54
0.36
0.06
–0.21 0.62
0.11 0.23
0.82
0.23
–0.02
0.26
0.09
0.08
1.42 0.79 1.54
SE(d)
0.79
0.23
–0.06 0.35 0.05
0.17 0.27 0.13
0.13
0.15
0.10 0.14
0.18 0.20
0.40 0.34 0.31
0.30 0.04 –0.15 0.44 0.00 0.11
–0.01 0.11
–0.05 –0.88 –0.04
0.25 0.24 0.11
0.46 –0.01 0.77
0.23 0.18 0.23
0.00 0.00 0.24
0.27 0.25 0.10
0.28 0.16
0.23 0.06
–0.06 0.27
0.11 0.22
0.58
0.21
–1.00 2.00 0.15
0.29 0.31 0.08
349
350
6 Psychosocial Treatment for Drug Dependence
effect sizes (d/W) for the three levels of interventions with the longest outcome time, and Figure 6.7 and Table 6.3, divided into four outcome time intervals. Collectively, re-educative therapies have a significant effect in relation to treated control groups. The effect size was small. Supportive intervention and psychotherapy had no significant effects. The effects from re-educative interventions were greatest during the first 6 months. Retention in Cocaine Studies Analyses of those who remain in treatment for cocaine abuse have been possible in 19 studies with 3327 patients. In the group of supportive therapies, there are three studies, in the group of re-educative therapies there are eleven studies, and in the group of psychotherapies there are four studies. The variation in effect size is large in each grouping of levels. Figure 6.8 and Table 6.4 show confidence intervals for the weighted effect sizes for retention in the three groups of methods over the four time intervals in treatment of cocaine abuse. Supportive interventions have larger effects than the control conditions during the short followup interval (<4 months). A small study using supportive intervention with environmental therapy for 2 months has a high positive effect on retention in short-term followup [137]. Generally, behavioral therapy interventions have a lower effect on retention than the control conditions. One exception is a study with followup of community reinforcement which shows a highly stable effect [73, 74]. Other comparisons are negative. The psychotherapies are the group showing high positive and constant effects over 4 to 12 months, mainly for two of the family therapy studies. 6.5.2.2
Figure 6.8. Weighted effect sizes (Hedges’ d) in 19 randomized controlled trials of retention in psychosocial intervention for cocaine dependence: supportive (n=1272), re-educative (n=1516), and psychotherapeutic (n=593). Three outcome intervals and longest outcome measurement.
6.5 Results
Conclusions Mainly, it is the psychotherapies that have a good effect on retention for up to 1 year of the treatment. It appears that all methods with a good retention concentrate on multimodal interventions with family therapy. Here, to an even higher degree than in other sections, this appears to apply to specific methods, not to the theoretic orientation of the treatment interventions. 6.5.2.3
6.5.3
Limitations in Interpreting the Results of Meta-analyses
Separate statistical tests, which are not elaborated on further here, show a significant heterogeneity in the meta-analyses of heroin treatment and cocaine treatment. This means that results from studies grouped into one of the three main categories differ, not only because of chance variations but also because of differences in the actual effect size. These differences may be due to, e.g., different treatment methods, the intensity or duration of treatment, and the inclusion of different diagnostic or socially disabled categories of patients in the different studies. Differences among subgroups of studies can be carefully analyzed, but reliable conclusions cannot be made from this type of categorization afterward. However, such subgroup analyses can provide hypotheses concerning differences which will then be tested in new comparative studies. Combination Therapy with Antidepressants and Cognitive Therapy in Cocaine Dependence In a series of treatment studies of cocaine abuse published by Carroll et al., cognitive behavioral therapeutic relapse prevention was compared with general support from the caregiver and with antidepressant treatment (desipramine or, in the previous studies, imipramine) [27–30]. One hundred and thirty-nine test subjects were randomized to one of four groups in a 12-week study: (1) relapse prevention plus desipramine, (2) clinical/professional approach and support plus desipramine, (3) relapse prevention plus placebo, and (4) clinical/professional approach plus placebo [28]. The effects were measured at completed treatment and at a followup 12 months after the study started [29]. An initial finding was the lack of significant main effects after completed treatment (12 weeks) measured either in retention, reduced cocaine abuse, or other outcome measures. Significant symptom improvement was observed in all groups. The second finding was that the severity of abuse interacted selectively with psychotherapy and pharmacotherapy so that patients with high severity of abuse had significantly better outcomes in treatment with relapse prevention compared to clinical support. Desipramine, however, yielded a higher effect measured in abstinence among patients with low severity. A third finding was that desipramine was more effective than placebo for reducing cocaine abuse over 6 weeks but not over 12 weeks. Finally, the fourth finding was that depressed test subjects had a greater reduction in abuse than nondepressed test subjects and had a greater benefit from relapse prevention than from clinical/professional approach and support. 6.5.3.1
351
352
6 Psychosocial Treatment for Drug Dependence Table 6.4. Effect sizes of retention in randomized controlled studies of psychosocial interventions for cocaine dependence.
Ref. 137 148 149
Authors
Schumacher et al. (1995) Sonsin et al. (1995) Stahler et al. (1995) Weighted summary 28, 29 Carroll et al. (1994a, b) 73 Higgins et al. (1993) 74 Higgins et al. (1994) 89 Joe et al. (1994) 115 Milby et al. (1996) 128 Rawson et al. (1995) 129 Richard et al. (1995) 135 Schmitz et al. (1997) 143 Silverman et al. (1996) 165 Weinstein et al. (1997) 174 Woody et al. (1995) Weighted summary 41, 42 Crits-Christoph et al. (1999) 112 McLellan et al. (1993) 161 Szapocznik et al. (1989) 173 Woody et al. (1987) 173 Woody et al. (1987) Weighted summary
Treatment vs Control Enhanced care + hous vs usual care Case M vs social aftercare Resid treatm vs housing + couns
T
69 232 420 721 RPT + desipr – clin manag + placebo 29 CRA + conting vs counseling 19 CBT vs 12-step 20 Node-link mapp vs counseling 150 Enh day treat vs 12-step + couns 69 CRA vs standard treatment 50 NBT + acupunct vs NBT 57 NMT + contingency vs non cont 16 Contingency vs non conting 19 Int couns + lectures vs counseling 137 Counseling + therapy vs counsel 82 648 CBT or SE vs ind + group couns 121 Enhanced MMT vs stand MMT 60 Struct FT vs dyn child therapy 56 Couns + SE vs counseling 32 Couns + CBT vs counseling 39 308
C
TOT
62 187 302 551 27 19 20 161 62 50 168 16 18 286 41 868 123 32 52 39 39 285
131 419 722 1272 56 38 40 311 131 100 225 32 37 423 123 1516 244 92 108 71 78 593
6.5 Results
< 4 months
4–12 months
> 12 months
Max time
d
SE(d)
d
SE(d)
d
d
SE(d)
0.99
0.19 –0.44 –0.37 –0.40 –0.06 1.02 0.51 –0.01 0.24 –0.13
0.10 0.08 0.06 0.27 0.35 0.32 0.11 0.18 0.20
0.18
0.33
–0.13 0.07 0.01 0.81 1.13 –0.02 0.00 0.30
0.19 0.07 0.13 0.23 0.21 0.24 0.23 0.08
0.99 –0.44 –0.37 –0.26 –0.06 1.02 0.51 –0.01 0.24 –0.13 –0.49 0.00 0.18 –0.13 –0.80 –0.10 0.01 0.81 1.13 –0.03 0.00 0.30
0.19 0.10 0.08 0.06 0.27 0.35 0.32 0.11 0.18 0.20 0.16 0.35 0.33 0.10 0.20 0.05 0.13 0.23 0.21 0.24 0.23 0.08
0.99
0.19
1.27 0.39 0.00
0.36 0.32 0.11
0.17 –0.49 0.00
0.20 0.16 0.35
–0.13 0.00 –0.05 –0.10
0.10 0.19 0.06 0.13
1.06
0.21
0.22
0.11
SE(d)
0.51
0.32
–0.13
0.20
–0.80 –0.31
0.20 0.13
–0.03 0.00 –0.02
0.24 0.23 0.16
353
354
6 Psychosocial Treatment for Drug Dependence
The 1-year followup showed that the effects remained over the followup time and reduced cocaine abuse during treatment had a strong association with less cocaine at the followup [29]. A delayed improvement over the followup time was shown for those patients treated with cognitive behavioral therapeutic relapse prevention. This later improvement was not found in the other treatment conditions. Psychotherapy had no effect on the symptoms of depression. Meta-analysis of Interventions in Cannabis Dependence Thirteen studies have included outcome data for cannabis abuse or have marijuana abuse as the central problem in the treatment intervention [5–7, 59, 70, 88, 97, 137, 138, 150, 152, 153, 158, 161]. Three more studies have reported effect sizes (d), but distribution measures are lacking. The studies include 1205 patients, from 26 to 212 patients in each study. They have a somewhat lower average quality score than other studies (m=23.3) (Figure 6.9, Table 6.5). 6.5.3.2
Conclusions In 4 out of 13 published studies, behavior therapy [5, 7] and family therapy [70, 88, 97] have a significant effect over control conditions for marijuana-smoking teenagers with a still-existing family network. Effect sizes in some of the studies are probably underestimated because of lack of analyzable base data available to us. See Stanton and Shadish (1997) [151]. 6.5.3.3
pos. cannabis pos. cannabis pos. cannabis pos. cannabis pos. cannabis pos. cannabis pos. cannabis pos. cannabis pos. cannabis pos. cannabis pos. cannabis pos. cannabis pos. cannabis
Figure 6.9. Effect sizes (Hedges’ d) in 13 randomized controlled trials of psychosocial interventions for cannabis abuse in samples of teenagers (n=1205).
6.5 Results
6.5.4
Randomized Studies of Institutional Treatment
Despite the complexity of randomizing patients in different institutions, 18 studies were found, cited in 22 articles [2–4, 8–10, 23, 35, 54, 62, 65, 75, 82, 85, 94, 105, 106, 117, 149, 155, 169]. On average, the quality scores for the studies where quality could be estimated is high (m=25.7). Two studies are discussed, more from a methodological standpoint, but the studies where sufficient data are presented involve 2438 patients [8, 62]. All studies have actively treated control groups. Usually the treatment in the control group is almost equivalent to the experimental condition, like structured day-treatment in residential care. Meta-analysis of Institutional Treatment with Opiate Abuse as Outcome Measure The effect estimates in the meta-analysis on opiate dependence include 6 studies with 15 comparisons [4, 9, 10, 65, 147, 155]. All comparisons here have been calculated for the longest registered followup time, which may vary from 3 months to several years. In total, the reported studies involve 1492 patients. Figure 6.10 and Table 6.6 present effect sizes for institutional treatment of opiate dependence. The effect is significant, but very small when experimental and control conditions are compared. Nor is institutional treatment well described over different measurement intervals. Hence, it is not possible to distinguish whether institutional treatment is superior at any specific time of measurement. Figure 6.11 shows results for the longest followup time for opiates in the left field of the diagram and cocaine in the right field (Figure 6.11, Tables 6.6, 6.7). 6.5.4.1
Meta-analysis of Institutional Treatment with Reduced Opiate and Cocaine Abuse as Outcome Measure Figure 6.11 also shows outcome for the individual studies of institutional treatment in opiate and cocaine abuse. Six studies of opiate abuse with seven comparisons and four studies of cocaine with six comparisons are reported (Figure 6.11, Tables 6.6 and 6.7). The comparisons involve 2438 patients. 6.5.4.2
pos. cocaine
0.15
pos. opiates
0.10
Figure 6.10. Weighted effect sizes in randomized controlled trials of institutional treatment in opiate and cocaine abuse/dependence in 9 different studies and 13 comparisons (n=2438). Longest outcome measurement.
355
356
6 Psychosocial Treatment for Drug Dependence Table 6.5. Effect sizes in randomized controlled trials of psychosocial interventions in treatment of cannabis abuse.
Ref.
Authors
Treatment vs Control
T
C
TOT
6 5, 7 59 70 88 97 152 153 158 161 137 138 150
Azrin et al. (1994b) Azrin et al. (1994, 1996) Friedman (1989) Henggeler et al. (1991) Joanning et al. (1992) Lewis et al. (1990, 1993) Stephens et al. (1994) Stephens et al. (1993) Szapocznik et al. (1983) Szapocznik et al. (1989) Silverman et al. (1998) Scopetta et al. (1979) Stanton & Todd (1982) Weighted summary
Soc skills vs counseling Behav ther vs support Functional fam-ther vs parent gr Fam ther vs counseling Fam ther vs education Fam ther vs ind ther RPT vs soc support RPT vs soc support Fam ther vs counseling Fam ther vs stand treat Contingency vs non con Structural FT vs ecologic Fam ther vs stand treat
15 30 85 28 60 95 80 106 19 54 40 15 44 671
11 30 50 19 29 41 87 106 18 54 19 15 43 522
26 60 135 47 89 136 167 212 37 108 59 30 87 1193
Table 6.6. Effect sizes in randomized controlled trials of institutional/residential treatment of opiate dependence
Ref. Authors
Treatment vs Control
T
C
TOT
3 9 9 9 9 9 10 10 10 10 10 10 65 147 155
Day-treatment vs enhanced methadone Short term stay vs methadone Short term stay vs detoxification Long term stay vs methadone Long term stay vs detoxification Methadone vs detoxification Family vs quadrants Family vs Satori Quadrants vs Satori Family vs detoxification Quadrants vs detoxification Satory vs detoxification Therapeutic Com vs struct day treatment Residential treatm vs ambulant treatment Psychiatric specialist service vs regular psychiatric service in hospital
145 75 75 75 75 59 25 25 77 25 77 79 115 67 29
146 59 128 59 128 128 77 79 79 166 166 166 101 82 14
291 134 203 134 203 187 102 104 156 191 243 245 216 149 43
687
1028
1715
Avants et al. (1998) Bale et al. (1980) Bale et al. (1980) Bale et al. (1980) Bale et al. (1980) Bale et al. (1980) Bale et al. (1984) Bale et al. (1984) Bale et al. (1984) Bale et al. (1984) Bale et al. (1984) Bale et al. (1984) Guydish et al. (1998) Smith et al. (1995) Strang et al. (1997) Weighted summary
6.5 Results
1–3 months
4–6 months
7–12 months
> 12 months
Max time
d
d
d
SE(d)
d
d
SE(d)
0.00 1.18 –0.01
0.40 0.43 0.18
0.00 1.18 –0.01 0.93 1.01 0.49 –0.04 0.00 0.09 0.02 0.11 0.00 0.38 0.24
0.40 0.43 0.18 0.31 0.24 0.19 0.15 0.14 0.33 0.19 0.28 0.00 0.46 0.06
0.06 0.00
0.46
0.08
SE(d)
0.15 0.14
0.28
0.10
0.01
0.11
0.04
SE(d)
0.15
–0.04
0.15
0.09 0.02
0.33 0.19
0.93 1.01 0.49 –0.04
SE(d)
0.31 0.24 0.19 0.15
0.25
0.28
0.14
0.11
0.09
0.00 0.38 0.40
0.00 0.46 0.09
1–3 months
4–6 months
7–12 months
> 12 months
Last measurement
d
SE(d)
d
SE(d)
d
d
SE(d)
d
SE(d)
–0.04
0.12
0.19
0.12 –0.43 –0.54 0.17 0.03 0.39 –0.14 0.08 0.26 0.10 0.29 0.05
0.18 0.15 0.17 0.15 0.16 0.23 0.23 0.16 0.21 0.14 0.14
0.19 –0.43 –0.54 0.17 0.03 0.39 –0.14 0.08 0.26 0.10 0.29 0.05 0.00 0.65 1.07
0.12 0.18 0.15 0.17 0.15 0.16 0.23 0.23 0.16 0.21 0.14 0.14 0.12 0.17 0.36
0.10
0.04
0.00 0.12 –1.49 0.19 0.71
0.33
0.04
0.11
–0.18 0.08
SE(d)
–1.10 1.07
0.18 0.36
0.65
0.17
–0.68
0.16
0.08
0.05
357
358
6 Psychosocial Treatment for Drug Dependence
pos. opiates
0.19
pos. opiates
-0.43
pos. opiates
0.17
pos. opiates
0.16
pos. opiates
0.00
pos. opiates
0.65
pos. opiates
pos. cocaine
0.03
pos. cocaine
0.05
pos. cocaine pos. cocaine
0.88
pos. cocaine
0.88
pos. cocaine
Figure 6.11. Effect sizes in randomized controlled trials of institutional treatment in opiate and cocaine abuse/dependence in 9 different studies and 15 comparisons (n=2438).
The meta-analysis of institutional treatment in cocaine dependence shows a very low, bordering on significant, effect in favor of experimental conditions. In the studies of cocaine abusers the data analysis does not make it possible to determine whether the treatment is more effective at any particular point in time. Retention in Institutional Treatment Time in treatment can vary from 3 months to 2 years. Nearly all studies where time multiplied by effect can be estimated note that improvement increases as treatment time increases [2, 4, 9, 10, 35, 65, 75, 80, 94, 118, 147]. However, this applies to the group of studies not based on nonrandomization (Table 6.8). A study published in four articles, but not included in the meta-analyses, is a study that randomized patients to different treatment times to study the effects of planned time in treatment [105, 106, 107, 167]. The results are interesting since they modify the nearly uniform conclusions from cohort studies, stating that time in treatment in itself increases the positive outcome of several variables. The re6.5.4.3
6.5 Results
searchers conclude that the association between improvement and time in treatment clearly persists at 3 months, at the most up to 6 months, but not longer. They also found that abusers sentenced to care show a higher effect than the control group up to 3 months, but not longer [167]. Patients with a lengthy planned duration of care who discontinue treatment prematurely have a poorer outcome than those with a short duration of care who quit early. Furthermore, in comparing treatment methodology the same study found that the conditions of relapse-prevention were more effective up to 6 months while the control group had a somewhat higher effect at 12 months. Conclusion No significant effect differences were found between institutional care and structured outpatient care in opiate and cocaine abusers. One study reported a greater effect from 6 months of institutional treatment than from 3 months. 6.5.4.4
6.5.5
Structure-enhancing Interventions
Structure-, framework-, and motivation-creating activities were investigated in five randomized studies covering 461 patients [68, 104, 134, 155]. These could not be included in the meta-analysis. Reporting of treatment results differs from other studies. An attempt to address lateral abuse during ongoing maintenance treatment with methadone is reported in a comparison of an intervention with a highly structured treatment setting, including strictly enforced discharge from the program in cases of repeated relapse, compared to a program with less clearly defined rules [104]. The results were significantly better in the group where the strict discharge rule was applied. Another study with 80 patients investigated whether drug abusers who had taken overdoses or attempted suicide function better in followup care with a psychiatric specialist compared to a general practitioner. Both the interventions yielded an improvement in mental function and in substance abuse, but specialist treatment was not superior to followup care with general practitioners measured in psychiatric symptoms or in new suicide attempts [68]. A brief motivational interview was tested on 122 patients in ongoing metha– done treatment [134]. At 6-month followup, the patients who received methadone and the motivational interview showed a significantly more rapid and higher level of drug abstinence, a higher level of positive expectations for abstinence, and fewer opiate-related problems. The experimental group also showed better compliance with the program and relapsed later than the patients in the control group who received only methadone treatment and a brief educational intervention. An Israeli study of patients treated with methadone, where the experimental group had less frequent contact but received material incentives, reported a higher degree of drug abstinence, confirmed in urine samples, than patients who received doses daily in a methadone clinic [96].
359
360
6 Psychosocial Treatment for Drug Dependence Table 6.7. Effect sizes in randomized controlled trials of institutional/residential treatment in cocaine dependence (n=723).
Ref.
Authors
Treatment vs Control
T
C
TOT
2 4 54 54 54 94
Alterman et al. (1994) Avants et al. (1998) Fisher et al. (1996) (E1 vs K1) Fisher et al. (1996) (E1 vs K2) Fisher et al. (1996) (E3 vs K3) Lam et al. (1995)
Therapeutic com vs day hospital Day hospital vs enhanced methadone Inst treat + therapy vs ambulant do Inst treatment vs “natural group” Ambulant treatment vs natural group 90 day TC v + ambulant treatment vs standard treatment
51 145 6 6 6 182
51 146 6 6 6 112
102 291 12 12 12 294
396
327
723
Weighted summary
Table 6.8. Effect sizes of retention in randomized controlled trials of institutional interventions for opiate and cocaine dependence. (n=2751 patients in 13 comparisons with n=2855).
Ref.
Authors
Dominant drug abuse
T
C
TOT
2 4 9 10 10 10 35 65 75 80 118 147 155
Alterman et al. (1994) Avants et al. (1998) Bale et al. (1980) Bale et al. (1984) (1 vs 2) Bale et al. (1984) (1 vs 3) Bale et al. (1984) (2 vs 3) Conrad et al. (1998) Guydish et al. (1998) Hiller et al. (1996) Hughes et al. (1995) Nuttbrock et al. (1998) Smith et al. (1995) Strang et al. (1997) Weighted summary
Cocaine Opiates Opiates Opiates Opiates Opiates Cocaine + op Cocaine ? Cocaine Opiates Cocaine Opiates
55 145 150 25 25 77 178 255 11 31 373 67 69 1461
56 146 59 77 79 79 180 253 10 22 321 82 30 1394
111 291 209 102 104 156 358 508 21 53 694 149 99 2855
6.5 Results
1–3 months
4–6 months
7–12 months
Max time
d
SE(d)
d
SE(d)
d
SE(d)
d
SE(d)
0.03
0.20
0.10 2.34 0.95 0.95 0.18
0.12 0.78 0.61 0.62 0.12
0.05
0.12
1.24
0.09
0.03 0.05 2.34 0.95 0.95 1.24
0.20 0.12 0.78 0.61 0.62 0.09
0.19
0.08
0.05
0.14
0.10
0.15
0.08
0.12
< 4 months
4–12 months
> 12 months
Max time
d
SE(d)
d
d
d
SE(d)
0.44 0.03 –1.08 –0.63 0.00 0.69 0.00
0.19 0.12 0.16 0.23 0.23 0.16 0.11
–0.43 0.49 –0.26 –0.50 0.63 –0.11
0.44 0.28 0.08 0.17 0.22 0.04
0.44 0.03 –1.20 0.71 0.63 –0.11 0.00 –0.25 –0.43 0.56 –0.22 0.49 0.63 –0.07
0.19 0.12 0.16 0.24 0.23 0.16 0.11 0.09 0.44 0.28 0.08 0.17 0.22 0.04
SE(d)
–1.28 0.71 0.15 –0.54
0.17 0.24 0.23 0.16
–0.25
0.09
0.96 –0.22 0.71 –0.19
SE(d)
–1.20 0.71 0.63 –0.11
0.16 0.24 0.23 0.16
0.29 0.08 0.17
0.56 –0.22 0.49
0.28 0.08 0.17
0.05
–0.11
0.05
361
362
6 Psychosocial Treatment for Drug Dependence
Treating Mentally Ill and Homeless Abusers The literature search revealed 8 randomized studies, involving 1965 persons, that specifically concerned severe mental disorders in drug dependent individuals [23, 34, 82, 86, 87, 95, 117, 118, 162]. In addition to a diagnosis of substance abuse, inclusion required at least one Axis-I disorder, mainly schizophrenia and affective disorders. Axis-II disorders (personality disorders) are not reported. Quality scores in the studies are, on average, lower than in most other studies of psychosocial interventions; m=17.1 points. Four studies concern homeless persons with abuse problems in large cities in the United States. The prevalence of mental disorders in the group of homeless is estimated at approximately 20% [23]. One study is a method study [162]. All of the studies include acceptable operational diagnostics and adequate outcome measures. The four studies of homeless abusers include well-defined population data, but show the difficulties in recruiting a representative sample from this group [23, 82]. The dropout levels were extreme even prior to the initiation of treatment. Compliance is a major problem [23, 82, 95]. In three out of four studies that compare case management conditions, only 25% of the patients remained in treatment after 12 months [87, 117, 118]. Few actual effects can be shown, and the recruitment problems weaken the generalizability of the results. One of the four studies of homeless and mentally ill substance abusers investigates institutional treatment versus outpatient treatment, and the second study compares the effect under two conditions, with and without the possibility of a housing contract [23, 82]. Two studies compare therapeutic community and sheltered living [117, 118]. Case management plus a housing contract yields significantly greater improvement in housing stability than case management without a contract after both 12 and 24 months, and the gain is twice as high among women as among men [82]. The initial clinical profile of the patients did not influence their ability to manage housing. In a 3-year followup of patients with mental illness and abuse, visiting teams with specialized skills in treating abuse treated the experimental group. The control treatment was standard case management. Measurements every 6 months showed improvements in both the experimental and the control groups. Standard case management yielded greater improvement during the first 2 years, while the patients of the specialist teams improved more during the third, and final, year of followup [34]. One study compared three conditions: 12-step treatment, skills training, and intensive case management for patients with mainly affective disorders [87]. Skills training yielded the most significant improvements in alcohol abuse and drug abuse. Case management yielded the greatest improvements in symptoms and offered the conditions under which patients expressed the highest level of life satisfaction after treatment. The 12-step model had the greatest influence on the patients’ total symptomatic profile. The effects increased with increasing time in treatment. 6.5.5.1
6.5 Results
Conclusions Short-term followups show better results from institutional treatment for persons with co-morbidity, drug abuse, and mental illness. Effects are observed on housing conditions and on the extent of abuse, but not on psychiatric symptoms. Therapeutic communities were superior to regular supportive housing. This conclusion must be regarded as preliminary. 6.5.5.2
6.5.6
Before-and-After Changes in Treatment
Since the phenomenon of improvement across treatment and control conditions has been emphasized by the authors in most of the studies, we have calculated “d” for pre- versus post-treatment outcome across experimental and control conditions. When the different conditions in a study are combined, we observe “results” corresponding to those in studies without control groups. Studies of Opiate Abuse In comparing abuse behavior before and after treatment, a clear reduction in abuse is observed. The effect is much greater than that found in comparisons between different treatments and is well in line with the results observed in the treatment of chronic diseases (Figure 6.12, Table 6.9). 6.5.6.1
Studies of Cocaine Abuse Total improvement (before-and-after measurement) under experimental and control conditions does not show the same consistent profile as in the opiate studies (Figure 6.13, Table 6.10). On the contrary, improvement over time cannot be confirmed. 6.5.6.2
opiates opiates opiates opiates opiates opiates opiates opiates opiates opiates opiates
0.00 0.55 0.36 0.16 0.06 0.27 0.09 -0.42 -0.49 0.34 -0.47
treatment for opiate dependence: supportive Figure 6.12. Effect sizes of pre- versus posttreatment (single-group design) in randomized (n=511), re-educative (n= 4175), psychotherapeutic (n=743). Four outcome intervals. controlled trials of psychosocial interventions in combination with methadone maintenance
363
364
6 Psychosocial Treatment for Drug Dependence Table 6.9. Effect sizes of single-group design in randomized controlled trials of psychosocial treatment for opiate dependence: pre- versus post-treatment effects (n=5429). Meta-analysis based on 4847 patients. 1–3 months Ref.
Authors
T
C
TOT
d
SE(d)
43 45 127
Dansereau et al. (1995) Dees et al. (1997) Rawson et al. (1983) Weighted summary Abbott et al. (1998) Booth et al. (1996) Catalano et al. (1997) Dawe et al. (1993) Fals-Stewart et al. (1992) Joe et al. (1994) Joe et al. (1997 McAuliffe et al. (1990) Schmitz et al. (1998) Woody et al. (1995) Weighted summary Bernal et al. (1997) Fals-Stewart et al. (1996) Krinsley & Bry (1997) Liddle et al. (1993) McLellan et al. (1993) McLellan et al. (1997) Rounsaville et al. (1983) Szapocznik et al. (1983) Stanton & Todd (1982) Woody et al. (1983) Woody et al. (1987) Woody et al. (1987) Weighted summary
151 82 25 258 103 250 77 34 19 150 81 93 15 57 879 15 40 12 95 60 45 22 19 46 71 25 31 426
155 73 25 253 63 2723 58 35 38 161 99 75 17 27 3296 15 40 17 0 32 49 28 18 72 39 31 31 317
306 155 50 511 166 2973 135 69 57 311 180 168 32 84 4175 30 80 29 95 92 94 50 37 118 110 56 62 743
0.23 2.33
0.08 0.15
0.72
0.07
1.58 1.28
0.32 0.09
0.20
0.36
1.24
0.08
2.37
0.21
0.09
0.22
0.04
0.21
0.86
0.12
1 16 26 44 50 89 90 103 136 174 14 51 93 98 112 114 131 158 150 172 173 173
6.5 Results
4–6 months
7–12 months
d
SE(d)
d
SE(d)
0.51
0.08 2.17 2.17
0.51
0.08
0.77
0.07
> 12 months
Max time
d
d
SE(d)
0.14
0.51 2.17
0.08 0.14
0.14
0.92
0.07
0.77 0.37
0.07 0.12
0.26 1.33
0.28 0.09 0.17 0.36 0.16 0.05
SE(d)
0.37
0.12
0.26
0.28
1.04
0.30
0.26 1.33
0.28 0.09
1.35
0.17
1.46
0.17
0.85
0.06
0.48 1.27
0.16 0.08
0.56 0.36
0.16 0.11
1.46 0.20 0.56 0.89
1.68
0.18
1.38
0.18
1.38
0.18
0.85 –0.16 0.09
0.15 0.21 0.23
0.09 0.85 –0.16 0.09
0.22 0.15 0.21 0.23
2.85 2.25 1.13
0.27 0.23 0.08
2.76 4.11 0.99
0.27 0.32 0.08
2.76 4.11 2.21
0.27 0.32 0.13
365
366
6 Psychosocial Treatment for Drug Dependence Table 6.10. Effect sizes of single-group design in randomized controlled trials of psychosocial treatment for cocaine dependence: pre- versus post-treatment effects (n=6042). 1–3 months Ref.
Authors
T
C
TOT
d
SE(d)
45
Dees et al. (1997) Weighted summary Azrin et al. (1994) Booth et al. (1996) Catalano et al. (1997) Carroll et al. (1994a, b) Crits-Christoph et al. (1999) Higgins et al. (1993) Higgins et al. (1994) Joe et al. (1994) Joe et al. (1997) Maude-Griffin et al. (1998) McKay et al. (1997) Milby et al. (1996) Rawson et al. (1995) Schmitz et al. (1997) Silverman et al. (1996) Silverman et al. (1998) Weinstein et al. (1997) Woody et al. (1995) Weighted summary Carrol et al. (1991) Crits-Christoph et al. (1999) McLellan et al. (1993) Stanton & Todd (1982) Woody et al. (1987) Woody et al. (1987) Weighted summary
82 82 46 250 77 29 121 19 20 150 81 59 46 69 50 16 19 40 137 57 1286 21 243 60 46 25 31 426
73 73 36 2723 58 27 123 19 20 161 99 69 52 62 50 16 18 19 286 27 3865 21 123 32 72 31 31 310
155 155 82 2973 135 56 244 38 40 311 180 128 98 131 100 32 37 59 423 84 5151 42 366 92 118 56 62 736
0.00 0.00 –0.71
0.10 0.10 0.23
–0.61 –1.24 –1.25 0.26
0.13 0.36 0.35 0.10
0.65 0.21 1.00
0.18 0.13 0.19
1.97 1.03 5.53
0.23 0.35 0.45
0.16
0.06
–0.49 0.03 –0.54 –0.42
0.11 0.22 0.19 0.09
6, 7 16 26 28, 29 42 73 74 89 90 102 109 115 128 135 143 144 165 174 27 42 112 150 173 173
6.5 Results
4–6 months
7–12 months
d
SE(d)
d
SE(d)
0.55 0.55 –0.76 0.00
0.10 0.10 0.23 0.07
0.36 0.36 –0.81
0.10 0.10 0.23
1.09
0.17
–2.15 –1.70
0.41 0.37
–0.59 –1.52 –1.56 0.27 –0.04 0.61 0.30
10.27 0.79 2.95
0.13 0.37 0.36 0.10 0.09 0.18 0.13
Max time
d
d
SE(d)
0.36 0.36 –0.82 0.00 0.27 0.03 –0.61 –2.15 –1.70 0.27 –0.21 0.61 0.30 0.74 1.31 10.27 0.79 2.95 0.91 0.30 0.16
0.10 0.10 0.23 0.07 0.14 0.16 0.13 0.41 0.37 0.10 0.09 0.18 0.13 0.18 0.15 0.49 0.34 0.30 0.17 0.17 0.03
–0.51 –0.14 –0.49 –1.00 0.50 –0.45
0.11 0.22 0.11 0.15 0.19 0.07
SE(d)
–0.82
0.23
0.27 0.03 –0.61
0.14 0.16 0.13
–0.21
0.09
0.74 1.31
0.18 0.15
0.30 0.09
0.17 0.05
–0.51
0.11
–1.00 0.50 –0.47
0.15 0.19 0.08
0.49 0.34 0.30
0.06
0.04
–0.49
0.11
–0.49
> 12 months
0.11
0.91 0.23 0.27
0.17 0.17 0.09
–0.14
0.22
0.45 0.50 0.34
0.14 0.19 0.10
367
368
6 Psychosocial Treatment for Drug Dependence
cocaine cocaine cocaine cocaine cocaine cocaine cocaine cocaine cocaine cocaine cocaine
0.00 0.55 0.36 0.16 0.06 0.27 0.09 -0.42 -0.49 0.34 -0.47
Figure 6.13. Effect sizes of pre- versus post-outcome measurement (single-group design) in randomized controlled trials of psychosocial interventions for cocaine dependence: supportive (n=155), re-educative (n= 5151), psychotherapeutic (n=736). Four outcome intervals.
Studies of Institutional Treatment In opiate abuse, no improvement is noted (before-and-after measurement) under experimental and control conditions in followup up to 3 months; however, moderate or large effects are noted for longer followup times. For the longest intervention time, a low to moderate effect is observed. For institutional treatment of cocaine abuse, a small effect is observed for the longest followup time. In the different followup intervals there is a low effect size in improvement at 1 to 3 months, negative effect size at 4 to 6 months, and a high effect size in improvement at 6 to 12 months. One study shows a clearly negative before-and-after result (Tables 6.11 and 6.12) [4]. It is evident from the tables that even here the various institutional programs differ considerably. Individual studies show high or very high consistent effect sizes in improvement remaining over time. Time in treatment shows a more curved linear profile. Conclusions must be drawn with some caution, but are similar to those from large national cohort studies in the United States [36]. The interventions that are shown to be favorable are those for homeless substance-abusing mothers [147] and detoxification in a drug-dependency unit compared to detoxification in a psychiatric unit. Massive interventions with institutional care followed by different structured outpatient care interventions have also been shown to be effective [54, 94]. It is interesting to note that the studies that show clear effect differences between the experimental and control conditions are also those which show high effect sizes in the pre- versus post-treatment outcome. 6.5.6.3
Conclusions Improvement (before-and-after measurement) is clearly demonstrated in both the experimental and the control groups in most of studies on opiate abuse. The same inference of improvement over time is not possible to draw in the studies on cocaine abuse (only two studies could be used for the analysis). 6.5.6.4
6.6 Appendix
An explanation for the differences may be that the patients in nearly all of the opiate studies were also treated with methadone, while effective drugs are not available for cocaine dependence. 6.5.7
Effects on Factors other than Abuse
The studies where methadone treatment was combined with counseling and different forms of structured psychotherapy showed that better results were achieved over time than when methadone was given alone or combined with counseling only [172–174]. It was also found that working capacity improved, as did mental health, and that the number of crimes committed decreased. The patients in combination treatment also required lower methadone doses. More recent studies have also shown a similar supplemental effect from combination treatment [175]. Treatment Focus The current meta-analyses and previous literature reviews clearly show that the primary focus of treatment should be the abuse itself. Successful treatments are highly structured, and treatment continues for at least 3 months [12, 40–42, 58, 119–122, 145, 146]. The studies do not show that effects on abuse increase with treatment extending longer than 6 months. 6.5.7.1
Limitations of Randomized Treatment Studies Several important factors have not been studied with randomized methodology. Cohort studies generally show better treatment results for women than for men. Studies from Sweden show that amphetamine abusers have better treatment results than heroin addicts. Cohort studies also indicate that patients improve more on the second or third treatment occasion [35], while other studies have shown a negative association between many treatment attempts and a poor prognosis [20]. This can probably be explained by the fact that patients who are particularly difficult to treat return several times for treatment, while those who improve in the long term do not need to return. Hence, it is probably important to consider previous treatment effects when recruiting patients for a study. The question of the optimal duration of treatment cannot be answered by the research available to date. 6.5.7.2
6.6
Appendix
(See page 372 – 403)
369
370
6 Psychosocial Treatment for Drug Dependence Table 6.11. Effect sizes of single-group design in randomized controlled trials of residential treatment for opiate dependence: pre- versus post-treatment effects (n=1564).
Ref. Authors
Treatment vs Control
T
C
TOT
4 9 9 9 9 9 10 10 10 10 10 10 65 147 155
Day-treatment vs enhanced methadone Short term stay vs methadone Short term stay vs detoxification Long term stay vs methadone Long term stay vs detoxification Methadone vs detoxification Family vs quadrants Family vs Satori Quadrants vs Satori Family vs detoxification Quadrants vs detoxification Satori vs detoxification TC vs structured day treatment Residential treatm vs ambulant treatment Psychiatric specialist service vs regular psychiatric service in hospital
145 75 75 75 75 59 25 25 77 25 77 79 115 67 29
146 59 128 59 128 128 77 79 79 166 166 166 101 82 14
291 134 203 134 203 187 102 104 156 191 243 245 216 149 43
633
931
1564
Avants et al. (1998) Bale et al. (1980) Bale et al. (1980) Bale et al. (1980) Bale et al. (1980) Bale et al. (1980) Bale et al. (1984) Bale et al. (1984) Bale et al. (1984) Bale et al. (1984) Bale et al. (1984) Bale et al. (1984) Guydish et al. (1998) Smith et al. (1995) Strang et al. (1997) Weighted summary
Table 6.12. Effect sizes of single-group design in randomized controlled trials of residential treatment for cocaine dependence: pre- versus post-treatment effects (n=723).
Ref. Authors
Treatment vs Control
T
C
TOT
2 4 54 54 54 94
Therapeutic com vs day hospital Day hospital vs enhanced methadone Inst treat + therapy vs ambulant do Inst treatment vs “natural group” Ambulant treatment vs natural group 90 day TC v + ambulant treatment vs standard treatment
51 145 6 6 6 182
51 146 6 6 6 112
102 291 12 12 12 294
396
327
723
Alterman et al. (1994) Avants et al. (1998) Fisher et al. (1996) Fisher et al. (1996) Fisher et al. (1996) Lam et al. (1995) Weighted summary
6.6 Appendix
1–3 months
4–6 months
7–12 months
> 12 months
Max time
d
SE(d)
d
d
d
SE(d)
d
SE(d)
–0.69
0.09
–0.60 0.08 0.52 0.43 0.46 0.39 0.47 0.56 0.59 0.50 0.49 0.44 0.45
0.12 0.10 0.12 0.10 0.10 0.14 0.14 0.11 0.10 0.09 0.09
–0.60 0.52 0.43 0.46 0.39 0.47 0.56 0.59 0.50 0.49 0.44 0.45 0.69 4.21 0.65
0.08 0.12 0.10 0.12 0.10 0.10 0.14 0.14 0.11 0.10 0.09 0.09 0.09 0.21 0.23
0.44
0.03
0.73
0.22
–0.50
0.08
SE(d)
0.69 4.05
0.09 0.20
0.34
0.06
SE(d)
4.35 0.65
0.21 0.23
4.21
0.21
2.63
0.16
0.56
0.03
1–3 months
4–6 months
7–12 months
Max time
d
SE(d)
d
SE(d)
d
SE(d)
d
SE(d)
0.15
0.14
0.15
0.14
–0.48 1.11 3.47 0.50 1.24
0.08 0.44 0.66 0.42 0.09
–0.33
0.08
1.24
0.09
1.24
0.09
0.37
0.06
–0.33
0.92
0.08
0.92
0.08
0.08
371
Drug type/ Patient selection
Cocaine and heroine addicts (n=193) Excluded
Siegal [142] (1996)
Experiment: Case management versus Control: a 10-week intervention aimed to increase capabilities in abusers compared with Control: standard treatment. Measurement: Baseline, 6 months. Retention: No data.
Experiment: Intensive case management versus Control: Standard case management. Studied in a large sample of homeless abusers (38%) at baseline and after 4 months. Followup after 12–14 months. Attrition: Experiment: 88% of 163=143, Control: 77% of 160=123.
Heroine addicts in 21 A simple comparison of outpatient detoxification for heroine addicts: days of outpatient detoxi- Experiment: Detoxification with compulsory counseling, versus Control: fication (n=50) detoxification only. Measurement: Baseline, Completed treatment, and followup after 6 months. Attrition: Exp. = 16%, Control = 12%.
Rawson [127] (1983)
Two treatment approaches are tested in a study of opiate abusers with other substance abuse during methadone maintenance treatment for 12 months. Experiment: Node-link mapping + methadone (n=155) versus Control: Standard counseling. Measurement: Baseline, 3–6 months, 7–12 months. Attrition: No information.
Opiate abusers in methadone program after 12 months in treatment
Dees [45] (1997)
Experiment: Node-link mapping for abusers with a high and low attention deficit disorder compared with Control: Standard counseling for abusers with high and low attention deficit disorder. Measurement: Baseline, 3 months. The study is a completers analysis. Attrition: 66%.
Opiate abusers in methadone treatment, stays more than 3 months (n=331)
Dansereau [43] (1995)
1.2 Case management and counseling with techniques like node-link mapping without manual intervention
Homeless with abuse (n=323)
Braucht [19] (1995)
Intervention/Control group/Dropout rate
Randomized controlled studies in meta-analyses of effects in psychosocial treatment for opioid dependence.
1. Supportive Interventions 1.1 Case management
Article
Table A-6.1.
0.38
0.21
0.13
0.11
– 0.07
d
0.29
0.16
0.11
0.08
0.18
Se
22/30
20/30
20/30
23/30
21/30
Quality Score
372
6 Psychosocial Treatment for Drug Dependence
Opiate abusers/addicts on waiting-list in methadone program (n=61)
Two 5-months interventions are compared for opiate abusers prior to (E1): methadone maintenance treatment. Experiment: Individual counseling + Hatha Yoga versus Control: Individual counseling + group therapy. Measurement: Baseline and 5 months. Attrition: Experiment = 28%, Control = 33%.
Opiate abusers in methadone treatment + therapy (n=350)
Opiate abusers in three methadone programs (n=123)
Joe [90] (1997)
Woody [174] (1995)
A study of methadone maintenance treatment plus counseling in two different treatment approaches over three different methadone programs and a duration of the intervention of 1 session per week for 6 months. All treatments are manual based. A study where the caregivers are NOT educated therapists. Measurement: Baseline, Followup 7 months, Followup 12 months. Attrition: 10%.
Treatment under two approaches: Experiment: More than 6 months of treatment with node-link mapping and standard counseling versus Control: Less than 6 months of treatment with node-link mapping and standard counseling. Measurement: Baseline, 6 months methadone treatment, and 12 months of followup. Attrition: 53% at 6 months.
Patients in methadone Experiment: Six months of node-link mapping for patients with low and maintenance treatment. high levels of positive urine tests and Control: Counseling for patients with 1990–1992 (n=311) high and low levels of positive laboratory tests (urine): Measurement: Baseline, 6 months of methadone. Attrition: 53%. Small differences at 6 months between groups.
Joe [89] (1994)
Attempt to reduce risk behavior in 2973 opiate abusers in a national sample with 3 months of intervention. Experiment: HIV counseling, risk behavior work (manual) versus Control: education/motivation work. Measurement: Baseline, 6 months. Attrition: Tot = 92%.
Multicenter study from 15 cities (United States) of opiate abusers (n=2973)
Booth [16] (1996)
2. Reeducative Therapy 2.1 Manual based counseling techniques: drug, standard, or node-link mapping
Shaffer & La Salvia [140] (1997)
0.00
0.12
0.20
0.18
–
0.23
0.15
0.11
0.07
–
31/33
28/30
24/33
25/30
22/30
6.6 Appendix 373
(cont.)
Drug type/ Patient selection
Opiate abusers in a detoxification unit (n=21) Excluded
Powell [126] (1993)
Brooner [22] (1998)
Opiate abusers with an antisocial personality disorder (n=40) Excluded
d
Two types of very brief treatment with cue exposure (E1) 2 sessions with cue exposure and (E2) 2 sessions with cue exposure + cognitive aversion therapy versus (C): no treatment. Measurement: Before-and after-test. Attrition: Not stated.
Two experimental conditions with (E1): cue exposure and methadone in inpatient treatment for 10 weeks, and (E2): behavioral therapy unit + clonidine for 3 weeks, versus two control conditions (C1): cue exposure + general psychiatric unit for 8–12 weeks and (C2): behavioral therapy in an unit for 1 week. Measurement: Baseline, 6 months followup. Attrition: E2: 4 (44%), C1: 7 (30%), C2: 3 (25%).
Recently admitted patients and previously hospitalized patients in – institutional treatment with 4 weeks of baseline + 13 weeks of intervention for opiate abusers were stabilized on a methadone dose of 55 mg/d with two different interventions: Experiment (E): contingent increase of psychosocial interventions depending on negative drug tests, and Control (C): non-contingent counseling sessions. Measurement: Weekly throughout the study. Attrition: (E): 30% and (C): 10%.
–
0.21
Opiate abusers in methadone treatment who could not stop their other sub- – stance abuse. Experiment: 7–10 sessions with aversion therapy versus Control: Waiting list. Measurement: Baseline, Followup after 6 months. Attrition: Not stated. Not included due to effects on cocaine abuse only.
Intervention/Control group/Dropout rate
2.4 Contingency enhancement – behavioral skills, etc.
Opiate abusers in methadone program (n=186)
Dawe [44] (1993)
2.3 Stimulus control – cue exposure, etc.
Houston & Milby [79] Opiate abusers in (1983) methadone treatment (n=12) Excluded
2.2 Aversion Therapy
Article
Table A-6.1.
–
–
0.24
–
Se
24/30
21/30
25/30
17/30
Quality Score
374
6 Psychosocial Treatment for Drug Dependence
Opiate abusers in methadone treatment (n=353) Excluded
Clients in therapeutic community (TC) Re-entry phase. (n=130)
Opiate abusers in methadone treatment (n=16) Excluded
Cocaine abusers with other abuse in methadone program (n=49)
Other substance abuse in patients in methadone treatment (n=53) Excluded
Calsyn [24] (1994)
Hawkins [66, 67] (1986, 1989)
Iguchi [83] (1988)
Silverman [144] (1998)
Stitzer [154] (1992)
0.31
–
5-week baseline + 3 months of treatment with three treatments per week 1.50 during ongoing methadone treatment. Experiment: (E1): Abstinence enhancement by increasing voucher rewards, (E2): increased abstinence enhancement with initial booster dosage and Control (C): non-contingent voucher enhancement. Measurement: Baseline, (5 weeks), continuous measurement/week for 24 weeks, post-measurement, week 21. Attrition: 0%. 6 months of intervention: Experiment: (E1) contingent take-home doses in relation to 2 weeks of consecutive drug abstinence, versus Control: (C1): non-contingent take-home doses. Attrition: (E):10=38% and (C):7=(26%), respectively. Little difference in dose (E): 23.1 w versus (C): 22.8 w.
–
–
12-week baseline + 20-week intervention with take-home contingency doses – + penalty versus same duration of baseline and intervention and take-home contingency doses but without penalty after positive urine tests. Measurement: 12 weeks, 32 weeks, Followup at 4 months. Attrition: E=25%, C: 25%. Outcome regarding cocaine was studied but insufficiently reported.
–
–
–
–
Two 10-week interventions as addition to TC treatment: Experiment: Behavioral skills training and networking versus Control: Remaining in TC but no extra training. Measurement: Baseline for the study, Followup 12 months. Attrition: E=33%, C=30%. Does not state which drug is measured.
Opiate abusers in methadone treatment were randomized to two, 6-month interventions with Experiment: three groups of contingency management versus Control: three groups who did not receive contingency management. Measurement: Baseline, 3 months, 6 months, and 4: 12 months. Attrition: E: 76%, C: 54%.
26/30
25/30
20/30
23/30
23/30
6.6 Appendix 375
(cont.)
Drug type/ Patient selection
Intervention/Control group/Dropout rate
Sample of 32 opiate abusers in methadone treatment with other substance abuse
Schmitz [136] (1998)
Bernal [14] (1997)
30 families with young abusers
Patients in (TC) for 1 month with OCD Axis-II-diagnosis, (n=60) Cocaine (39%)
Fals-Stewart [50] (1992)
3. Psychotherapies 3.1 Family therapy
Opiate abusers in methadone treatment (n=133)
Catalano [26] (1997)
Intervention with Experiment (E): Contextual family therapy versus Control (C): Family education Measurement: Baseline, post-test, and followup, 6 months.
0.00
0.00
0.36
PART A: Total of 26 weeks treatment: Phase I: 2 weeks of stabilization and 0.50 methadone adjustment. Phase II: 8 weeks without enhancement in other substance abuse and baseline adjustment. (E): (high) 2 times/week and C: (high) take-home contingency doses 5 times/week, Phase III: 12 weeks of treatment where the take-home frequency is varied contingent on negative drug tests in urine. Finally, Phase IV: 4 weeks of treatment with the same frequency of take-home doses as in Phase II. Measurement: baseline, urinalysis 2 times per week during all 6 months.
0.18
Se
0.29
0.37
d
0.57
Recently admitted patients in therapeutic community (TC) with DSM-III-R, Axis-II-diagnosis of obsessive-compulsory disorder which is treated under two conditions. Experiment: Environmental therapy + individual behavioral therapy for compulsory symptoms, versus Control: (C1): Milieu therapy + response prevention, and (C2): Milieu therapy + relaxation treatment. Measurement: Baseline, 6 months, Followup 12 months. Attrition: n=3 (5%).
Two treatment approaches are compared. Experiment: Methadone maintenance treatment with relapse prevention versus Control: Standard methadone maintenance treatment. Measurement: Baseline, 9 months. Attrition: E: 12% (6), C: 12% (6).
2.5 Relapse prevention & cognitive relapse prevention, individually and in groups
Article
Table A-6.1.
From Stanton
28/30
25/30
25/30
Quality Score
376
6 Psychosocial Treatment for Drug Dependence
–
– 0.04
Followup of the above study. Measurement: Baseline, 24 months followup. Attrition: not stated. 3 months of intervention. Experiment: (E1): Structural conjoint family therapy. (E2) Family therapy with family members only, Control: (C1): peer group. Measurement: Baseline, 12 weeks, and followup 5 and 6 months..
As above
Adolescents in a therapeutic community (drug-free) (n=79)
Szapocznik [160] (1986)
Ziegler-Druscoll [177] (1977)
McLellan [112, 113] (1993, 1994)
Patients in methadone treatment with or without psychosocial treatment (n=92)
Three approaches for patients in methadone maintenance treatment are 0.88 tested. Experiment: (E1): Extended – methadone treatment with work training, counseling and family/couples therapy, (E2): Standard methadone treatment with drug counseling and enhancement schedule, versus Control: (C): Minimum methadone treatment with only individual adjustment of dose. Measurement: Start, 6 months. Attrition: 0%.
0.09
Family intervention program with two types of family therapy for adolescents with mild abuse of narcotics, mainly marijuana. Experiment: Single-person family therapy versus Control: Conjoint family therapy: Measurement: Baseline, Followup 6–12 months. Attrition: Not stated.
Spanish-speaking abusers, mostly marijuana (n=37)
Szapocznik [158] (1983)
3.2 Cognitive and dynamic psychotherapies
0.70
18 weeks of structural family therapy in two versions and two control groups with other treatment. Experiment: (E1): Family therapy with reward for participation. (E2) Family therapy without reward, Control: (C1): Methadone + individual counseling, (C2): Family film. Measurement: Baseline, followup 12 months. Attrition: Not stated, but low according to Stanton & Shadish, 1997.
Stanton & Todd [150] Abusers of different (1982) drugs and in different age groups (n=118)
0.27
Patients randomized after 1 month of orientation. Experiment: Behavioral couples therapy + individual therapy 1 time/week for 12 weeks (manual) versus Control: Individual therapy 2 h/week plus home tasks for 12 weeks (manual). Measurement: Baseline, End of treatment = 12 weeks, Followup 3, 6, 9, and 12 months. Attrition: 0 = all complete the treatment.
80 couples where one member is substance abuser
Fals-Stewart [51] (1996)
0.23
0.33
–
0.33
0.16
0.00
26/30
19/20
25/30
25/30
22/30
28/30
6.6 Appendix 377
Drug type/ Patient selection
Matching of abusers with different drugs to 4 private treatment programs (n=94)
Opiate abusers in methadone treatment (n=72)
Opiate abusers in methadone maintenance treatment (n=110)
Opiate abusers in methadone maintenance treatment (n=110)
McLellan [114] (1997)
Rounsaville [131] (1983)
Woody [172] (1983)
Woody [173] (1987)
(cont.)
Article
Table A-6.1.
0.88
d
* Dynamic **Cognitive
Three different types of intervention which are presented above. Followup: 12 months after completed treatment.
Three different intervention types are tested with methadone maintenance treatment as the basis in all treatment models. Experiment: (E1): Drug counseling + supportive expressive psychotherapy (E2): Drug counseling + cognitive behavioral therapy, versus Control: Drug counseling only. All interventions last for 6 months. Measurement: Baseline, Followup 7 and 12 months. Attrition: 10%.
– 0.65* 0.0*`*
–
24 weeks of intervention with methadone maintenance treatment as stabiliz- – 0.16 ing intervention plus group therapy and an additional treatment model. Experiment: MM + group + interpersonal psychotherapy versus Control: MM + group + support treatment. Measurement: Baseline 6, 12, and 24 weeks. Attrition: E: 50%, C: 42%.
Study in a somewhat less severe set of clients than in studies of drug abusers in general. Two interventions compared, both offering 21 days of treatment. Experiment: Patients were matched after randomization to standard intervention versus Control: Patients were only given the particular treatment without matching. Measurement: Baseline, and 6 months. Attrition: n=12 (12%).
Intervention/Control group/Dropout rate
0.28 0.25
–
0.30
0.22
Se
29/30
24/30
25/30
27/30
Quality Score
378
6 Psychosocial Treatment for Drug Dependence
Drug type/ Patient selection
Homeless abusers (n=419) Excluded
Sosin [148] (1995)
Opiate abusers in methadone treatment, n=331 stays more than 3 months Excluded
Opiate abusers in methadone program after 12 months in treatment (n=155)
Dansereau [43] (1995)
Dees [45] (1997)
d
Two treatment approaches are tested in a study of opiate abusers with 0.08 other substance abuse while receiving methadone maintenance treatment for 12 months. Experiment: Node-link mapping + methadone versus (n=155) Control: Standard counseling. Measurement: Baseline, 3–6 months, 7–12 months. Attrition: No data.
Experiment: Node-link mapping for abusers with high and low attention deficit disorder compared with Control: Standard counseling for abusers with high and low attention deficit disorder. Measurement: Baseline, 3 months. The study is a completers analysis. Attrition: 66%.
–
Two experimental conditions are compared with a control condition for – homeless with abuse problems. Experiment: (E1): case management for 3 months, (E2): case management + sheltered housing for 6 months and Control: normal social aftercare. Measurement: Baseline, 3 months, 6 months. Attrition: E=22% and C=42%. Dose/drug treatment: E1=2.2 (n=131), E2=2.9 (95), C=2.1 (185).
Experiment: Case management versus Control: 10 weeks of intervention 0.11 aimed to increase capacities in the abuser compared with Control: Standard treatment. Measurement: Baseline, 6 months. Retention: No data.
1.2. Case management and counseling with methods like node-link mapping
Cocaine and heroine abusers (n=632) Excluded
Siegal [142] (1996)
Intervention/Control group/Dropout rate
Randomized controlled studies in meta-analyses of effects in psychosocial treatment for cocaine dependence.
1. Supportive Interventions 1.1 Case management
Article
Table A-6.2.
0.16
–
–
0.08
Se
20/30
20/30
24/30
23/30
Quality Score
6.6 Appendix 379
Homeless crack abusers (n=176) Excluded
Homeless abusers (n=722) with abuse problems Excluded
Schumacher [137] (1995)
Stahler [149] (1995)
Multicenter study from 15 cities in the United States of opiate abusers (n=2973)
Opiate abusers in three methadone programs (n=123)
Booth [16] (1996)
Woody [174] (1995)
d
Study of methadone maintenance treatment plus counseling in two different treatment approaches over three different methadone programs and a duration of the intervention of 1 session per week for 6 months. All treatments are manual based. A study where the caregivers are NOT educated therapists. Measurement: Baseline, Followup 7 months, Followup 12 months. Attrition: 10%
Attempt to reduce risk behavior in 2973 opiate abusers in a national sample with 3-month intervention. Experiment: HIV counseling, risk behavior work (manual) versus Control: Education/motivation work. Measurement: Baseline, 6 months. Attrition: Total = 92%.
0.28
0.26
Two, 2-months intervention types for homeless abusers were tested: – Experiment: Enhanced care with daily treatment in TC, individual goal planning etc, and Control: Usual care with counseling individually and in a group 2 times/week. Measurement: Baseline, 2 months, F-U 6, 12 months. Followed up = 74%. – Two experimental conditions with counseling compared with one control condition. Experiment: 6 months of institutional treatment, (E2): 4–9 months of intensive counseling + sheltered housing, and Control: Regular short-term sheltered housing + standard counseling. Measurement: Baseline, discharge. Followup 6 months after discharge. Attrition: E = 86%, C = 71%.
Intervention/Control group/Dropout rate
2. Reeducative Therapy 2.1 Manual-based counseling methods: drug, standard, or node-link mapping
Drug type/ Patient selection
(cont.)
Article
Table A-6.2.
0.23
0.07
–
–
Se
31/33
25/30
22/30
24/30
Quality Score
380
6 Psychosocial Treatment for Drug Dependence
Pregnant cocaine abusers (n=12) Excluded
Cocaine abusers, outpatient care (n=448) Excluded
Consecutive selection of cocaine abusers + Axis II-disorder (n=264) Excluded
Cocaine abusers in outpatient care (n=448)
Cocaine abusers with other substance abuse in methadone program (n=37)
Elk [49] (1998)
Gottheil [61] (1998)
Marlowe [101] (1997)
Weinstein [165] (1997)
Silverman [143] (1996)
– 0.05
–
–
–
3 months of treatment with three treatments per week during ongoing 0.79 methadone treatment. Experiment: Experiment: (E1): Abstinence enhancement by voucher and Control: (C): Non-contingent voucher enhancement. Measurement: Baseline, (5 weeks), cont. measurement/week for 12 weeks, followup measurement at week 21. Attrition: 11% versus 17%.
3 months intervention, three approaches. Experiment: (E1): Intensive outpatient counseling + drug education 3 days/week, Control: (C1): Individual counseling once/w, (C2): Individual counseling + group once/week. Measurement: Baseline, 1 month, 2 months, 3 months. Attrition: 77%.
12 weeks of treatment in two approaches: Experiment: (E1): day care + high level of contingency enhancement, (E2): Outpatient counseling + high level of contingency enhancement versus Control: Outpatient behavioral counseling + low level of contingency enhancement, and (C2): Outpatient counseling + low level of contingency enhancement. Measurement: Baseline = 2 weeks assessment. Attrition: Not stated.
3 months of intervention, three approaches: Experiment: (E1): Intensive outpatient counseling + drug education 3 days/week, Control: (C1): Individual counseling once/week, (C2): Individual counseling + group once/week. Measurement: Baseline, 1, 2, 3, and 9 months. Attrition: 77%. Same study as Weinstein (1997) below. Longer followup.
Cocaine abusing pregnant women in two interventions where all are given a visit to a community health center + drug counseling, but with the difference in Experiment (E): Contingent enhancement for drug abstinence and Control (C), respectively: No enhancement schedule. Measurement: Continuously over 26 weeks. Attrition: 0% – all completed 16 weeks.
2.2 Contingency enhancement – behavioral skills, etc.
0.34
0.25
–
–
–
25/30
28/30
24/30
28/30
25/30
6.6 Appendix 381
Cocaine abusers with other substance abuse in methadone program (n=49)
Supplemental abuse in patients in methadone treatment (n=53) Excluded
Silverman [144] (1998)
Stitzer [154] (1992)
Marijuana (70%) and cocaine abusers (65%), (n=82)
Abusers from sample above, (n=74)
Clients in therapeutic community Re-entry phase. Completed treatment. (n=130)
Azrin [5] (1994)
Azrin [7] (1996)
Hawkins [66, 67] (1986, 1989)
2.3 Modeling, behavioral skills training, etc.
Drug type/ Patient selection
(cont.)
Article
Table A-6.2.
1.54
d
Two, 10-week interventions in addition to TC treatment: Experiment: Behavioral skills training and networking, versus Control: Remaining in TC but no extra training. Measurement: Baseline for the study, Followup 12 months. Attrition: E=33%, C=30%. Does not show drug measured.
9 months of followup after completed treatment of the above sample. Measurement: 12 + 9 months. Attrition: n=10, (14%).
Treatment intervention over 12 months: Experiment: Behavioral therapy versus Control: Supportive discussion. Measurement: Baseline, 12 months. Attrition: n=11 (24%).
–
as above
0.79
6 months of intervention. Experiment: (E1) Contingent take-home doses in – relation to 2 weeks consecutive drug abstinence, versus Control: (C1): Non-contingent take-home doses. Attrition: (E): 10=38% and (C), respectively: 7=26%. Small difference in dose (E): 23.1 w versus (C): 22.8 w.
5-week baseline period + 3 months of treatment with three treatments per week during ongoing methadone treatment. Experiment: (E1): Abstinence enhancement by intensification of voucher reward, (E2): Intensified abstinence enhancement with introductory booster dose and Control: (C): Non-contingent voucher enhancement. Followup for 8 weeks after completed treatment. Measurement: Baseline, (5 weeks), continuous measurement/week for 24 weeks, followup measurement at week 21. Attrition: 0%.
Intervention/Control group/Dropout rate
–
0.23
–
0.31
Se
23/30
22/32
20/30
27/30
25/30
Quality Score
382
6 Psychosocial Treatment for Drug Dependence
Abusers with cocaine dependence and concurrent alcohol dependence (n=122)
Cocaine abusers with Above conditions but with level of depression as one of the outcome diagnosis of depression measures. (n=110), outpatient care
Carroll [30] (1995)
Carroll [32] (1998)
Cocaine abusers, four different approaches (n=121) – outpatient care
Carroll [29] (1994)
– 0.15
Reported separately
–
Disulfiram and three types of manual-based therapy for 12 weeks. (I) Reported Cognitive behavioral therapy (CBT) plus disulfiram, (II) 12-step treatment separately (TSF) plus disulfiram, (III) Clinical management (CM) plus disulfiram – Clinical management (CM) plus disulfiram, (IV) Cognitive behavioral therapy (CBT) without medication, (V) 12-step (TSF) without medication. Measurement: Urinalysis each week during the study period. Sample: 117 of 122 (96%) start the treatment. Attrition: 83=(68%). Measurement: Urinalyses each week.
One-year followup of the above study with four different approaches.
Four interventions for 12 weeks: Experiment: (E1): Relapse prevention 0.35 (RPT) + desipramine, (anti-depr) (E2): Clinical management + desipramine, (E3): relapse prevention + placebo, and (C): clinical management + placebo. Measurement: Baseline, monthly, 6 months completed treatment. Attrition: 60% did not complete all 12 sessions: (E1)=51%, (E2)=63%, (E3)= 64%, and (C)=61%.
Cocaine abusers, four different approaches (n=169) – outpatient care
Carroll [28, 29] (1994, 1994)
Two interventions of 12-week duration, Experiment: Relapse prevention therapy (RPT), and Control: (C): Interpersonal short-term dynamic psychotherapy as control. Measurement: Start of therapy, completion – 12 weeks. Attrition: E: 33%, C: 62%.
Cocaine abusers in cocaine clinic (n=42)
Carroll [27] (1991)
2.4 Relapse prevention and cognitive relapse prevention, individual and group
–
0.27
0.44
29/30
29/30
29/30
29/30
24/30
6.6 Appendix 383
Drug type/ Patient selection
Opiate abusers in methadone treatment (n=133)
Patients in (TC) since 1 month with obsessive-compulsive Axis-II-diagnosis, (n=60) Cocaine (39%) Excluded
Cocaine dependent men in aftercare (n=98)
Homeless abusers of crack (n=176)
Cocaine abusers (n=32)
Catalano [26] (1997)
Fals-Stewart [50] (1992)
McKay [109] (1997)
Milby [115] (1996)
Schmitz [135] (1997)
(cont.)
Article
Table A-6.2.
– 0.06
d
PART A: Total 24 weeks of treatment: Phase I: 3 weeks of detoxification and 1.42 stabilization, Phase II: 8 weeks of treatment with Experiment: Group relapse prevention and Control: Individual relapse prevention. Measurement: Baseline, completed treatment, and 2, 4, 8, 12, and 24 weeks, respectively after completed treatment. Attrition: E = 21%, C = 22%.
0.10 Two approaches of psychosocial measures for homeless abusers: Experiment: Enhanced day treatment with group therapy, relapse prevention etc. and Control: one group with social standard measures. Within the scope for 12-step treatment. Measurement: T.1: Baseline, T.2: 2 months, T.3: 6 months, T.4: and followup at 12 months. Attrition: 23.6%.
– 0.14 Outpatient program with one month of introduction acclimatization and 5 + 18 months of intervention with randomization. Experiment: Individual relapse prevention + group, versus Control: 12-step treatment + drug counseling. Measurement: End of acclimatization month, and 6 months after completed treatment.
Recently admitted patients in therapeutic community with DSM-III-R, – Axis-II-diagnosis of obsessive-compulsive disorder treated under two approaches. Experiment: Environmental therapy + individual behavioral therapy for compulsory symptoms versus Control: (C 1): Environmental therapy + relapse prevention, and (C 2): Environmental therapy + relaxation treatment. Measurement: Baseline, 6 months, followup 12 months. Attrition: n=3 (5%).
Two treatment approaches compared. Experiment: Methadone maintenance treatment with relapse prevention versus Control: Standard methadone maintenance treatment. Measurement: Baseline, 9 months. Attrition: E: 12% (6), C: 12% (6).
Intervention/Control group/Dropout rate
0.40
0.18
0.20
–
0.17
Se
28/30
29/30
29/30
25/30
25/30
Quality Score
384
6 Psychosocial Treatment for Drug Dependence
Cocaine abusers in outpatient care treatment (n= 38)
Cocaine abusers, outpatient care/ treatment (n=40)
Cocaine abusers, outpatient care/ treatment (n=303)
Cocaine abusers, outpatient care/ treatment (n=184)
Cocaine abusers in acute phase in outpatient care (n=100)
Crack abusers, outpatient treatment (n=225) Excluded
Stimulant dependence (n=146) Excluded
Higgins [73] (1993)
Higgins [74] (1994)
Hoffman [77] (1994)
Hoffman [78] (1996)
Rawson [128] (1994)
Richard [129] (1995)
Shoptaw [141] (1994)
–
–
0.14
–0.49
–
4 months of intervention with manual-based treatment: Experiment: Intensive group therapy with two additional treatments versus Control: Standard group treatment with two additional treatments. Measurement: Baseline, 4 months. Followup 12 months. Attrition (E) = 37%, (C) = 56%. 26 weeks of intervention with manual-based interventions: Experiment: Matrix treatment versus Control: Standard treatment. Measurement: Baseline, 3 months, 6 months. Followup, 12 months. Attrition: 40–52%. Neurobehavioral treatment (Matrix model) is compared in three different intervention variants with neurobehavioral treatment only. Experiment: (E1): NbT + acupuncture, (E2): NbT + anti-craving medication, (E3): NbT + biofeedback, versus Control: NbT only. Measurement: Baseline. Followup 9 months, Attrition: E = 8%, C = 8%. 6 months of intervention is randomized to two approaches. Experiment: (E1): Matrix treatment, and desipramine treatment, versus Control: Matrix treatment only. Measurement: Baseline, T2: 2 months. Followup Retention: 56.8% total.
–
0.16
0.20
–
–
4 months of intervention, manual-based treatment. Experiment: Intensive group therapy with two additional treatments, versus Control: Standard group treatment with two additional treatments. Measurement: Baseline, 4 months. Attrition: (E) = 37%, (C) = 56%.
0.32
0.32
0.28
24 weeks of intervention, two approaches: Experiment: Contingency management + community reinforcement versus Control: Drug counseling in group and individually. Measurement: Baseline. Followup: 12 weeks, Followup: 24 weeks. Attrition: 12 weeks (10%), 24 weeks (35%).
24 weeks intervention, two approaches: Experiment: Contingency manage0.00 ment + community reinforcement versus Control: Drug counseling in group and individually. Measurement: Baseline, 24 weeks. Retention: E:11 (58%), C: 2 (11%).
2.5 Community reinforcement, matrix-model, and other combined models
25/30
22/30
24/30
28/30
26/30
26/30
25/30
6.6 Appendix 385
(cont.)
Drug type/ Patient selection
Intervention/Control group/Dropout rate
Consecutive selection of institutional treatment of drug addicts with mild to moderate depression (n=28) Excluded
3 treatment approaches in a department and an outpatient clinic (n=36) Excluded
Patients with cocaine abuse recruited from veterans administration (n=128, of whom 126 were men)
Bowman [17] (1996)
Fisher [54] (1996)
Maude-Griffin [102] (1998)
1 month of drug abstinence + 3 months of intervention for patients with cocaine as the main abuse. Experiment: (E): Cognitive behavioral therapy (CBT) and Control: (C): 12-step treatment. Measurement: Baseline, 4, 8, 12 weeks. Followup at 26 weeks. Attrition: (?) but does not differ significantly between groups. Dose: M (group) =14, M (indiv.) =5. Followup: 92% (12 weeks), 84% (26 weeks).
Dual-diagnosed (Axis-II) abusers were compared in Experiment: Outpatient treatment with Control: Patients who were hospitalized: Both approaches had two experimental groups: (E1): Cognitive-behavioral therapy, (E2): 12-step treatment, and (C): ”standard treatment”. Measurement: Baseline, and after 12 weeks. Attrition: n=0.
Drug addicts of various types of drugs were randomized to two approaches, of which one is a treatment model developed for treatment of depression: Experiment: Self-examination therapy versus Control: Discussion group (Current events). Measurement: Before treatment, after 4 weeks. Attrition: E=3 (11%), C=3 (11%).
2.6 Cognitive behavioral therapy individual and group – intended to change drug behavior only
Article
Table A-6.2.
0.21
–
–
d
0.18
–
–
Se
29/30
24/30
23/30
Quality Score
386
6 Psychosocial Treatment for Drug Dependence
0.26
Intervention with max of 12 family therapy sessions. Experiment: –0.02 Structural family therapy versus Control: Standard intervention – counseling. Measurement: Varies. Attrition: E: 7%, C: 58%.
Spanish-speaking abusers of marijuana (n=74)
Szapocznik [160] (1988)
0.18
0.21
0.01
0.58
Multicenter study with 6 family programs and two interventions. Experiment: (E): Functional family therapy or Control: (C): parental group. The intervention lasted for 6 months, once/week. Measurement: Baseline and followup at 50 weeks after baseline. Attrition: No data.
0.22
18 weeks of structural family therapy in two versions and two control groups with another treatment. Experiment: (E1): Family therapy with reward for participation, (E2): Family therapy without reward, Control: (C1): Methadone + individual counseling, (C2): Family film. Measurement: Baseline. Followup 12 months. Attrition: Not stated – but low according to Stanton & Shadish 1997.
Family therapy for teenage drug abusers mostly marijuana (88%), Alc (87%), Cocaine (52%) (n=135)
Friedman [59] (1989)
Patients were randomized after 1 month of orientation to Experiment: 0.27 Behavior oriented couples therapy + individual therapy once/w for 12 weeks (manual), versus Control: Individual therapy 2 hours/w plus home tasks for 12 weeks (manual). Measurement: Baseline, end of treatment = 12 weeks. Followup 3, 6, 9, and 12 months. Attrition: 0 = all complete the treatment.
Stanton & Todd [150] Abusers of different (1982) drugs and in different age groups (n=118)
80 couples where one member abuses
Fals-Stewart [51] (1996)
3 Psychotherapies 3.1 Family therapy
25/30
22/30
23/30
28/30
6.6 Appendix 387
(cont.)
Drug type/ Patient selection
Multicenter study of cocaine abusers from 5 centers (n=487)
Cocaine abusers with good social stability (n=168) Excluded
Patients in methadone treatment with or without psychosocial treatment (n=92)
Cocaine abusers in outpatient care (n=30) Excluded
Crits-Cristoph [41, 42] (1999)
Kang [91] (1993)
McLellan [112] (1993)
O’Brien [119] (1990)
3.2 Cognitive and dynamic psychotherapy
Article
Table A-6.2.
d
Two interventions were tested in an 18-week pilot study of cocaine abusers. – Experimental conditions: (E1): Supportive-expressive psychotherapy + cue exposure, (E2): Standard drug counseling + cue exposure, versus Control conditions: (C1): Supportive-expressive psychotherapy + attention and (C2): Standard drug counseling + attention. Measurement: Baseline after 7–10 days of detoxification. Completed treatment after 15 weeks. Attrition: None.
0.77 Three approaches tested on patients in methadone maintenance treatment. Experiment: (E1): Extended methadone treatment with work training, counseling, and family/couples therapy, (E2): Standard methadone treatment with drug counseling and enhancement schedules versus Control: (C) Minimum methadone treatment with only individual dose adjustment. Measurement: One week after start, and after 24 weeks of treatment. Attrition: 0%.
Four manual based treatment interventions: (E1): Individual + group drug – 0.06 counseling, (E2): Cognitive therapy + group drug counseling, (E3): Supportive-expressive therapy + group drug counseling, and (C): Group drug counseling only. Intervention: 36 individual and 24 group sessions over 6 months. Group counseling stimulated participation in 12-step programs and self-help groups. Measurement: Each month during treatment and followup: 9 months and 12 months, respectively, after baseline. Attrition: (E1) higher attrition than (E2) and (E3). – Three intervention models are compared in a study of cocaine abusers with employment for more than 3 years. It is a comparative study with three equivalent therapy approaches with an intensity of once/week (E1): Family therapy, (E2): Individual supportive psychotherapy, and (E3): Group therapy. Measurement: Baseline. Followup 6–12 months. Attrition: 27%.
Intervention/Control group/Dropout rate
–
23/30
26/30
20/30
–
0.23
33/36
Quality Score
0.11
Se
388
6 Psychosocial Treatment for Drug Dependence
Woody [173] (1987)
Opiate abusers in methadone maintenance treatment (n=110)
* Dynamic ** Cognitive
Three different intervention types are tested with methadone maintenance treatment as stabilizing base in all the treatment models. Experiment: (E1): Drug counseling + supportive-expressive psychotherapy (E2): Drug counseling + cognitive behavioral therapy, versus Control: Drug counseling only. All interventions last for 6 months. Measurement: Baseline. Followup 12 months. Attrition: 10%.
–1.0* 2.00**
0.29 0.31
29/30
6.6 Appendix 389
Drug type/ Patient selection
Intervention/Control group/Dropout rate
Randomized controlled trials in meta-analyses of effects in psychosocial treatment of cannabis abuse.
Marijuana (96%), cocaine abuse (35%), hallucinogen (31%), (n=82)
Marijuana (96%), cocaine abuse (35%), hallucinogen (31%), (n=26)
Abusers from the sample above (n=74)
Cocaine abusers with other substance abuse in methadone program (n=59)
Azrin [5] (1994)
Azrin [6] (1994)
Azrin [7] (1996)
Silverman [143, 144] (1996, 1998)
1.18
0.00
0.00
d
0.11 5 weeks baseline period, + 3 months treatment with three treatments per week during ongoing methadone treatment. Experiment: (E1): Abstinence reinforcement, intensified abstinence reinforcement with initial booster dose and Control (C): Non-contingent voucher reinforcement. Followup for 8 weeks after completed treatment. Measurement: Baseline, (5 weeks), continual measurements/week for 24 weeks, followup measurement week 21. Attrition: 0%.
9 months of followup after completed treatment of the above sample. Measurement: 12 + 9 months. Attrition: n=10, (14%).
Treatment intervention over 6 months. Experiment: Modeling, behavioral skills training, and stimulus control of max 15 sessions versus Control: Supportive counseling. Measurement: Baseline, continual urinary test sampling, and at 6 months. Attrition: 0%.
Treatment intervention over 6 months. Experiment: Modeling, behavioral skills training, and stimulus control of max 15 sessions versus Control: Supportive counseling. Measurement: Baseline, continual urinary test sampling, and at 6 months. Attrition: 0%.
1. Reeducative therapy, modeling, behavioral skills training, etc
Article
Table A-6.3.
0.28
0.43
0.40
0.40
Se
25/30
22/32
25/30
25/30
Quality Score
390
6 Psychosocial Treatment for Drug Dependence
Marijuana abusers in outpatient treatment (n=212)
Stephens [152] (1994)
Family therapy for teenage drug abusers with criminality (n=200)
Criminal teenagers with abuse of different drugs (n=84)
Teenage drug abusers (n=89)
Teenage abusers from a larger study (n=136)
Henggeler [70] (1991)
Henggeler [71] (1992)
Joanning [88] (1992)
Lewis [97] (1990)
3. Psychotherapies 3.1 Family therapy
Marijuana abusers in outpatient treatment (n=106)
Stephens [153] (1993)
–
0.24
0.19
–
1.01
Two treatment models with family therapy as experimental model are compared. Treatment time lasts between 2 months up to 12 months. Experiment: Home-based multisystemic family therapy versus Control: Standard outpatient treatment. Measurement: Baseline and at completion. Attrition: E: n=1 (2%), C: n=13, (22%). Three treatment models over 15 sessions of Experiment: (E1): Family system therapy, (Eb2): Group therapy for adolescents, and Control: (C): Family education against drugs. Measurement: Baseline, completed treatment. Attrition: 23% (FST), 56% (AGT), and 33% (FDE), respectively.
Two interventions over 12 weeks and 12 sessions Experiment: (E1): Purdue 0.49 Brief Family Therapy (PBFT), and Control: (C1): individual therapy, respectively. Measurement: Baseline, 3 months. Followup: 6 and 12 months. Attrition: not reported.
0.14
0.31
0.00
0.15
0.93
Two interventions: Experiment: (E): Multisystemic family therapy (24 sessions), and Control: (C): Individual drug counseling, (28 sessions). Measurement: Baseline and on completion.
Two 4-month interventions are compared. Experiment: Relapse prevention versus Control: Social support. Measurement: Baseline. Followup 3 months, followup 9 months, T4: Followup 12 months. Attrition: 31%.
Two 4-month interventions are compared. Experiment: Relapse prevention – 0.04 versus Control: Social support. Measurement: Baseline. Followup 3 months, followup 9 months, T4: Followup 12 months. Only prediction data are presented in this part study. Attrition: 31%.
2. Relapse prevention and cognitive relapse prevention, individual and group
20/30
24/30
23/30
19/30
27/30
27/30
6.6 Appendix 391
Immigrant families with teenagers (n=30)
Spanish speaking abusers, mostly marijuana (n=37)
Spanish speaking abusers of marijuana (n=108)
Scopetta [138] (1979)
Szapocznik [158] (1983)
Szapocznik [161] (1989)
Ziegler-Driscoll [177] Adolescents in a (1977) therapeutic community (drug-free) (n=79)
Drug type/ Patient selection
(cont.)
Article
Table A-6.3.
0.02
–
3 months of intervention. Experiment: (E1): Structural conjoint family therapy. (E2): Family therapy with family members only, Control: (C1): peer group. Measurement: Baseline, 12 weeks, and followup: 5 and 6 months. Drugs not specified – unclear reference to alcohol and drugs.
0.09
0.00
d
Intervention with max 12 family therapy sessions. Experiment: Structural family therapy versus Control: Standard intervention – counseling. Measurement: Varies. Attrition: E: 70%, C: 58%.
Family intervention program with two types of family therapy for adolescents with mild abuse of drugs, mainly marijuana. Experiment: Single-person family therapy versus Control: Conjoint family therapy. Measurement: Baseline. Followup 12 months. Attrition: not stated.
Three interventions: Experiment: (E1): Intramural structural family therapy, Control: (C): Ecological structural family therapy. Measurement: Baseline, completed treatment. Attrition: unknown.
Intervention/Control group/Dropout rate
–
0.19
0.33
0.00
Se
19/20
25/30
25/30
–
Quality Score
392
6 Psychosocial Treatment for Drug Dependence
6.6 Appendix
393
394
6 Psychosocial Treatment for Drug Dependence Table A-6.4.
Randomized controlled trials institutional treatment for drug abuse.
Article/Year
Drug type/ Patient selection
Design/ Comparison group
Retention
Treatment time
Alterman [2] (1994)
Cocaine abusers (n=111)
E=Inst (TC) (n=55) C=Day hospital (n=56)
89% (50) 54% (30)
1 month
Avants [3] (1998)
Opiate dependent patients with/without anxiety (n=307)
E=Day hospital (n=145) C=Enhanced methadone (n=146)
82%=119 81%=118
3 months
Avants [4] (1999)
Opiate dependent patients (n=308) Same study as above
E=Day hospital (n=145) C=Enhanced methadone (n=146)
82%=119 81%=118
3 months 6 months
Bailey [8] (1980)
An advanced organization and treatment project within the framework of correctional care where interns were to be randomized to three different groups of officers according to their knowledge and quality. In total, 280 patients were to
Bale [9] (1980)
Population (n=710) Randomized (n=457) Int to treat sample (n=227) = Detoxified opiate abusers
E1= TC/Family (n=23) E2= TC/Quadrants (n=73) E3=TC/Satori (n=64) E4=Methadone (n=67) C = Detoxification only: No RCT group (n=128)
1-2 years
ASI=Addiction Severity Index, Time-Line=Time-Line-Follow-back, a technique to measure drug/alcohol consumption over time with higher reliability. EMIT=laboratory measurement technique of drugs in urine, BDI=Beck Depression Inventory; standardized scale to measure depression, DSM-III-R, Standardized Diagnostic instrument, Self-Esteem=Rosenberger’s Self-Esteem Scale. TCU/SFR=American question inventory for knowledge on AIDS problems, self-estimation version. Effect estimation according to “intention-to-treat” definition where not otherwise specified. TC= Therapeutic Community.
6.6 Appendix
395
Time of measurement
Measure
Outcome
Quality
Baseline 7 months
ASI, Time-line Economy EMIT
Completed treatment: E>C, Chi2=17.06, p<0.001 Cocaine abst: E>C Chi2=0.21, n.s. Costs: E = $ 6898, p < C=$ 4218 Results: Improvement in ASI areas, 6 sign
27/30
Baseline 3 months
DSM-III-R BDI, SADS, STAI/EMIT
Abstinence: DPT=44%, E-Std = 38%, n.s. Abstinence/anxiety: High anxiety yields higher abstinence (52%) compared to low anxiety (38%), p<0.03. Quasiexperimental design
No RCT
Baseline 3 months 6 months
DSM-III-R BDI, SADS TAI/EMIT
Abstinence opiates – 6 months: E=53%, E-std=62% Abstinence cocaine – 6 months: E=52% E-std=54% Day hospital 3 times more expensive than extended methadone treatment at the same result level
28/30
be randomized to three groups of 53 staff members. However, the project had to be discontinued after resistance from the personnel to submit to assessment and categorization into these groups. Instructive and problematic. Baseline, 6 months followup and 12 months response (93%)
Interview
Complete treatment: 88%–99% Results: Improvement in drugs, criminality, and work. No differences between TC/MM. All conditions > no treatment Time: Min 50 days in TC to achieve an effect.
26/30
396
6 Psychosocial Treatment for Drug Dependence Table A-6.4.
(cont.)
Article/Year
Drug type/ Patient selection
Design/ Comparison group
Bale [10] (1984)
Int to treat-sample (n=181+166) = Detoxified abusers
E1=TC/Family (n=25) 18% (5) E2=TC/Quadrants (n=77) 25% (19) E3=TC/Satori (n=79) 25% (20) C=brief detox (n=166) This group was not randomized
Conrad [35] (1998)
Homeless abusers E=Case management in cocaine + opiate (53%) institution (n=358) C=21 days of hospital care + general community service
Missing
6 months
Fisher [54] (1996)
Patients with personality disorder (n=57) ITT sample = 38
None
3 months
Glider [62] (1996)
Drug-abusing women Comparison of two institutional treatment programs with and without their (TCs) – one where mothers could bring their children children (n not into treatment and one where they were not allowed to reported)
Guydish [65] (1998)
Drug abusers, mainly cocaine (74%) (n=534)
E=Therapy Community (TC) (n=255) C = Outpatient daily treatment (n=253)
6 months E=43 (29%) C=39 (34%)
6–12 months
Hiller [75] (1996)
Female substance abusers (n=21)
E=6 w. Psychoeducative treatment (n=11) C=No treatment (n=10)
8 (76%) 9 (90%)
1.5 months
Hughes [80] (1995)
Cocaine abusing women with children in TC (n=53)
E=TC Live-in children (31) C=TC – No children (n=22)
12 months (29%) 12 months (5%)
1–2 years
E = Institutional care with cognitive or 12-step C = Outpatient care with cognitive or 12-step C2 = natural group
Retention
Treatment time 1 year
6.6 Appendix
397
Time of measurement
Measure
Outcome
Quality
Baseline F-U: 2 years 24 months Response: 96%
Interview
Time in treatment: Sign rel to outcome (p<0.05) Post TC effects vs no treatment: Differential opiate abuse outcome for different outcome variables in different TCs. TC (n=181) Detox only (166) Results: drug-free: Fam=38%, Quadr=46%, Satori=23%, and Detoxification=24%.
26/30
3, 6, 9 months F-U: 12, 18, 24 months
ASI PHF EMIT
Differential retention not stated ASI/Drug: Reduced from 12 days/month to 3 days/months at 12 months. E>C. E>C at 3 months for drug, alcohol, housing (ASI) E>C best result up to 9 months. At 2 years, the effects are lost.
27/30
Baseline + 3 months
ASI SCID-II SCID-P
Institutional care with both cognitive and 12-step better than comparison group for ASI area of family function and social relations (p<0.001). In outpatient care, CBT was significantly better than either 12-step or clinical comparison group in the ASI areas of alcohol (p<0.05), social relations and family function (p<0.001), and mental function (p<0.004).
24/30
bring their children into treatment. Measured 12 months after completed treatment. Exemplary as illustration with RCT studies in TCs with high level of co-worker influence over admission process, etc. The study was discontinued.
No RCT
1, 6, 12 months FU: 83%
ASI, BDI, SCL-90 TC patients more depression, more alcohol and psychiatric problems initially (p<0.05) High drop-out within 2 weeks: E=42%, C=55% Pos. relation for time in treatment for TC and outcome > 6 months > briefer. Not applicable to day treatment.
28/30
Baseline, 6 months
TCU/SRF
Psychosocial knowledge: E > C, F=4.91, p<0.05 18/30 Self esteem × time in treatment: E > C, F=8.5, p<0.05 Time in treatment: E > C, F=11.42, p<0.01
Baseline 12 months 24 months
DSM-III-R
Time in treatment: E (300 d) > C (102 d) t=2.83, p<0.05
24/30
398
6 Psychosocial Treatment for Drug Dependence Table A-6.4.
(cont.)
Article/Year
Drug type/ Patient selection
Design/ Comparison group
Retention
Treatment time
Lam [94] (1995)
Cocaine and mixed abusers, homeless men (n=300)
E=90 days TC + aftercare 6 months (n=182) C=Standard treatment (n=112)
33%
90 days
McCusker [105] (1995)
Drug abuse population (n=628)
E=TC Relapse prevention 30% (221) at 6 months (n=294) 33% (97) C=TC Ind/group (n=122)
6 months 12 months
McCusker [106] (1997)
Drug abuse (n=539)
E=TC Relapse prevention 30% at 6 months Brief: 3 months (n=192) Long: <6 months (n=186) C=TC Ind/group Brief: 3 months (n=86) Long: <6 months (n=75)
3, 6, 12 months
McCusker [107] (1997)
Drug abuse (n=539)
Same study as above
30%
Above
Milby [115] (1996)
Homeless with crack abuse (n=176)
E=Enhanced day treatment group therapy, RPT (n=69) C=Social standard measure (n=62)
74.4%
2 months + 4 months
Smith [147] (1995)
Homeless mothers with abuse (n=149) Cocaine = 85%
E= Institutional treatment 13% (n=20) (n=67, 45%) 10% (n=8) C=Outpatient care (n=82, 55%)
90 days
Strang [155] (1997)
Patients in opiate detoxification (n=186)
E=Specialist unit (DDU), 52=75% (n=69) 13=43% C=General psych unit (GEN), (n=30) Patients were randomized before asked for consent.
10 days
6.6 Appendix
399
Time of measurement
Measure
Outcome
Quality
Baseline 12 months Response: 85%
ASI
Cocaine: Baseline (89%), 9 months (E=28%, C=37%) Alcohol: Base (80%), 9 months (E=39%, C=48%) 5 of 7 ASI indexes sign better for E than for C Time in treatment: E more improved at 21 months than C.
24/30
Baseline 6 months 12 months Response: 80%
BDI self-esteem interview
Retention: (6 months): E = C, but at 12 months somewhat higher for C than for E. Differential attrition: Drug use: 6 months: E=44%, C=50%. Result: Sign for 4 of 7 measures in E and 5 of 7 in C.
28/30
FU: 85.1%
ASI
No sign of effect from planned duration in 28/30 treatment. In the RPT program, patients randomized to 6-month programs had longer time until the first relapse than those in 3-month programs. (Risk=0.74). No effects beyond 6 months can be confirmed.
Above
Above
Patients who stayed longer than 80 days benefited 28/30 from the treatment up to 6 months, not longer. Those who planned longer treatment, but interrupted, had poorer outcome than those interrupting from brief programs.
Baseline 3, 6, 12 months
ASI
Retention: E > C (p<0.03), Pos cocaine E < C (p<0.003), Homelessness: E < C (p<0.03).
29/30
6, 12 months
ASI DSM-III-R DIS
Patients in institutional treatment had a 3.2 times lower dropout risk than those in outpatient programs. Drug abuse decreased in both groups, no sign differences: E=C.
24/30
Baseline 10 days F-U=30 days
EMIT
In the experimental group 79% were drug-free compared with 31% in the C-group. In the experimental group 42% were opiate-free compared with 0% in the C-group. In all measures, the specialized unit was superior to general psychiatric unit in detoxification.
25/30
400
6 Psychosocial Treatment for Drug Dependence Table A-6.4.
(cont.)
Article/Year
Drug type/ Patient selection
Design/ Comparison group
Retention
Treatment time
Vickers-Lahti [167] (1995)
Clients in two TC conditions (n=438) with and without court order
E=TC with 3 months treatment (n=221) C=TC with 6 months treatment (n=217) 3 levels of pressure from court
See results
3 months 6 months
6.6 Appendix
401
Time of measurement
Measure
Outcome
Quality
1–3 months
ASI Interview
Early dropout: High legal, moderate, low (–40 days) 16% 29% 33% Odds/Ratios: 0.38 0.86 0.76 Late dropout : High legal, moderate, low (40–79 days) 25% 19% 30% Odds/Ratios: 0.76 0.53
27/30
402
6 Psychosocial Treatment for Drug Dependence Table A-6.5.
Randomized controlled trials of psychosocial treatment for drug abuse and mental illness.
Article/Year
Drug type/ Patient selection
Design/ Comparison group
Retention
Burnam [23] (1995)
Homeless drug abusers with mental illness (n=276) Axis-I-diagnosis
E1=Institutional treatment (n=67) E2=Psychiatric outpatient care (n=144) C = General service (n=65)
58%=160
Clark [34] (1998)
Patients with mental illness and drug and alcohol abuse (n=223)
E: Assert community tr (n=100) C: Stand case management (n=93)
91%=193
Hurlburt [82] (1996)
Homeless drug with mental illness (n=361) schizophrenia, bipolar 25% alcohol or drug abuse
E= Contract for housing + case management (n=64) C= No contract for housing + case management (n=59)
?
Jerrell [86] (1995)
Abuse alcohol or drugs and Axis-I-diagnosis (n=132)
E1=12-step intervent (n=?) E2=Behavioral skills (n=?) C=Int case management (n=?)
?
Lehman [95] (1994)
Abuse alcohol or drugs and Axis-I-diagnosis (n=54)
E=Rehab + case management (n=29) C=Outpatient care (n=25)
?
Nuttbrock [117] Drug abuse and (1997) Axis-I-diagnosis (n=219)
E=Therapeutic community (n=192) 25%=48 C=Sheltered housing (n=129) 27%=35
Nuttbrock [118] Homeless with mental (1998) illness and abuse (N=694)
E=Therapeutic community (n=129) 25%=43 C=Sheltered housing (n=121) 37%=45 42% of those randomized started treatment
Teague [162] (1995)
E= Continuous treatment team (n=17) C=Standard case management (n=16)
Abuse alcohol or drugs & Axis-I-diagnosis (n=36)
SCID-II and DIS are standardized instruments to measure Axis-I and Axis-II diagnoses according to DSM-III-R. ASI=Addiction Severity Index, (McLellan et al., 1985). SAS=Social Adjustment Scale (Schooler et al., 1979). RFS=Role Functioning Scale (Green & Gracely, 1978), SLS = Life Satisfaction Scale (Stein & Test, 1980). SCL-90 = Symptom Checklist 90-item (Derogatis et al., 1974). All n where not otherwise stated = At least once/dose of the treatment = intention to treat.
6.6 Appendix
403
Time of measurement
Measure
Outcome
Quality
Baseline, 3, 6, and 9 months
SCID-II SCL-90 ASI
E1 better than E2 for substance abuse at 3 months, but no later. No effects on mental disorder
25/30
SATS Life-Qual
E and C sign lower abuse to 3 years (p<0.001). But E = C. DSM-III-R. Quality of life improved in both groups. But E = C. Costs lower over time in both groups. E = C
26/30
Baseline, + every 6 months – 3 years
Baseline, 12 months
DSM-III-R DIS Housing
E 4.9 times better than C for housing. Women 2 times > Men Psychiatric diagnosis does not influence initially or in the outcome
19/30
Baseline, 12, 18 months
DSM-III-R SAS, DIS SLS, RFS
Number of symptoms: E1 > C-M Sympt+social adjustment: E2 > C > E1
20/30
Baseline, 6, 12 months
SCID-II ASI
Very low compliance (20%) 18/30 No changes in abuse and no time x treatment effects
Baseline, 6, 12 months
CES-D BPRS DSM-III-R
Those with 12 months in TC had sign higher improvement in relations and personal care than those in sheltered housing.
22/30
Baseline, 6, 12 months
ASI, GAF, DSM-III-R BPRS
High attrition already prior to treatment (58%) Mentally ill had lower dropout Mentally ill improved symptomatically
26/30
Method study: Does not study treatment effects but treatment fact. Organization important.
15/27
Baseline, every Own scales month for 6 months
404
6 Psychosocial Treatment for Drug Dependence
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Terapeutisk Samfunn. Akad. Avhandl, Universitetsforlaget, Oslo 1979. Waldron HB. Adolescent Substance Abuse and Family Therapy Outcome. – A review of randomized trials. I Ollendick TH, Prinz RJ (Eds): Advances in clinical child psychology 1997; 19:199-234. Plenum Press, New York. Weinstein SP, Gottheil E, Sterling RC. Randomized comparison of intensive outpatient vs individual therapy for cocaine abusers. J Addict Dis 1997; 162:41–56. Weiss RD, Martinez-Raga J, Griffin MI, Greenfield SF, Hufford C. Gender differences in cocaine dependent patients: a 6-month follow-up study. Drug Alcohol Depend 1997; 441:35–40. Vickers-Lahti M, Garfield F, McCusker J, Hindin R, Bigelow C, Love C, Lewis B. The relationship between legal factors and attrition from a residential drug abuse treatment program. J Psychoactive Drugs 1995; 27:17–25. Wickler C. Dynamics of drug dependence: Implications of a conditioning theory for research and treatment. Arch Gen Psychiatry 1973; 28:611–616. Winick C. Retention and outcome at ACI – A unique therapeutic community. Int J Addict 1990; 251:1–26.
170 Wolberg LR (Ed): Short-Term Psy-
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177
chotherapy. Grune, Stratton, New York 1965. Wolberg LR. The Technique of Psychotherapy Vol 1: Grune, Stratton, New York 1988. Woody GE, Luborsky L, McLellan AT, O’Brien CP, Beck AT, Blaine J, Hole A. Psychotherapy for opiate addicts: does it help? Arch Gen Psychiatry 1983; 40:639–645. Woody GE, McLellan AT, Luborsky L, O’Brien CP. Twelve-month follow-up of psychotherapy for opiate dependence: Am J Psychiatry 1987; 144:590–596. Woody GE, McLellan AT, Luborsky L, O’Brien CP. Psychotherapy in community methadone programs: a validation study. Am J Psychiatry 1995; 152:1302–1308. Woody GE, Metzger D, Navaline H, McLellan AT, O’Brien CP. Psychiatric symptoms, risky behavior, and HIV infection. NIDA Res Monogr 1997; 172:156–170. Yalom I. The Theory and Practice of Group Psychotherapy. Basic Books, New York, (3rd Ed),1985. Ziegler-Driscoll G. Family research study at Eagleville Hospital and Rehabilitation Center. Fam Process 1977; 16:175–190.
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1 Kolumnentitel
7
Pharmacotherapy for Opioid Withdrawal Björn Axel Johansson
7.1
Background
Opioid dependence is often associated with extensive problems including, e.g., psychiatric comorbidity, multiple drug dependence, family dysfunction, unemployment, and criminality [24]. Withdrawal treatment is not treatment of the opioid dependence per se, but often a first step towards some other intervention. Withdrawal treatment may also terminate years of methadone treatment. Treatment usually takes place in a hospital, but outpatient treatment is also an option. The opioid withdrawal syndrome consists of symptoms associated with neurophysiological rebound in the organ systems affected by opioids with, e.g., cardiovascular, central nervous, and gastrointestinal symptoms as a consequence. The effect is mainly mediated by noradrenalin. Heroin withdrawal usually occurs 4 to 6 hours after the last heroin dose. Maximum symptoms are observed after 24 to 48 hours, although withdrawal may last for 7 to 14 days [24]. Aim The aim of the following systematic literature review is to attempt to answer the question: “Is pharmacological treatment effective in opioid withdrawal?” Search strategy and method A literature search using the search terms “alcohol”, “substance use”, and “RCT” (Randomized Controlled Trials) was conducted in MEDLINE for 1966 through 2000. A manual workup of the material was done. The Cochrane Library was also searched. Reference lists in published articles and reviews were hand-searched. The results are based exclusively on randomized and double-blind controlled studies. Diagnostic criteria Opioid dependence was defined according to the DSM or ICD systems. In some older studies other diagnostic criteria have been used, e.g., narcotic addicts.
Treating Alcohol and Drug Abuse. Edited by M. Berglund, S. Thelander, E. Jonsson Copyright c 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 3-527-30682-X
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7 Pharmacotherapy for Opioid Withdrawal
Included studies Included in this review were 33 studies with 2258 patients. Two studies, Kleber and Rounsaville, are based on the same patient data and are considered to be one study [17, 25]. Five studies appear in two different sections of the chapter [7, 8, 13, 22, 26]. In consolidating all data, the respective placebo groups have been counted twice. All 33 studies are presented in figures and tables. Six review articles have been included. Meta-analyses were not found in the literature. Excluded studies Twenty studies were excluded. None of these studies were clinical trials. Outcome measures The primary outcome measures have been withdrawal severity and retention in treatment. Secondary outcome measures have been opioid abuse and hypotension. Among comparisons between different adrenergic agonists, hypotension was considered a primary outcome measure. Tables The material is presented in three tables (non-rapid, rapid, and ultra-rapid). Each table presents firstly the primary outcome measures and existing significance (a nonsignificant effect is marked with a zero) and secondly the background data more thoroughly, including the treatment that patients received. The treatment is usually titrated in the first days and gradually discontinued towards the end of the treatment period. The tables do not reflect this in detail, but show only the maximum doses. Meta-analyses Meta-analyses were not performed due to the heterogeneity of the studies.
7.2
Principles of Withdrawal Treatment Non-rapid This treatment usually runs over 2 weeks. Two main approaches are used: treatment with nonopioids and opioid agonists, respectively. Non-opioid treatment mainly entails antiadrenergic agents such as clonidine, a drug originally used in treating hypertension. The alpha2 agonist clonidine (and also other adrenergic agonists) affects the pre-synaptic noradrenaline receptor alpha2 in locus coeruleus. Thereby, the release of noradrenalin, which contributes to development of withdrawal in association with discontinuation of opioids, is inhibited. Thus, the effect of clonidine is anti-adrenergic. The patient’s blood pressure is controlled before and during treatment to ensure that the drop is not too pronounced. The advantage of anti-adrenergic agents is that they do not cause tolerance or have any potential for dependence.
7.3 Non-Rapid
Methadone is usually used in opioid agonist treatment. The principle is based on cross-tolerance; one opioid agonist is replaced by another. The partial opioid agonist buprenorphine has also been tested. Buprenorphine was recently accepted by the Food and Drug Administration (FDA). Opioid agonist treatment is associated with risks for tolerance and dependence. Rapid In rapid withdrawal treatment, treatment time is shortened by precipitating withdrawal by adding an opioid antagonist, usually naltrexone. Treatment is often initiated with clonidine. Later the same day or the day after, naltrexone is added. The adrenergic agonist reduces the onset of symptomatology associated with antagonist treatment. The treatment lasts less than a week. Ultra-rapid Ultra-rapid withdrawal treatment is based on the rapid technique, but treatment takes place partly under anesthesia or under sedation. The patients are treated intravenously with an opioid antagonist. Treatment ranges from hours to one or more days (including post-treatment aftercare).
7.3
Non-Rapid (see Tables 7.1a–c) 7.3.1
Adrenergic Agonists Clonidine (unless otherwise stated) versus Placebo In two crossover studies with patients treated with methadone, Gold et al. reported fewer withdrawal symptoms for active substance compared with placebo after 90 and 120 min, respectively [10, 11]. In the first study, 10 of 11 patients continued with clonidine in outpatient care [10]. Jasinski et al., who also treated methadone patients, showed that clonidine had a better effect than placebo on autonomously regulated withdrawal symptoms [14]. In the study by Ghodse et al., which also presented results from patients treated with methadone, withdrawal severity for active substance and placebo was similar [9]. Gerra et al. reported fewer withdrawal symptoms among patients in the clonidine group. At a 3-month followup, 28 out of 33 patients in the clonidine group remained in the study, compared with 11 out of 19 in the placebo group. Of the clonidine patients, 40% turned in opioid-positive urinalyses versus 72% in the placebo group [7]. 7.3.1.1
Methadone Washton and Resnick reported similar withdrawal severity for clonidine and methadone. However, the clonidine patients were more troubled initially, while the methadone patients had more symptoms toward the end of treatment. The treat7.3.1.2
417
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7 Pharmacotherapy for Opioid Withdrawal
ment alternatives were equally effective in keeping the patients drug free 10 days after the final methadone dose [35]. Cami et al. reported similar withdrawal and side effects for the two agents. During the later part of the treatment, clonidine was more effective, and upon discharge these patients had almost no symptoms. The clonidine patients were more often affected by orthostatic hypotension [3]. Rounsaville and Kleber studied methadone patients and reported equivalent results regarding successful treatment, defined as 10 days of abstinence after the last methadone dose. Forty percent in both groups succeeded in this. Withdrawal and retention were similar. Methadone reduced the initial symptoms more effectively. The agents had equivalent effects on abuse and blood pressure. At followup after 6 months in patients without methadone treatment, 23% in the clonidine group and 39% in the methadone group were opioid free [17, 25]. San et al. reported similar results for methadone and clonidine, which were also compared with guanfacine, another adrenergic agonist. Generally, there was a similar profile of withdrawal severity, side effects, and blood pressure for methadone and the adrenergic agonists. Methadone was more effective in reducing the initial withdrawal symptoms [26]. San et al., in their 1994 study, examined patients treated with methadone. In withdrawal treatment, methadone alone was compared with methadone combined with guanfacine in various doses. No differences were found between the groups [28]. Bearn et al. compared methadone with yet another adrenergic agonist, lofexidine, in withdrawal treatment of methadone patients. On 6 out of 10 days, methadone was better than lofexidine in reducing withdrawal symptoms. Retention was similar in the two groups [1]. Gerra et al. found that clonidine was more effective than methadone in reducing withdrawal symptoms [8]. Buprenorphine Nigam et al. showed a similar withdrawal severity between clonidine and buprenorphine, although the buprenorphine patients demonstrated fewer symptoms between the third and fourth day. Of the clonidine patients 14% dropped out because of hypotension. No side effects were found in the buprenorphine group [21]. Janiri et al. compared buprenorphine with clonidine and lefetamine and found a similar retention for the two agents but fewer withdrawal symptoms in the buprenorphine group [13]. Cheskin et al. showed that buprenorphine, with respect to self-reported withdrawal, was superior to clonidine for the first 3 days, but not later. Furthermore, a lower blood pressure was noted in the clonidine group in the first 3 days [5]. O’Connor et al. showed that buprenorphine was more effective than clonidine in reducing withdrawal symptoms during days 1–4 [22]. 7.3.1.3
Doxepin Täschner et al. reported no differences between clonidine and doxepin [32]. 7.3.1.4
Other Adrenergic Agonists San et al. compared clonidine with guanfacine. No differences in blood pressure reduction or withdrawal symptoms were observed [26]. Janiri et al. included methadone-treated patients and studied the difference between clonidine and lefe7.3.1.5
7.3 Non-Rapid
tamine. The agents were equally effec-tive in treating withdrawal symptoms, and retention was similar [13]. Kahn et al., who also included patients treated with methadone, pointed to a similar withdrawal severity between clonidine and lofexidine; however, an increased subjective discomfort was reported in the clonidine group. Lofexidine was preferable as regards blood pressure because of a lower drop in systolic blood pressure on days 4 to 7 [16]. Lin et al. showed that clonidine, from a withdrawal and retention standpoint, was similar to lofexidine. Less hypotension in the lofexidine group was reported [18]. Carnwath et al. concluded that both clonidine and lofexidine can be used successfully in withdrawal treatment in methadone-treated patients. Less hypotension was observed in the lofexidine group [4]. Table 7.1a.
Non-rapid detoxification (adrenergic agents). Primary outcome measures
Clonidine (where not otherwise stated) versus • Placebo, 5 studies, n=189 Gold et al. [10] 1978 Gold et al. [11] 1980 Jasinski et al. [14] 1985 Ghodse et al. [9] 1994 Gerra et al. [7] 1995
+ [withdrawal severity] p < 0.01 + [withdrawal severity] p < 0.01 + [withdrawal severity] p = 0.05 0 + [withdrawal severity] p < 0.001
• Methadone, 7 studies, n=506 Washton & Resnick [35] 1980 Cami et al. [3] 1985 Rounsaville [25] 1985, Kleber [17] 1985 San et al. [26] 1990 [clonidine, guanfacine] San et al. [28] 1994 [guanfacine] Bearn et al. [1] 1996 [lofexidine] Gerra et al. [8] 2000
0 0 0 0 0 – [withdrawal severity] p < 0.05 + [withdrawal severity] p < 0.05
• Buprenorphine, 4 studies, n=216 Nigam et al. [21] 1993 Janiri et al. [13] 1994 [clonidine, lefetamine] Cheskin et al. [5] 1994 O´Connor et al. [22] 1997
0 – [withdrawal severity] p < 0.05 0 – [withdrawal severity] p < 0.01
• Doxepin, 1 study, n=100 Täschner et al. [32] 1986
0
• Other adrenergic agonists, 5 studies, n=244 San et al. [26] 1990 [guanfacine] Janiri et al. [13] 1994 [lefetamine] Kahn et al. [16] 1997 [lofexidine] Lin et al. [18] 1997 [lofexidine] Carnwath et al. [4] 1998 [lofexidine]
0 0 – [blood pressure] p < 0.01 – [blood pressure] p < 0.005 – [blood pressure] p < 0.05
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7 Pharmacotherapy for Opioid Withdrawal
7.3.2
Opioid Agonists Methadone versus Placebo San et al. reported a study with 22 patients who had spontaneously shifted from heroin to buprenorphine. Buprenorphine was discontinued immediately, after which the patients received either methadone or placebo. Eight out of eleven placebo patients needed treatment with methadone because of withdrawal symptoms [27]. 7.3.2.1
Buprenorphine Bickel et al. found no differences between the treatments with regard to withdrawal symptoms, retention, or abuse [2]. Johnson et al. included 162 methadone patients who were randomized to three different treatments: methadone 60 and 20 mg/day, respectively, and buprenorphine 8 mg/day. Only 50 patients participated in the full 17 treatment weeks; 17, 11, and 22 patients, respectively. These patients were then given withdrawal treatment for 8 weeks. The patients who were treated with the high dose alternatives remained longer than the patients who received 20 mg/day methadone. No differences in abuse were observed [15]. 7.3.2.2
Propoxyphene Tennant et al. showed that methadone was more effective with respect to withdrawal symptoms and retention, while the results for opioid-positive urinalyses were similar. At followup 1 month after completed treatment, 50% in both groups had relapsed to heroin abuse [31]. 7.3.2.3
Chlordiazepoxide Drummond et al. showed similar withdrawal severity and retention for methadone and chlordiazepoxide [6]. 7.3.2.4
Table 7.1b.
Non-rapid detoxification (opioid agonists and partial agonists). Primary outcome measures
Methadone versus • Placebo, 1 study, n=22 San et al. [27] 1992
+ [withdrawal severity] p = 0.0005
• Buprenorphine, 2 studies, n=95 Bickel et al. [2] 1988 Johnson et al. [15] 1992
0 0
• Propoxyphene, 1 study, n=72 Tennant et al. [31] 1975
+ [withdrawal severity, retention] p < 0.05, p < 0.05
• Chlordiazepoxide, 1 study, n=24 Drummond et al. [6] 1989
0
7.3 Non-Rapid
Summary (Non-Rapid) Clonidine is more effective than placebo and as effective as methadone with respect to withdrawal and retention. The adrenergic agonists lack the potential for dependence. Buprenorphine is better than clonidine in two out of four studies. Patients treated with opioid agonists have the least withdrawal symptoms initially in treatment. The adrenergic agonists are equally effective, but lofexidine causes less hypotension than clonidine. Methadone is more effective than placebo and similar to buprenorphine. 7.3.2.5
421
422
7 Pharmacotherapy for Opioid Withdrawal Table 7.1c. Non-rapid. Study
n
Agent
Treatment period (days)
Primary outcome measures Withdrawal Retention severity
1
NARS
Adrenergic agonists Clonidine (where not otherwise stated) versus 1. Placebo Gold [10] 1978
11
1. Clonidine 5 µg/kg x 2 2. Placebo
1. 100% 2. 100%
BL–90 min–120 min 1. 14–0.5–0.2p 2. 0p
Gold [11] 1980
30
1 Clonidine 6 µg/kg x 1 2. Placebo
1
NARS
1. 100% 2. 100%
BL–90 min–120 min 1. 14–6–0.6 2. 0p
Jasinski [14] 1985
10
1. Clonidine 0.6 mg/d 2. Clonidine 1.2 mg/d 3. Morphine 9 mg/d 4. Morphine 18 mg/d 5. Placebo
1
Himmelsbach 1. 79p 2. 49p 3. 105p 4. 96p 5. 142p
*
Ghodse [9] 1994
86
1. Clonidine 1.2 mg/d 2. Placebo
14
*
1. 57% 2. 73%
ARCI = Addiction research center inventory; ASRS = Abstinence symptoms rating scale; BL = Baseline; BP = Blood pressure; CQ = Craving questionnaire; DBP = Diastolic blood pressure; HDRS = Hamilton depression rating scale; im = Intramuscular; iv = Intravenous; mg = milligram; mmHg = millimeter mercury; NARS = Nurse abstinence rating scale; OOWS = Objective opiate withdrawal scale; OWC = Opiate withdrawal checklist;
7.3 Non-Rapid
423
Secondary outcome measures Blood pressure Other (mmHg)
Quality score
*
SBP 1. 124–106 2. 0 DBP 1. 85–69 2. 0
Methadone patients Cross-over design
24
*
SBP 1. 131–102 2. 0 DBP 1. 91–70 2. 0
Methadone patients Cross-over design
25
*
SBP/DBP 1. 103/69 2. 100/79 3. 115/75 4. 113/75 5. 117/80
50% methadone patients
26
*
*
Methadone patients
26
Abuse
OWS = Opiate withdrawal syndrome; po = peroral, oral administration; SCL = Symptom checklist; SBP = Systolic blood pressure; SOWS = Short opiate withdrawal scale; µg = microgram; VAS = Visual analoge scale; WOW = Weak opiate withdrawal scale; ( ) = Outcome completers analysis; * = Data missing or incompletely reported; £ = Naltrexone treatment initiated. Table continues on next page
424
7 Pharmacotherapy for Opioid Withdrawal Table 7.1c. (cont.) Study
n
Agent
Treatment period (days)
Primary outcome measures Withdrawal Retention severity
Gerra [7] 1995
52
1. Clonidine 0.15 mg iv x 3/d 2. Placebo
7
9 withdrawal sympt. d 2–3 1. 5–4p 2. 49–56p
1. 94% 2. 74%
Washton & Resnick [35] 1980
26
1. Clonidine, individual 30 dosage 2. Methadone 15–30 mg/d
Start End 1. ↑sympt. 2. ↑sympt.
*
Camí [3] 1985
45
1. Clonidine 1.1 mg/d 2. Methadone 35 mg/d
12
19 opiate withdrawal symptoms d 1–3–6–9–12 1. (55–60–40– 30–15%) 2. (75–60–40– 50–50%)
*
Rounsaville [25, 17] 1985
49
1. Clonidine 1.0 mg/d Placebo d 16–30 2. Methadone 20 mg/d Placebo d 21–30
30
ARCI
d 14–28 1. 77–36% 2. 100–48%
2. Methadone
d 0–7–14–21–28 1. 15–36–41–37– 22p 2. 12–13–13–18– 27p
ARCI = Addiction research center inventory; ASRS = Abstinence symptoms rating scale; BL = Baseline; BP = Blood pressure; CQ = Craving questionnaire; DBP = Diastolic blood pressure; HDRS = Hamilton depression rating scale; im = Intramuscular; iv = Intravenous; mg = milligram; mmHg = millimeter mercury; NARS = Nurse abstinence rating scale; OOWS = Objective opiate withdrawal scale; OWC = Opiate withdrawal checklist;
7.3 Non-Rapid
Abuse
1. 30% 2. 48%
425
Secondary outcome measures Blood pressure Other (mmHg)
Quality score
*
27
HDRS d 1–8 1. 44–22p 2. 40–37p Outpatient care
*
*
10 days drug-free after last methadone dose 1. 31% 2. 46% Methadone patients Outpatient care
21
*
Patients with orthostatic hypotension
17 symptoms of side effects d 1–3–6–9–12 1. (65–60–40–40–10%) 2. (70–60–45–40–20%)
26
10 days opioid- free after last methadone dose 1. 42% 2. 39%
29
1. (20%) 2. (7%)
1. 58% 2. 43%
Lowest blood pressure SBP/DBP 1. 100/71 2. 101/68 Methadone patients Outpatient care
OWS = Opiate withdrawal syndrome; po = peroral, oral administration; SCL = Symptom -checklist; SBP = Systolic blood pressure; SOWS = Short opiate withdrawal scale; µg = microgram; VAS = Visual analoge scale; WOW = Weak opiate withdrawal scale; ( ) = Outcome completers analysis; * = Data missing or incompletely reported; £ = Naltrexone treatment initiated. Table continues on next page
426
7 Pharmacotherapy for Opioid Withdrawal Table 7.1c. (cont.) Study
n
Agent
Treatment period (days)
Primary outcome measures Withdrawal Retention severity
San [26] 1990
90
1. Clonidine 1.05 mg/d 2. Guanfacine 3.6 mg/d 3. Methadone 37 mg/d
12
Withdrawal scale 21 items d 1–2–3–4–5–6–12 1. (7–8–7–5–5–4–3p) 2. (8–8–5–5–4–4–2p) 3. (7–5–3–3–3–3–3p)
*
San [28] 1994
144 1. Methadone 28 mg/d x VIII, then guanfacine 4 mg/d x IX 2. Methadone 28 mg/d x VIII, then guanfacine 3 mg/d x VII 3. Methadone 28 mg/d x XII
18
OWC d 1–10–20 1. 13–8–6p 2. 10–6–2p 3. 11–4–2p
1. 35% 2. 60% 3. 40%
86
10
Bearn [1] 1996
1. Lofexidine 2.0 mg/d 2. Methadone 58 mg/d
OWS d 1–10–20 1. 10–4–6p 2. 10–6–2p 3. 10–4–2p SOWS d 1–3–7–10–14–21 1. 5–11–14–15– 10–6p 2. 6–6–9–11– 14–8p
1. 86% 2. 98%
ARCI = Addiction research center inventory; ASRS = Abstinence symptoms rating scale; BL = Baseline; BP = Blood pressure; CQ = Craving questionnaire; DBP = Diastolic blood pressure; HDRS = Hamilton depression rating scale; im = Intramuscular; iv = Intravenous; mg = milligram; mmHg = millimeter mercury; NARS = Nurse abstinence rating scale; OOWS = Objective opiate withdrawal scale; OWC = Opiate withdrawal checklist;
7.3 Non-Rapid
427
Secondary outcome measures Blood pressure Other (mmHg)
Quality score
*
SBP d 1–2–3–12 1. (115–100–95–110) 2. (110–105–100–110) 3. (120–110–110–110)
Side effects 24 items d 1–2–3–4–12 1. (5–8–8–7–2) 2. (4–7–6–6–2) 3. (4–6–5–6–2)
29
*
*
Methadone patients
29
*
SBP/DBP
Methadone patients
29
Abuse
d 1–10 max 1. 112/70–128/82 2. 112/70–120/79
OWS = Opiate withdrawal syndrome; po = peroral, oral administration; SCL = Symptom checklist; SBP = Systolic blood pressure; SOWS = Short opiate withdrawal scale; µg = microgram; VAS = Visual analoge scale; WOW = Weak opiate withdrawal scale; ( ) = Outcome completers analysis; * = Data missing or incompletely reported; £ = Naltrexone treatment initiated. Table continues on next page
428
7 Pharmacotherapy for Opioid Withdrawal Table 7.1c. (cont.) Study
n
Agent
Treatment period (days)
Primary outcome measures Withdrawal Retention severity
Gerra [8] 2000
66
1. Clonidine V 0.15 mg x 6 x II. Clonidine iv 0.15 mg x 3 x III. Clonidine po 0.15 mg, days I–W. 2. Methadone 40 mg.
5. 10
9 withdrawal symptoms 0–5p d 1–2–3–4–5–8– 10–12–15 1. 1–3–2–1–1–1–1 2. 1–1–3–3–3–16 28–35–5
*
3. Buprenorphine Nigam [21] 1993
44
1. Clonidine 0.3–0.9 mg/d 2. Buprenorphine 0.6–1.2 mg/d
10
SOWS d 1–2–3–4–5–6–10 1. 12–20–20–16– 12–8–3p 2. 11–16–14–10– 7–5–2p (p< 0.001) days 3-6 OOWS d 1–2–3–4–5–6–10 1. 3–5–5–4–2–2–1p 2. 3–4–3–2–2–1–0p (p< 0.002) days 3–4
*
Janiri [13] 1994
39
1. Clonidine im 0.9 mg/d 2. Lefetamine im 240 mg/d 3. Buprenorphine im 0.9 mg/d
9
Withdrawal scale with 27 items d 1–5–8 1. 3–16–13p 2. 7–19–18p 3. 3–4–3p (p< 0.05) days 1–3
1. 85% 2. 77% 3. 85%
ARCI = Addiction research center inventory; ASRS = Abstinence symptoms rating scale; BL = Baseline; BP = Blood pressure; CQ = Craving questionnaire; DBP = Diastolic blood pressure; HDRS = Hamilton depression rating scale; im = Intramuscular; iv = Intravenous; mg = milligram; mmHg = millimeter mercury; NARS = Nurse abstinence rating scale; OOWS = Objective opiate withdrawal scale; OWC = Opiate withdrawal checklist;
7.3 Non-Rapid
Abuse
1. 40% 2. 62%
429
Secondary outcome measures Blood pressure Other (mmHg)
Quality score
*
27
Neg/pos craving VAS before after detoxification detoxification 1. 2.4/1.6p 3.4/2.5p 2. 2.0/5.8p 7.4/7.6p
Outpatient care
Day 4 and onward [n=27] 1. (0%) 2. (0%)
Interruption due to hypotension 1. 14% 2. 0%
*
28
*
*
Methadone patients
28
OWS = Opiate withdrawal syndrome; po = peroral, oral administration; SCL = Symptom checklist; SBP = Systolic blood pressure; SOWS = Short opiate withdrawal scale; µg = microgram; VAS = Visual analoge scale; WOW = Weak opiate withdrawal scale; ( ) = Outcome completers analysis; * = Data missing or incompletely reported; £ = Naltrexone treatment initiated. Table continues on next page
430
7 Pharmacotherapy for Opioid Withdrawal Table 7.1c. (cont.) Study
n
Agent
Treatment period (days)
Primary outcome measures Withdrawal Retention severity
Cheskin [5] 1994
25
1. Clonidine 0.9 mg/d 2. Buprenorphine 6–8 mg/d
10
ARCI BL–d1–2–3–10 1. (11–9–12–8–4p) 2. (10–6–4–6–6p) (p< 0.05) days 1–3
*
O’Connor [22] 1997
108 1. Clonidine po 8 0.6–1.2 mg/d x VII. Naltrexone po 50 mg day VIII. 2. Buprenorphine po 3 mg/d x III. Clonidine as above from day IV. Naltrexone po 25 mg day IV. Naltrexone po 50 mg day V.
24 withdrawal parameters, 0–3p BL–d1–2–3–4–5–8 1. 17–20–19–22– 14–13–12£p 2. 15–13–14–13– 10£–17–13p (p< 0.01) days 1–4 Average 1. 18p 2. 13p
1. 65% 2. 60%
100 1. Clonidine 0.7 mg/d 2. Doxepin 350 mg/d
10
d 1–5–10 1. (41–14–1p) 2. (39–12–1p)
1. 5.7 d 2. 5.1 d
12
Withdrawal scale, 21 items d 2–6–12 1. (8–4–3p) 2. (8–4–2p)
4. Doxepin Täschner [32] 1986
5. Other adrenergic agonists San [26] 1990
60
1. Clonidine 1.05 mg/d 2. Guanfacine 3.6 mg/d
ARCI = Addiction research center inventory; ASRS = Abstinence symptoms rating scale; BL = Baseline; BP = Blood pressure; CQ = Craving questionnaire; DBP = Diastolic blood pressure; HDRS = Hamilton depression rating scale; im = Intramuscular; iv = Intravenous; mg = milligram; mmHg = millimeter mercury; NARS = Nurse abstinence rating scale; OOWS = Objective opiate withdrawal scale; OWC = Opiate withdrawal checklist;
7.3 Non-Rapid
431
Secondary outcome measures Blood pressure Other (mmHg)
Quality score
*
Average blood pressure drop from BL SBP DBP 1. (–12 –10) 2. ( 0 0)
*
29
*
*
Successful detoxification 1. 65% 2. 81% Outpatient care
24
*
SBP/DBP d 1–9 1. (103/62–115/65) 2. (110/71–103/67)
Craving d 1– 5–10 1. (2.8–1.6–1.0p) 2. (2.2–1.3–0.8p)
24
*
SBP d 1–3–12 1. (115–95–110) 2. (110–100–110)
Side effects 24 items d 1–2–3–4–12 1. (5–8–8–7–2) 2. (4–7–6–6–2)
29
Abuse
OWS = Opiate withdrawal syndrome; po = peroral, oral administration; SCL = Symptom checklist; SBP = Systolic blood pressure; SOWS = Short opiate withdrawal scale; µg = microgram; VAS = Visual analoge scale; WOW = Weak opiate withdrawal scale; ( ) = Outcome completers analysis; * = Data missing or incompletely reported; £ = Naltrexone treatment initiated. Table continues on next page
432
7 Pharmacotherapy for Opioid Withdrawal Table 7.1c (cont.) Study
n
Agent
Treatment period (days)
Janiri [13] 1994
26 1. Clonidine im 0.9 mg/d 9 [39] 2. Lefetamine im 240 mg/d
Primary outcome measures Withdrawal Retention severity withdrawal scale with 27 items
1. 85% 2. 77%
d 1–5–8 1. 3–16–13p 2. 7–19–18p Kahn [16] 1997
28
1. Clonidine 0.9 mg/d 2. Lofexidine 1.8 mg/d
18
OWS d 0–7–14 1. 0.2–0.6–0.30p 2. 0.3–0.6–0.35p
*
Subjective discomfort 1. 86% 2. 14% Lin [18] 1997
80
1. Clonidine 0.6 mg/d 2. Lofexidine 1.6 mg/d
9
ASRS d 1–2–6 1. 2.6–4.9–0.0p 2. 2.6–5.9–1.7p
Day 4 1. 60% 2. 90% Average duration 1. 4d 2. 5d
Carnwath & 50 Hardman [4] 1998
1. Clonidine 0.8 mg/d 2. Lofexidine 1.6 mg/d
12
SOWS d 1–3–8–12 1. 2–9–11–10p 2. 2–10–14–12p
1. 50% 2. 71%
ARCI = Addiction research center inventory; ASRS = Abstinence symptoms rating scale; BL = Baseline; BP = Blood pressure; CQ = Craving questionnaire; DBP = Diastolic blood pressure; HDRS = Hamilton depression rating scale; im = Intramuscular; iv = Intravenous; mg = milligram; mmHg = millimeter mercury; NARS = Nurse abstinence rating scale; OOWS = Objective opiate withdrawal scale; OWC = Opiate withdrawal checklist;
7.3 Non-Rapid
433
Abuse
Secondary outcome measures Blood pressure Other (mmHg)
Quality score
*
*
Methadone patients
28
*
SBP d 0–7–14 1. 105–90–100 2. 105–105–100
Methadone patients
23
*
29
Follow-up 4 w; opioid-free patients 1. 50% 2. 71% Methadone patients Outpatient care
26
Hypotension 1. 93% 2. 53%
*
Patient days without medication due to hypotension 1. 21% 2. 10% Missed doses due to hypotension 1. 9% 2. 4%
*
SBP d 1–5–8–10–12 1. 108–95–77–85–100 2. 110–100–100–102– 100
OWS = Opiate withdrawal syndrome; po = peroral, oral administration; SCL = Symptom checklist; SBP = Systolic blood pressure; SOWS = Short opiate withdrawal scale; µg = microgram; VAS = Visual analoge scale; WOW = Weak opiate withdrawal scale; ( ) = Outcome completers analysis; * = Data available elsewhere in the tables; ** = Data missing or incompletely reported; fi = Patient material included in more than one study; £ = Naltrexone treatment initiated. Table continues on next page
434
7 Pharmacotherapy for Opioid Withdrawal Table 7.1c (cont.) Study
n
Agent
Treatment period (days)
Primary outcome measures Withdrawal Retention severity
1.Methadone 60 mg/d 2. Placebo
13
OWC 1. <10p/d 2. >15p/d
1. 91% 2. 73%
1. Methadone 30 mg/d 2. Buprenorphine 2 mg/d
90
Withdrawal scale, max 180p w 1–6 1. 40–22–20–34– 38–42p 2. 50–42–42–50– 47–48p
1. 5% 2. 0%
*
1. 62% 2. 27% 3. 73%
Opioid agonists Methadone versus 1. Placebo San [27] 1992
22
2. Buprenorphine Bickel [2] 1988
Johnson [15] 1992
45
50
1. Methadone 60 mg/d 2. Methadone 20 mg/d 3. Buprenorphine 8 mg/d
56
day 49 1. 40% 2. 50%
ARCI = Addiction research center inventory; ASRS = Abstinence symptoms rating scale; BL = Baseline; BP = Blood pressure; CQ = Craving questionnaire; DBP = Diastolic blood pressure; HDRS = Hamilton depression rating scale; im = Intramuscular; iv = Intravenous; mg = milligram; mmHg = millimeter mercury; NARS = Nurse abstinence rating scale; OOWS = Objective opiate withdrawal scale; OWC = Opiate withdrawal checklist;
7.3 Non-Rapid
435
Abuse
Secondary outcome measures Blood pressure Other (mmHg)
Quality score
*
*
Buprenorphine patients
31
Average pos or missed u–tox W 1–3–6 1. 1.4–1.5–1.8 2. 1.3–1.5–2.4
*
Outpatient care Placebo day 50–90
27
Average of u-tox neg for opioids 1. 34 %
*
Methadone and buprenorphine patients Outpatient care 2. 23% 3. 33%
28
OWS = Opiate withdrawal syndrome; po = peroral, oral administration; SCL = Symptom checklist; SBP = Systolic blood pressure; SOWS = Short opiate withdrawal scale; µg = microgram; VAS = Visual analoge scale; WOW = Weak opiate withdrawal scale; ( ) = Outcome completers analysis; * = Data missing or incompletely reported; £ = Naltrexone treatment initiated. Table continues on next page
436
7 Pharmacotherapy for Opioid Withdrawal Table 7.1c (cont.) Study
n
Agent
Treatment period (days)
Primary outcome measures Withdrawal Retention severity
3. Propoxyphene Tennant [31] 1975
72
1. Methadone 24 mg/d 21 2. Propoxyphene 800 mg/d
Himmelsbach 1. 6.7p 2. 9.7p
1. 69% 2. 42%
1. Methadone 25 mg/d 2. Chlordiazepoxide 250 mg/d
OOWS d 1, 3, 6, 9, 12 1. 53, 40, 35, 4, 24 2. 64, 80, 46, 42, 57
1. 38% 2. 36%
4. Chlordiazepoxide Drummond [6] 1989
24
13
ARCI = Addiction research center inventory; ASRS = Abstinence symptoms rating scale; BL = Baseline; BP = Blood pressure; CQ = Craving questionnaire; DBP = Diastolic blood pressure; HDRS = Hamilton depression rating scale; im = Intramuscular; iv = Intravenous; mg = milligram; mmHg = millimeter mercury; NARS = Nurse abstinence rating scale; OOWS = Objective opiate withdrawal scale; OWC = Opiate withdrawal checklist;
7.3 Non-Rapid
437
Secondary outcome measures Blood pressure Other (mmHg)
Quality score
1. 51% 2. 54%
*
Outpatient care
24
*
*
*
26
Abuse
OWS = Opiate withdrawal syndrome; po = peroral, oral administration; SCL = Symptom checklist; SBP = Systolic blood pressure; SOWS = Short opiate withdrawal scale; µg = microgram; VAS = Visual analoge scale; WOW = Weak opiate withdrawal scale; ( ) = Outcome completers analysis; * = Data missing or incompletely reported; £ = Naltrexone treatment initiated.
438
7 Pharmacotherapy for Opioid Withdrawal
7.4
Rapid (Tables 7.2a,b)
7.4.1
Adrenergic Agonist + Opioid Antagonists Clonidine versus Clonidine + naltrexone/naloxone versus Placebo Gerra et al. showed that clonidine was superior to clonidine plus naltrexone/naloxone and placebo in reducing withdrawal symptoms after 48 hours. The initially accentuated withdrawal for the combination alternatives was associated with the addition of the opioid antagonist. After 72 h, however, the same level of withdrawal was seen for the active treatment alternatives, which were all superior to placebo. The early accentuation of withdrawal severity for the rapid alternatives did not increase the dropout rate. At followup, 3 months after completed treatment, 85% of the clonidine patients who continued with placebo remained in the study. The figure was 91% in the combination alternatives who continued with naltrexone, and 58% in the placebo group. Concerning opioid-positive urinalyses, rates of 40%, 4%, 7%, and 72% were noted for the respective groups [7]. 7.4.1.1
Buprenorphine O’Connor et al. compared (1) clonidine and (2) clonidine plus naltrexone with (3) buprenorphine – later with the addition of clonidine and naltrexone, and reported that the treatment alternatives were equivalent in terms of successful treatment; clonidine group 65%, combination group 81%, and buprenorphine group 81%, respectively. Successful treatment implied accepting 50 mg of naltrexone. With respect to withdrawal severity, buprenorphine was more successful than the two other alternatives which were assessed as similar. The same retention was seen in the three treatment alternatives [22]. 7.4.1.2
Methadone The second study by Gerra et al. compared three treatment alternatives: (1) clonidine for 5 days, (2) clonidine + opioid antagonists for 2 days, and (3) methadone for 10 days. Gerra et al. noted a similar withdrawal severity of abstinence between the first two alternatives, which were superior to methadone in reducing the withdrawal symptoms from day 6. The first two treatment models were also better in treating negative craving. At followup, 3 months after completed treatment, 53% of the patients in group 1, 75% in group 2, and 26% of the patients in group 3 had continued with naltrexone. Among the naltrexone patients, 41%, 38%, and 33%, respectively, had relapsed in the different groups. Among patients not treated with naltrexone, the corresponding figures were 73%, 75%, and 88%, respectively [8]. 7.4.1.3
7.4 Rapid
7.4.2
Partial opioid agonist + opioid antagonist + adrenergic agonist Buprenorphine + Naltrexone + Clonidine versus Buprenorphine + Clonidine Umbricht et al. studied two treatment principles: buprenorphine + clonidine with (1) or without (2) naltrexone. When naltrexone was added on day 2 in the first treatment group, withdrawal symptom severity was accentuated, and 25% of the patients dropped out. The cumulative withdrawal severity was, however, equivalent in the two treatment models. Likewise, there was no difference in retention on day 8 [33]. Table 7.2a.
Rapid detoxification. Primary outcome measures
Clonidine (C) versus Clonidine + Naloxone/Naltrexone (CN) versus • Placebo (P) 1 study, n=152 Gerra et al. [7] 1995
C=CN + [withdrawal severity] p < 0.001
• Buprenorphine (B) 1 study, n=162 O’Connor et al. [22] 1997
C=CN – [withdrawal severity] p< 0.01
• Methadone (M) 1 study, n=98 Gerra et al. [8] 2000
C=CN + [withdrawal severity] p < 0.05
Buprenorphine + Naltrexone + Clonidine + (BNC) versus Buprenorphine + Clonidine (BC) 1 study, n=60 Umbricht et al. [33] 1999
0
Summary (Rapid) By adding an opioid antagonist, the duration of care can be shortened. Data do not reflect poorer retention in potentiation with an opioid antagonist. Opioid antagonist-induced withdrawal is associated with about the same overall severity as withdrawal with adrenergic agonists. An advantage of this method is that some patients can continue with naltrexone as pharmacological relapse prevention. 7.4.2.1
439
440
7 Pharmacotherapy for Opioid Withdrawal Table 7.2b. Rapid. Study
n
Agent
Treatment period (days)
Primary outcome measures Withdrawal Retention severity
Adrenergic agonists + opioid antagonists Clonidine versus clonidine + naltrexone/naloxone versus 1. Placebo Gerra [7] 1995
152 1. Clonidine iv 0.15 mg x 3 x VII. 2. Clonidine as above. Naltrexone po 12.5 mg day II. Naltrexone po 50 mg/d from day III.
7
9 withdrawal symptoms d 2–3 1. 5–4p 2. 23£–5p 3. 15§–4p 4. 49–56p
1. 94% 2. 95% 3. 98% 4. 74%
3. Clonidine as above. Naloxone iv 0.2 mg day II. Naloxone iv 0.4 mg x 2, day III–IV. Naltrexone po 50 mg/d from day V. 4. Placebo. BL = Baseline; DBP = Diastolic blood pressure; HDRS = Hamilton depression rating scale; iv = Intravenous; mg = Milligram; mmHg = millimeter mercury; OOW = Observer-rated opioid withdrawal scale; po = peroral, oral administration; SBP = Systolic blood pressure;
7.4 Rapid
Abuse
1. 30% 2. 5% 3. 11% 4. 48%
441
Secondary outcome measures Blood pressure Other (mmHg)
Quality score
*
27
HDRS d 1–8 1. 44–22p 2. 39–11p 3. 38–13p 4. 40–37p Outpatient care
VAS = Visual analog scale; £ = Naltrexone treatment initiated; § = Naloxone treatment initiated; < = Less than; * = Data missing or incompletely reported. Table continues on next page
442
7 Pharmacotherapy for Opioid Withdrawal Table 7.2b. (cont.) Study
n
Agent
Treatment period (days)
Primary outcome measures Withdrawal Retention severity
8
24 withdrawal symptoms, 0–3p BL–d 1–2–3–4–5–8 1. 17–20–19–22– 14–13–12£p 2. 16£–18–18–18– 17–14–11p 3. 15–13–14–13– 10£–17–13p
2. Buprenorphine O’Connor [22] 1997
162 1. Clonidine po 0.6–1.2 mg/d x VII. Naltrexone po 50 mg day VIII. 2. Clonidine as above and naltrexone po 12.5 mg day I, naltrexone po 12.5 mg day II and naltrexone po 50 mg day III.
3. Buprenorphine po 3 mg/d x III. Clonidine as above from day IV. Naltrexone po 25 mg day IV. Naltrexone po 50 mg day V.
1. 65% 2. 54% 3. 60%
Average 1. 18p 2. 18p 3. 13p
BL = Baseline; DBP = Diastolic blood pressure; HDRS = Hamilton depression rating scale; iv = Intravenous; mg = Milligram; mmHg = millimeter mercury; OOW = Observer-rated opioid withdrawal scale; po = peroral, oral administration; SBP = Systolic blood pressure;
7.4 Rapid
443
Abuse
Secondary outcome measures Blood pressure Other (mmHg)
Quality score
*
*
24
Successful detoxification 1. 65% 2. 81% 3. 81% Outpatient care
VAS = Visual analog scale; £ = Naltrexone treatment initiated; § = Naloxone treatment initiated; < = Less than; * = Data missing or incompletely reported. Table continues on next page
444
7 Pharmacotherapy for Opioid Withdrawal Table 7.2b. (cont.) Study
n
Agent
Treatment period (days)
98
1. Clonidine iv 0.15 mg 5 x 6 x II. 2 Clonidine iv 0.15 mg x 3 10 x III. Clonidine po 0.15 mg, day I–V.
Primary outcome measures Withdrawal Retention severity
3. Methadone Gerra [8] 2000
2. Clonidine iv 0.15 mg x 6 x II. Clonidine po 0.15 mg, day I–II. Clonidine po 0.15 mg x 3 day III. Repeated naloxone injections day I. Naltrexone po 5 mg day I. Naltrexone po 50 mg day II.
9 withdrawal parameters, 0–5p d 1–2–3–4–5–8– 10–12–15 1. 1–3–2–1–1–1–1 2. 2£§–5–2–1–1 3. 1–1–3–3–3–16– 28–35–5
*
3. Methadone 40 mg. BL = Baseline; DBP = Diastolic blood pressure; HDRS = Hamilton depression rating scale; iv = Intravenous; mg = Milligram; mmHg = millimeter mercury; OOW = Observer-rated opioid withdrawal scale; po = peroral, oral administration; SBP = Systolic blood pressure;
7.4 Rapid
Abuse
1. 40% 2. 4% 3. 62%
445
Secondary outcome measures Blood pressure Other (mmHg)
Quality score
*
27
Neg/pos craving VAS before after detoxification detoxification 1. 2.4/1.6p 3.4/2.5p 2. 2.6/2.1p 3.9/3.3p 3. 2.0/5.8p 7.4/7.6p Outpatient care
VAS = Visual analog scale; £ = Naltrexone treatment initiated; § = Naloxone treatment initiated; < = Less than; * = Data missing or incompletely reported. Table continues on next page
446
7 Pharmacotherapy for Opioid Withdrawal Table 7.2b. (cont.) Study
n
Agent
Treatment period (days)
Primary outcome measures Withdrawal Retention severity
Partial opioid agonist + opioid antagonist + adrenergic agonist Buprenorphine + Naltrexone + Clonidine versus 1. Buprenorphine + Clonidine Umbricht [33] 1999
60
1. Buprenorphine po 12 mg/d at a decreasing dose days I–IV. Naltrexone placebo day I. Naltrexone po at an increasing dose days II–VIII, 50 mg. Clonidine <0.35 mg/d days I–VIII, maximal dose day II. 2. Buprenorphine as above. Naltrexone placebo days I–VII. Naltrexone po 50 mg day VIII. Clonidine <0.35 mg/d, days I–VIII, maximal dose day VIII.
8
OOW d 1–2–3–4–5–6– 7–8 1. 3–5£–3–3–2– 1–1–1p 2. 4–2–2–2–2–3– 2–4£p
1. 56% 2. 76%
% patients with OOW 5p BL–d 1–2–3–4–5– 6–7–8 1. 50–28–60£–25– 28–10–0–0–0% 2. 47–32–10–22– 10–22–44–8– 35£%
BL = Baseline; DBP = Diastolic blood pressure; HDRS = Hamilton depression rating scale; iv = Intravenous; mg = Milligram; mmHg = millimeter mercury; OOW = Observer-rated opioid withdrawal scale; po = peroral, oral administration; SBP = Systolic blood pressure;
7.4 Rapid
Abuse
*
447
Secondary outcome measures Blood pressure Other (mmHg)
Quality score
SBP-elevation d 3 1. 23.1 2. 14.6
28
*
DBP-elevation d 3 1. 10.0 2. 5.6
VAS = Visual analog scale; £ = Naltrexone treatment initiated; § = Naloxone treatment initiated; < = Less than; * = Data missing or incompletely reported.
448
7 Pharmacotherapy for Opioid Withdrawal
7.5
Ultra-Rapid (Adrenergic agonist) + opioid antagonist under anesthesia, or under different levels of sedation (see Tables 7.3a,b) 7.5.1
Naloxone versus Placebo
Loimer et al. randomized 18 patients to either intravenous treatment with naloxone or to placebo. The treatment took place under anesthesia. Naloxone was more effective than placebo in reducing withdrawal symptoms [19]. 7.5.2
(Clonidine) + Naloxone/Naltrexone under Light Sedation versus Deep Sedation
Seone et al. randomized 300 patients to withdrawal treatment under either light or deep sedation. The anesthesia was propofol and midazolam. Treatment was then performed with, e.g., naloxone intravenously, clonidine subcutaneously, and naltrexone per os. Seone et al. reported successful treatment of withdrawal even among lightly sedated patients. The patients were discharged after 24 hours and continued with naltrexone 50 mg/day for 1 year. At followup 1 month after the detoxification, 93% of the patients were opioid free [29]. Table 7.3a.
Ultra-rapid detoxification. Primary outcome measures
Naloxone/under anaesthesia versus Placebo, 1 study, n=18 Loimer et al. [19] 1990
+ [withdrawal severity] p < 0.01
(Clonidine) + Naloxone/Naltrexone + under mild sedation versus Deep sedation, 1 study, n=300 Seoane et al. [29] 1997
0
7.5.3
Summary (Ultra-Rapid)
This is a new method which might be suitable for patients who are very anxious concerning withdrawal or who have failed in previous treatment attempts. Naloxone is more effective than placebo. The evidence, however, is not sufficiently investigated.
Table 7.3b see page 450/451.
7.6 Reviews
7.6
Reviews
O’Connor et al. discussed the rapid and ultra-rapid techniques. Twelve studies addressed rapid treatment while nine studies evaluated ultra-rapid treatment. O’Connor et al. pointed out that most studies suffered from methodological limitations. Two studies within the respective groups were randomized. O’Connor et al. call for further research concerning, e.g., safety, cost-effectiveness, and followup [23]. In the second review by O’Connor et al. the non-rapid technique was also discussed. Non-rapid Clonidine was considered to be as effective as lofexidine which, however, more rarely caused hypotension. Withdrawal treatment with clonidine was successful in outpatient care. Methadone and buprenorphine were comparable agents. Buprenorphine was also considered to be equal to clonidine. Rapid Buprenorphine with the addition of clonidine and naltrexone was better than clonidine or clonidine in association with naltrexone to treat withdrawal symptoms. Ultra-rapid The method had not yet been compared to other methods. The risks of anesthesia and safety limited its applicability in clinical practice. Rapid and ultra-rapid treatments may, however, create an opportunity for patients to start pharmacological relapse prevention with naltrexone more rapidly [24]. Concerning withdrawal treatment with methadone, the NIH report warned about discontinuing the agent too quickly, e.g., because of the risk of relapse. Buprenorphine was considered promising. Clonidine and clonidine together with naltrexone (rapid) were mentioned briefly. Both methods could be used to treat both inpatients and patients in open care [20]. Valmaña et al. mentioned that the adrenergic agonists clonidine and lofexidine were considered to be safe and equally effective and lacked the potential for dependence. Lofexidine was considered to cause less hypotension [34]. Gowing et al. reviewed the studies of rapid treatments. Three randomized studies fulfilled the inclusion criteria. Six other studies were also discussed. Gowing et al. concluded that it was possible to initiate withdrawal treatment by using clonidine in combination with naltrexone [12]. Strang et al. addressed the articles discussing lofexidine in the treatment of opioid withdrawal. Strang et al. summarized that lofexidine and clonidine were comparable concerning the ability to treat withdrawal, but that lofexidine caused fewer problems with hypotension. Lofexidine acted more rapidly than methadone in reducing withdrawal symptoms [30].
449
450
7 Pharmacotherapy for Opioid Withdrawal Table 7.3b. Ultra-rapid. Study
n
Agent
Treatment period (days)
Primary outcome measures Withdrawal Retention severity
(Adrenergic agonist) + opioid antagonist under anesthesia or under different levels of sedation Naloxone under anesthesia versus Placebo Loimer [19] 1990
18
1. Naloxone iv 10 mg under anesthesia (40 min). Then naloxone iv 2 mg, then naloxone infusion 0.8 mg/h under 48 hours.
2
2. Placebo
Wang (After awakening) before provocation with naloxone 2 mg 1. 6p 2. 3p
1. 100% 2. 100% 3 min after provocation with naloxone 2 mg 6p 17p
Kolb-Himmelsbach BL–d2–7 1+2. 4–20–3p (Clonidine) + naloxone/naltrexone under light vs deep sedation Seoane [29] 1997
300 1. Light sedation + clonidine sc 3 mg/kg x 6, naloxone infusion 0.06–0.08 mg/kg 5–10 min. Then naltrexone po 50 mg. Monitoring. 2. Deep sedation + medications as above. No monitoring.
1
Wang-Loimer 1. 100% 5 min 8 tim 2. 100% after after completed initiated inf. treatment 1. 4.8p 3.4p 2. 4.9p 3.9p
BL = Baseline; DBP = Diastolic blood pressure; h = Hours; iv = Intravenous; mg = Milligram; mmHg = millimeter mercury; SBP = Systolic blood pressure; sc = Subcutant, * = Data missing or incompletely reported.
7.6 Reviews
451
Secondary outcome measures Blood pressure Other (mmHg)
Quality score
1. 0% 2. 0%
*
*
27
*
SBP 1. 110–123 2. 110–124
*
26
Abuse
DBP 1. 64–81 2. 63–85
452
7 Pharmacotherapy for Opioid Withdrawal
7.7
Conclusion Non-rapid Clonidine is more effective than placebo and comparable with methadone and the partial opioid agonist buprenorphine. Lofexidine causes less hypotension than clonidine. Rapid An interesting method which shortens the treatment length and creates possibilities for pharmacological relapse prevention with naltrexone. Ultra-rapid Opioid antagonist treatment under anesthesia is still to be considered as experimental work.
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M. Efficacy of clonidine, guanfacine and methadone in the rapid detoxification of heroin addicts: a controlled trial. Br J Addict 1990; 85:141–147. San L, Camí J, Fernández T, Ollé JM, Peri JM, Torrens M. 1992. Assessment and management of opioid withdrawal symptoms in buprenorphine-dependent subjects. Br J Addict 1992; 87:55–62. San L, Fernandez T, Camí J, Gossop M. Efficacy of methadone versus methadone and guanfacine in the detoxification of heroin-addicted patients. J Subst Abuse Treat 1994; 11:463–469. Seoane A, Carrasco G, Cabré L, Puiggrós A, Hernández E, Álvarez M, Costa J, Molina R, Sobrepere G. Efficacy and safety of two new methods of rapid intravenous detoxification in heroin addicts previously treated without success. Br J Psychiatry 1997; 171:340–345. Strang J, Bearn J, Gossop M. Lofexidine for opiate detoxification: review of recent randomised and open controlled trials. Am J Addict 1999; 8:337–348. Tennant Jr FS, Russell BA, Casas SK, Bleich RN. Heroin detoxification. A comparison of propoxyphene and methadone. JAMA 1975; 232:1019–1022. Täschner KL. A controlled comparison of clonidine and doxepin in the treatment of the opiate withdrawal syndrome. Pharmacopsychiatry 1986; 19:91–95. Umbricht A, Montoya ID, Hoover DR, Demuth KL, Chiang CT, Preston KL. Naltrexon shortened opioid detoxification with buprenorphine. Drug Alcohol Depend 1999; 56:181–190. Valmaña, A. Nonmethadone pharmacotherapies in opioid addiction. Curr Op Psychiatry 1999; 12:307–310. Washton AM, Resnick RB. Clonidine versus methadone for opiate detoxification. Lancet 1980; 2:1297.
7.8 Appendix
7.8
Appendix
Since our search in MEDLINE (April 2000), further RCT studies have been published. Six randomized controlled studies with 394 patients were included; nonrapid 3 studies, rapid 1 study, and ultra-rapid 2 studies. In the non-rapid section, two new pharmacological principles have been studied: one GABA-receptor agonist and one dopamine agonist. Three recently published Cochrane reviews have also been included. Finally, two older studies (non-rapid, n=216), which were not included in the initial report, have been included here [4, 9]. 7.8.1
Non-Rapid (see Appendix Tables A-7.1 and A-7.2) Adrenergic Agonists Clonidine versus ● Methadone Jiang et al. randomized 200 patients to either clonidine or methadone. Between days 2 and 4, withdrawal severity was higher among the clonidine-treated patients, between days 8 and 12, withdrawal was instead higher in the methadone group [9]. Dawe and Gray included 16 patients, randomized to either clonidine or methadone. The clonidine-treated patients had their maximal withdrawal on day 2–3, whereas the methadone group had their withdrawal peak on day 10 [4]. 7.8.1.1
455
Akhondzadeh [1, 2] 2000, 2001
62
16
Dawe & Gray [4] 1995
Clonidine vs Baclofen
200
Jiang [9] 1993
n
Non-Rapid.
Adrenergic agonists Clonidine vs Methadone
Study
Table A-7.2.
1. Clonidine 0.8 mg/d 2. Baclofen 40 mg/d
1. Clonidine 0.12 mg/d 2. Methadone 57 mg/d
1. Clonidine 1.05 mg/d 2. Methadone 22 mg/d
Agent
14
13
12
Treatment period (days)
SOWS BL 1, 2, 3, 4, 7, 14 1. 5, 12, 16, 17, 13, 11, 8 2. 6, 12, 16, 16, 12, 8, 7 (ns)
SCL Max scores 1. 53p 2. 69p Day for max scores 1. 2–3 2. 10 (ns)
Himmelsbach Clonidine group Days 2–4 more symptoms Days 8–12 less symptoms (ns)
Withdrawal severity
1.45% 2.52%
–
–
Retention
Outcome measures
Mental symptom scores BL 1, 2, 3, 4, 7,14 1. 7, 7, 9, 8, 7, 6, 7 2. 8, 6, 5, 5, 4, 3, 2 (p=0.001) end of treatment
Orthostatic hypotension 1. 33% 2. 3% (p=0.015)
–
Side effects max diff day 2 1. 8.2 2. 1.9
Others
456
7 Pharmacotherapy for Opioid Withdrawal
(cont.)
n
40
26
1. Amantadine 250 mg/d 2. Placebo
1. Methadone + Carbamazepine 2. Buprenorphine + Carbamazepine
Agent
Abbreviations BL Baseline OWS Opioid Withdrawal Scale SCL Symptom Check List SOWS Short Opiate Withdrawal Scale
Pérez de los Cobos [12] 2001
Dopamine agonists Amantadine vs Placebo
Siefert [13] 2002
Opioid agonists Methadone vs Buprenorphine
Study
Table A-7.2.
14
14
Treatment period (days)
OWS No group differences in the completers analysis (n=25)
SOWS Buprenorphine had fewer symptoms than methadone (p<0.05)
Withdrawal severity
1) 60% 2) 60% (ns)
54% complete
Retention
Outcome measures
Craving No group differences in the completers analysis
No severe side effects in either group
Others
7.8 Appendix 457
458
7 Pharmacotherapy for Opioid Withdrawal
Baclofen Akhondzadeh et al. (2000, 2001) randomized 62 patients to either clonidine 0.8 mg/day or baclofen 40 mg/day. Concerning abuse and retention the substances had the same efficacy. Baclofen, however, was superior with respect to ortostatic hypotension and mental symptoms [1, 2]. ●
Opioid agonists Methadone versus buprenorphine Siefert et al. randomized 26 opioid-dependent and multidrug abusers to either methadone or buprenorphine to a 14-day inpatient detoxification study. All patients were also treated with carbamazepine. Patients treated with buprenorphine showed significantly fewer withdrawal symptoms. Fourteen of 26 patients (54%) completed the study. Seven of 12 noncompleters (58%) were treated with methadone, and 5 of 14 (36%) were treated with buprenorphine. The difference in dropout rate was not significant [13]. 7.8.1.2
Dopamine agonists Amantadine versus placebo Pérez de los Cobos randomized 40 patients to either amantadine 250 mg/day or placebo. Amantadine was not better than placebo [12]. 7.8.1.3
Table A-7.1.
Non-Rapid
Primary outcome measures
Clonidine vs • Methadone, 2 studies, n=216 Jiang et al. [9] 1993 Dawe & Gray [4] 1995
0 0
• Baclofen, 1 study, n=62 Akhondzadeh et al. [1, 2] 2000, 2001
– [blood pressure] p = 0.015
Methadone vs • Buprenorphine, 1 study, n=26 Siefert et al. [13] 2002
0
Amantadine vs • Placebo, 1 study, n=40 Pérez de los Cobos et al. [12] 2001
0
7.8.2
Rapid (see Appendix Tables A-7.3 and A-7.4) Adrenergic agonist + opioid antagonists Clonidine + naloxone/naltrexone versus lofexidine + naloxone/naltrexone Gerra et al. randomized 40 patients to either clonidine or lofexidine, 1.2 mg/day and 1.6 mg/day, respectively. All patients were also treated with, e.g., naloxone and nal-
Rapid.
n
Agent
40
1. Clonidine 1.2 mg/d plus oxazepam, baclofen, ketoprofene, naloxone, naltrexone 2. Lofexidine 1.6 mg/d Dito
Abbreviations POMS Profile of Mood States SBP Systolic Blood Pressure
Gerra [5] 2001
Adrenergic agonists + Opioid antagonists Clonidine vs Lofexidine
Study
Table A-7.4.
3
Treatment period (days)
Mean withdrawal scores d 1, 2, 3 1. 6, 10, 8 2. 5, 5, 3 (p<0.02) day 2 (p<0.001) day 3
Withdrawal severity
1. 85% 2. 90% (ns)
Retention
Outcome measures
POMS 3rd day 1. 5.3±0.4 2. 3.2±0.6 (p<0.01)
Hypotension The Clonidine group showed lower levels of SBP than the lofexidin group (p=0.001)
Others
7.8 Appendix 459
460
7 Pharmacotherapy for Opioid Withdrawal Table A-7.3.
Rapid Clonidine + naloxone/naltrexone vs • Lofexidine + naloxone/naltrexone, 1 study, n=40 Gerra et al. [5] 2001
Primary outcome measures
– [withdrawal severity] p < 0.05 – [blood pressure] p = 0.001
trexone. The patients were treated for 3 days. Lofexidine was better than clonidine to treat withdrawal symptoms. Differences in retention rates were not observed. The lofexidine group had less hypotension compared with the clonidine-treated patients [5]. 7.8.3
Ultra-Rapid (see Appendix Tables A-7.5 and A-7.6) (Adrenergic agonists) + opioid antagonists under anesthesia Propofol versus methohexital Kienbaum et al. treated 25 patients under general anesthesia. The patients were induced by either proprofol or methohexital. All patients were treated with naloxone for 24 h, clonidine and then naltrexone 50 mg/day ≥ 4 weeks. Differences in withdrawal severity were not observed between the two substances the day after detoxification, but subsequent withdrawal symptoms descended more rapidly after anesthesia induced by propofol [10]. Ultra-rapid versus Non-rapid McGregor et al. randomized 101 patients to either a 1-day precipitated withdrawal procedure using naloxone under anesthetic or to standard inpatient withdrawal treatment with clonidine. Both post-withdrawal groups were offered 9 months of naltrexone treatment. More of the patients in the precipitated withdrawal group completed withdrawal, commenced naltrexone, and stayed in treatment for the first 3 months [11].
Table A-7.5.
Ultra-Rapid
Primary outcome measures
Propofol vs • Methohexital, 1 study, n=25 Kienbaum et al. [10] 2000
+ [withdrawal severity] p < 0.05
Ultra-rapid vs • Non-rapid, 1 study, n=101 McGregor et al. [11] 2002
+ [abuse] p < 0.05
n
Ultra-Rapid. Agent
101
25
1. Naloxone under anesthesia 2. Clonidine
1. Proprofol 2. Methohexital
Abbreviations BL Baseline SOWS Short Opioid Withdrawal Scale
McGregor [11] 2002
Ultra-rapid vs non-rapid
Kienbaum [10] 2000
(Adrenorgic agonist) + opioid antogonist under anesthesia Proprofol vs Metohexital
Study
Table A-7.6.
1. 1 2. Non-rapid procedure
1
Treatment period (days)
Faster decrement in SOWS scores over time with proprofol (p<0.01)
SOWS Estim. BL, Day after detox 1. 3.5p, 16.3p 2. 18.2p, 18.2p
Withdrawal severity
Better long-term retention after ultra-rapid detoxification. All patients maintained on naltrexone for 3 month
1. 100% 2. 100%
Retention
Outcome measures
.
Lower opioid concentration after 6 months for patients treated with ultra-rapid technique (p<0.05)
Earlier extubation with proprofol
Others
7.8 Appendix 461
462
7 Pharmacotherapy for Opioid Withdrawal
7.8.4
Reviews
Three Cochrane reviews have recently been published: Amato et al. included 20 studies with 1357 patients randomized. Between methadone and adrenergic agonists there were no substantial differences in terms of retention, degree of discomfort, and detoxification success [3]. Gowing et al. revised articles of buprenorphine for the management of opioid withdrawal. Six studies (5 RCTs) involving 357 patients were included. Four studies compared buprenorphine with clonidine. All found withdrawal to be less severe in the buprenorphine treatment group. The rates of completion of withdrawal ranged from 65% to 100% [7]. Gowing et al. (2000, 2002) also reviewed the rapid technique. They included 10 studies (5 non-RCT) involving 770 patients. Antagonists-induced withdrawal was associated with similar or less overall severity than withdrawal managed primarily with an alpha2-adrenergic agonist. The use of opioid antagonists combined with an alpha2-adrenergic agonist was considered feasible and probably increased the likelihood of transfer to naltrexone compared to withdrawal managed primarily with an adrenergic agonist [6, 8]. 7.8.5
Conclusion
The new studies did not change the general conclusion.
Appendix References
Appendix References 1 Ahmadi-Abhari SA, Akhondzadeh S,
2
3.
4
5
6.
7
8
Assadi SM, Shabestari OL, Farzanehgan ZM, Kamplipour A. Baclofen versus clonidine in the treatment of opiates withdrawal, side-effects aspect: a double-blind randomized controlled trial. J Clin Pharm Ther 2001;26:67–71. Akhondzadeh S, Ahmadi-Abhari SA, Assadi SM, Shabestari OL, Kashani AR, Farzanehgan ZM. Double-blind randomized controlled trial of baclofen vs. clonidine in the treatment of opiates withdrawal. J Clin Pharm Ther 2000; 25:347–353. Amato L, Davioli M, Ferri M, Ali R. Methadone at tapered doses for the management of opioid withdrawal (Cochrane Review). In: The Cochrane Library, Issue 2, 2002. Oxford: Update Software. Dawe S, Gray JA. Craving and drug reward: a comparison of methadone and clonidine in detoxifying opiate addicts. Drug Alc Dep 1995; 39:207–212. Gerra G, Zaimovic A, Giusti F, Di Gennaro C, Zambelli U, Gardini S, Delsignore R. Lofexidine versus clonidine in rapid opiate detoxification. J Subst Abuse Treat 2001; 21:11–17. Gowing L, Ali R, White J. Opioid antagonists with minimal sedation for opioid withdrawal. Cochrane Database Syst Rev 2000; (3):CD002025 Gowing L, Ali R, White J. Buprenorphine for the management of opioid withdrawal. Cochrane Database Syst Rev 2002; (2):CD002025 Gowing L, Ali R, White J. Opioid antagonists with minimal sedation for
9
10
11
12
13
opioid withdrawal. Cochrane Database Syst Rev 2002; (2):CD002021 Jiang Z et al. Rapid detoxification with clonidine for heroin addiction. A comparative study on its efficacy vs methadone. Chinese J Neorol Psychiatry 1993; 26:10–13. Kienbaum P, Scherbaum N, Thürauf N, Michel MC, Gastpar M, Peters J. Acute detoxification of opioid–addicted patients with naloxone during propofol or methohexital anesthesia: A comparison of withdrawal symptoms, neuroendocrine, metabolic, and cardiovascular patterns. Crit Care Med 2000; 28:969–976. McGregor C, Ali R, Thomas P, Gowing L. A comparison of antagonist-precipitated withdrawal under anesthesia to standard inpatient withdrawal as a precursor to maintenance naltrexone treatment in heroin users: outcomes at 6 and 12 months. Drug Alcohol Depend 2002; 68:5. Pérez de los Cobos J, Duro P, Trujols J, Tejero A, Batle F, Ribalta E, Casas M. Methadone tapering plus amantadine to detoxify heroin-dependent inpatients with or without an active cocaine use disorder; two randomized controlled trials. Drug Alc Dep 2001; 63:187–195. Seifert J, Metzner C, Paetzold W, Borsutzky M, Passie T, Rollnik J, Wiese B, Emrich HM, Schneider U. Detoxification of opiate addicts with multiple drug abuse: a comparison of buprenorphine vs methadone. Pharmacopsychiatry 2002; 35:159–164.
463
1 Kolumnentitel
8
Pharmacotherapy for Opioid Dependence Björn Axel Johansson
8.1
Background
Opioid dependence is often accompanied by psychiatric comorbidity, multiple dependence, family dysfunction, unemployment, and criminality [46]. Opiate dependence in the form of heroin addiction is the greatest problem. Heroin (diacetylmorphine) is a semi-synthetic opioid manufactured from natural opioids. The broader term “opioid dependence” is used here as it also covers dependence on fully synthetic analogs, e.g., methadone. Methadone treatment for opioids dates back to the mid-1960s. Treatment usually lasts several years, and in some cases decades. During the 1980s and 1990s, other pharmacological principles have also been tested, e.g., the opioid agonist l-alphaacetylmethadol (LAAM), the partial agonist buprenorphine, and the opioid antagonist naltrexone. LAAM is an agonist which is chemically similar to methadone. The substance was registered in the United States in 1992. LAAM has been withdrawn from the European market because of cardiovascular side effects. Buprenorphine acts as a partial agonist on the µ-receptor, while the agent has a weak antagonistic effect on the k-receptor. Buprenorphine was approved by the U.S. Food and Drug Administration (FDA) in October 2002. The antagonist naltrexone makes opioidinduced euphoria impossible by binding to the opioid receptor and lacks the potential for abuse. Aim The aim of this systematic literature review is to attempt to answer the question: Does maintenance treatment have an effect on opioid dependence? Search strategy and method A literature search using the search terms “alcohol”, “substance use”, and “RCT” (Randomized Controlled Trials) was conducted in MEDLINE for 1966 through 2000. A manual workup was done of the material. The Cochrane Library was also searched. Reference lists in published articles and reviews were hand-searched.
Treating Alcohol and Drug Abuse. Edited by M. Berglund, S. Thelander, E. Jonsson Copyright c 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 3-527-30682-X
465
466
8 Pharmacotherapy for Opioid Dependence
The results are based exclusively on randomized and double-blind, controlled studies. Diagnostic criteria Opioid dependence according to the DSM or ICD systems. In some of the older studies other diagnostic criteria have been used, e.g., narcotic addicts. Included studies Sixty-nine RCTs have been included (n=7881). Also included were three meta-analyses [3, 14, 40], five reviews [10, 29, 43, 73, 71], two nonrandomized studies [7, 48], and a compilation of unpublished articles [4]. Kosten et al. [32, 33], Schottenfeld et al. [58, 59], and Strain et al. [63–68] used the same patients in their different studies. The articles have been clustered to one study for each author. Nine studies are reported in more than one place in the chapter [22, 23, 25, 32, 33, 37, 38, 49, 58, 59, 63–65]. The reason is that these articles contain two or more comparisons of the same substance or comparisons between different agents. In calculating the total patient database, the respective control groups have been counted more than once. Excluded studies Thirty-four studies were excluded. None of these studies were clinical trials. Outcome measures The primary outcome measures have been abuse (opioid positive urine analyses, objective, or self-reported data) and retention in treatment. On inclusion, most of the patients also abused other drugs, mainly cocaine. All results presented are significant (p<0.05) if nothing else is stated. Secondary outcome measures have been psychiatric symptoms and withdrawal severity. Meta-analyses Estimates of effect have been made for the primary outcome measures: abuse and retention. Improvement in depressive symptomatology has also been analyzed in studies of psychiatric comorbidity. If possible, the intention-to-treat (ITT) material has formed the basis for the mathematical calculations. Single studies are not included in the meta-analyses, but are presented in the tables. Tables The meta-analyses are presented in Tables 8.1, 8.2, 8.3, 8.6, 8.7, 8.10, and 8.13. Studies not included in the meta-analyses are presented in Tables 8.4, 8.5, 8.8, and 8.11. In these presentations significances are reported by + or – under the heading primary outcome measure. Plus (+) implies that the experimental substance is superior to the control (p < 0.05), while minus (–) implies the opposite. Zero indicates a non-significant effect. The material is also presented in Tables 8.9, 8.12, and 8.14 (opioid agonists, opioid antagonists, and adjunctive treatment with antidepressants). These tables report data from the studies more thoroughly.
8.2 Agonists
8.2
Agonists (see Tables 8.1 – 8.9)
Opioid abuse causes neuronal changes in locus ceruleus and in meso-limbic areas. These changes underlie the development of dependence, increased tolerance, and craving. An important goal of opioid agonist treatment is to reduce or prevent the development of withdrawal by stabilizing the neurochemical courses [46]. Treatment is based on cross-tolerance; one agonist (e.g., heroin) is replaced by another (e.g., methadone). The advantages of methadone compared to heroin include: (1) slower onset of action and less euphoric effect, (2) competitive antagonism; since the opioid receptors are blocked, any heroin intake can no longer produce the same euphoria, and (3) less spread of infection due to fewer injections [46]. 8.2.1
Agonists (Including Partial) Versus Control
Seven studies addressed methadone and one buprenorphine [8, 15, 23, 42, 60, 63–65, 72, 75]. Only one of the methadone studies and the buprenorphine study were placebo-controlled [23, 42]. Two of the methadone studies compared maintenance treatment with a gradually reduced dose for 45 and 180 days, respectively [60, 72]. Methadone versus control Methadone is a synthetic, long-acting u-opioid receptor agonist. The protein binding is >90%, which yields a stable serum level for 24 h. Long-term side effects do occur, e.g., constipation, weight gain, reduced libido, and irregular menses [46]. Dole et al., Newman & Whitehill, Gunne & Grönbladh, Yankovitz et al., Vanicheni et al., Strain et al., and Sees et al. have all studied the effect on abuse [8, 15, 42, 60, 63–65, 72, 75]. Three authors compared methadone with untreated controls [8, 15, 75]. One of these did not report doses [15]. In two of the studies only those who completed were analyzed [42, 75]. In all studies methadone reduced heroin abuse. Strain et al. reported two comparisons: 50 mg and 20 mg, respectively, versus 0 mg per day. The latter comparison was excluded from the meta-analysis because of suboptimal doses. All but one of the studies [15] also studied the effect on retention [8, 42, 60, 63–65, 72, 75]. In all studies there was an increased retention among the methadone patients [8, 42, 60, 63–65, 75, 72]. Meta-analysis Maintenance treatment with methadone is superior to controlled conditions regarding abuse; d (fixed model) = 0.56 (CI 0.44, 0.68). Test of heterogeneity positive. d (random model) = 0.65 (0.41, 0.89) and retention; d (fixed model) = 0.80 (0.68, 0.93). Test of heterogeneity positive. d (random model) = 0.92 (0.54, 1.29). See Tables 8.1a and 8.1b.
467
468
8 Pharmacotherapy for Opioid Dependence
Buprenorphine versus control Buprenorphine has a partial agonist effect on the µ-opioid receptor and a lesser antagonist effect on the k-receptor. The advantages compared with methadone (full agonist) are considered to be fewer withdrawal symptoms (=easier to discontinue), lower potential for abuse, and a smaller risk of respiratory depression and overdose [46, 71, 73]. Furthermore, buprenorphine dissociates more slowly from the opioid receptor, which yields a longer duration and the potential for administering fewer doses per week. Side effects occur, e.g., constipation and sleep disorders [46]. Only one controlled study was found. Johnson et al. studied the effect for both abuse and retention and showed in a 2-week study that buprenorphine (both 8 mg and 2 mg per day) reduced opioid abuse, but had no effect on retention [23]. The comparison between 2 mg (sub-optimal dose) and placebo was excluded from the meta-analysis.
Table 8.1a. Methadone or buprenorphine versus control. Outcome variable: abuse. bup = buprenorphine; met = methadone. Test of heterogeneity positive.
0.44 0.44 0.44
0.00 0.00 0.00
0.89 0.89 0.89
0.75 0.30 0.31 0.53 0.64
0.72 0.58 0.34 0.00 0.00 0.27 0.42
0.59 0.62 0.79 0.87
0.56 0.65
0.44 0.41
0.68 0.89
0.55 0.62
0.44 0.40
0.67 0.84
Table 8.1b. Methadone or buprenorphine versus control. Outcome variable: retention. bup = buprenorphine; met = methadone. Test of heterogeneity positive.
0.13 0.13 0.13
-0.31 0.57 -0.31 0.57 -0.31 0.57
0.94
0.60 0.52
0.66 0.88 0.32
0.34 0.61 0.09
0.98
0.80 0.92
0.68 0.54
0.93
0.75 0.81
0.63 0.45
0.87
0.55
8.2 Agonists
Meta-analysis Buprenorphine is superior to placebo in reducing abuse; d (fixed model) = 0.44 (CI 0.00, 0.89) but has no effect on retention. Tables 8.1a and 8.1b. Meta-analysis: agonists versus control Compiling all eight studies suggests that maintenance treatment with agonists (including partial) is effective; opioid abuse decreases d (fixed model) = 0.55 (CI 0.44, 0.67). Test of heterogeneity positive. d (random model) = 0.62 (0.40, 0.84) and retention improves d (fixed model) = 0.75 (0.63, 0.87). Test of heterogeneity positive. d (random model) = 0.81 (0.45, 1.17) in comparison with controlled conditions (Tables 8.1a and 8.1b).
8.2.2
Agonists versus Other Agonists Methadone versus LAAM LAAM is a long-acting methadone derivative which can prevent opioid withdrawal for up to 72 h. The long half-life means that the agent can be administered three times per week. Other advantages compared to methadone are a more stable and longer agonist effect and a reduced risk of relapse due to a missed dose. The side effects resemble those for methadone [46]. Both treatment methods were tolerated well; however, the patients who were treated with LAAM reported more side effects, which caused interruptions in treatment [14]. Only double-blinded RCTs were included in this part. Several RCTs, not double-blinded, were found in the literature. These articles were not included because LAAM has been withdrawn from the European market because of various medical complications. Jaffe & Senay, Jaffe et al., Ling et al., Savage et al., Panell et al., Freedman & Czertko, Karp-Gelernter et al., and Johnson et al. studied the effects on abuse [20, 12, 21, 25, 27, 35, 49, 57]. Savage et al. and Karp-Gelernter did not report any doses [27, 57, 27]. The study by Freedman and Czertko was excluded from the meta-analysis because of sub-optimal doses of both methadone and LAAM [12]. One of the comparisons by Johnson et al. (methadone 20 mg/day) was excluded for the same reason [25]. Ling et al. showed equivalent effects of methadone 100 mg/day and LAAM 80 mg 3 times/week. However, LAAM was superior to methadone at 50 mg/day [37]. All authors also studied the effect on retention [21, 37, 57, 49, 12, 27, 25, 20]. Johnson et al. and Ling et al. reported a positive methadone effect [37, 57, 25]. Meta-analysis LAAM has the same effect as methadone on abuse. d (fixed model) = –0.06 (CI –0.19, 0.06). Test of heterogeneity negative. On retention, however, methadone is superior: d (fixed model) = 0.34 (0.22, 0.46). Test of heterogeneity negative. (Tables 8.2a and 8.2b)
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8 Pharmacotherapy for Opioid Dependence Table 8.2a. Methadone versus LAAM. Outcome variable: abuse. Test of heterogeneity negative.
0.00 0.61 -0.33 0.10 0.00 -0.31 0.63 0.00 0.10
-0.11 -0.71 0.05 -0.31 0.51 -0.23 0.23 -0.54 -0.07 -0.03 1.28 -0.64 0.64 -0.30 0.50
-0.06 -0.19
0.06
Table 8.2b. Methadone versus LAAM. Outcome variable: retention. Test of heterogeneity negative.
0.00 0.28 0.41 0.35 0.43 0.23 0.54 0.20 0.36
-0.42 0.03 -0.06 0.19 0.00 -0.11 -0.45 0.03
0.99 0.79 0.76 0.67 0.46 1.19 0.84 0.69
0.34
0.22
0.46
Methadone versus buprenorphine Both substances were well tolerated [25, 58, 59]. The side effect profiles were similar [25, 38]. No obvious health risks were reported with buprenorphine [38]. Neither methadone nor buprenorphine caused side effects requiring a dose reduction or interruption of treatment [58, 59]. Bickel et al., Johnson et al., Kosten et al., Strain et al., Ling et al., Schottenfeld et al., Fischer et al., and Johnson et al. studied the effect on abuse [2, 11, 22, 25, 32, 33, 66–68, 38, 58, 59]. Ling et al. showed a positive methadone effect [38]. Bickel et al. and Kosten et al. were excluded from the meta-analysis because of sub-optimal doses [2, 32, 33]. All authors studied the effect on retention [2, 11, 22, 25, 32, 33, 38, 58, 59, 66–68]. Fischer et al. reported a positive methadone effect [59]. The agents were studied in 17 comparisons. Johnson et al., Kosten et al., Ling et al., Schottenfeld et al., and Johnson et al. reported two or more comparisons each [22, 25, 32, 33, 38, 58, 59]. In eleven comparisons, methadone and/or buprenorphine doses were below 50 mg and 8 mg per day, respectively [2, 22, 25, 32, 33, 38, 58, 59]. The literature presents evidence for what is considered to be optimal and suboptimal doses; 50 mg methadone and 8 mg buprenorphine are considered to be the lowest optimal doses. Comparisons containing at least one sub-optimal dose were excluded from the meta-analyses.
8.2 Agonists Table 8.3a. Methadone versus buprenorphine. Outcome variable: abuse. Test of heterogeneity negative.
-0.63 -0.55 -0.38 0.11 -0.30 -0.14
0.41 0.22 0.38 0.76 0.77 0.48
0.13 -0.03
0.28
-0.11 -0.17 0.00 0.44 0.24 0.17
Table 8.3b. Methadone versus buprenorphine. Outcome variable: retention. Test of heterogeneity negative.
0.67 -0.21 -0.80 0.24 0.59 0.00
0.14 1.20 -0.59 0.18 -1.20 -0.41 -0.09 0.56 0.05 1.14 -0.31 0.31
0.00 -0.15
0.16
Meta-analysis Methadone and buprenorphine are equally effective in terms of the primary outcome measures. On abuse d (fixed model) = 0.13 (CI –0.03, 0.28). Test of heterogeneity negative. On retention d (fixed model) = 0.00 (–0.15, 0.16). Test of heterogeneity negative (Tables 8.3a and 8.3b). Methadone versus buprenorphine: unpublished studies Chapleo reports three controlled, double-blind, European studies discussing treatment with methadone and buprenorphine with 190 patients in total. A preliminary assessment indicates that the studies confirm the similarity of the effects of the agents. Buprenorphine is considered to have a broad and effective dose interval. The agent is well tolerated and offers flexible dosage [4, 49b, 50b]. Methadone versus heroin Hartnoll et al. did not report any effect differences in illegal opioid abuse, but the heroin group remained longer in treatment than the methadone patients did. No differences between the agents concerning employment, criminality, or health were noted. Most of the patients abused illegal heroin daily: 59% in the methadone group and 64% in the heroin group [16]. In the study by Perneger et al., a smaller illegal heroin abuse occurred in the heroin group, who were social outcasts and had failed in previous treatment attempts. No dose level for methadone was reported. The heroin group made fewer suicide attempts, reported better mental health and a higher social functional level, and traded in heroin to a lesser extent than the
471
472
8 Pharmacotherapy for Opioid Dependence Table 8.4.
Methadone versus heroin.
Methadone versus heroin, 2 studies, n=147 Hartnoll [16] 1980 Perneger [50] 1998
– [retention] – [abuse; street heroin]
methadone patients. No effect differences concerning work or health condition were noted (Table 8.4) [50]. The studies by Hartnoll et al. and Perneger et al. are small and suffer from design problems. The results are not reported in meta-analysis. 8.2.3
Agonists versus Antagonists Methadone versus naltrexone No RCTs were found. Osborn did not report any difference for abuse, but better retention for the methadone patients. Osborn did not report any doses [48]. The study (non-RCT) is not reported in the meta-analysis or in the tables. 8.2.4
Agonists versus the Same Agonists Distribution Studies Methadone Contingency management (CM) versus non-CM: Higgins et al. and Stitzer et al. reported that opioid abuse decreased if the patients had the option to acquire extra methadone if they submitted a negative urinalyses (CM) compared to patients who could receive extra doses even if urinalysis showed positive for opioids (non-CM) [17, 62]. Kidorf did not report on doses, but showed that CM resulted in increased attendance in therapy sessions [28]. Preston pointed to the fact that CM had a positive effect on abuse [53]. The studies are not presented in the meta-analysis (Table 8.5). 8.2.4.1
Buprenorphine Outpatient care versus specialist clinic: O’Connor et al. showed that outpatient care was more successful than treatment in a specialist clinic [45, 46]. The outpatient care was associated with an established unit for abuse. The patients in outpatient care achieved three consecutive opioid-free weeks to a greater extent than the patients in the specialist clinic did. Retention in treatment was similar [45]. The study is not reported in the meta-analysis (Table 8.5).
8.2 Agonists Table 8.5. Distribution studies. Methadone: Contingency management versus non-contingency management. Buprenorphine: outpatient care versus specialist clinic.
Distribution studies Methadone, 4 studies, n=237 Higgins [17] 1986 Stitzer [62] 1992 Kidorf [28] 1994 Preston [53] 2000 Buprenorphine, 1 study, n=46 O´Connor [45] 1998
Comparisons
Primary outcome measures
CM versus non-CM + [abuse] + [abuse] 0 + [abuse] Outpatient care versus specialist clinic + [abuse]
8.2.4.2 Dose Level Studies Methadone Ling et al., Panell et al., Johnson et al., Strain et al., Kosten et al., Banys et al., Ling et al., Schottenfeld et al., Rhoades et al., Strain et al., and Johnson et al. studied the effect on both abuse and retention [1, 22, 25, 32, 33, 37, 38, 49, 55, 58, 59, 63–65, 69]. Eleven comparisons were made.
80–100 mg versus 50 mg: Ling et al., Panell et al., and Rhoades et al. presented comparisons between methadone 80–100 mg and 50 mg per day [37, 49, 55]. Rhoades et al. reported a positive result on abuse with the higher dose [55]. 50-80 mg versus 20-45 mg: Johnson et al., Strain et al., Kosten et al., Banys et al., Ling et al., Schottenfeld et al., Strain et al., and Johnson et al. compared methadone 50–80 mg with 20–45 mg per day [1, 22, 25, 32, 33, 38, 58, 59, 63–65, 69]. Ling et al., Schottenfeld et al., Johnson et al., and Strain et al. reported a positive result for abuse with the higher dose [25, 38, 58, 59, 69]. Johnson et al. also showed that the higher dose had a positive effect on retention [25]. Meta-analysis 80–100 mg is superior to 50 mg per day in reducing abuse. d (fixed model) 0.28 (CI 0.10, 0.46). Test of heterogeneity negative. The higher dose interval was also superior with regard to retention: d (fixed model) 0.25 (0.07, 0.43). Test of heterogeneity negative. 50–80 mg is superior to 20–45 mg on abuse. d (fixed model) 0.36 (0.23, 0.49). Test of heterogeneity negative. The higher dose was also superior on retention. d (fixed model) 0.30 (0.17, 0.43). Test of heterogeneity negative (Tables 8.6a, 8.6b). Buprenorphine Kosten et al., Johnson et al., Schottenfeld et al., and Ling et al. studied the effect on both abuse and retention [23, 24, 31, 32, 33, 39, 58, 59]. Kosten et al. reported four comparisons [31] and Ling et al. reported one [39] comparison between suboptimal doses, 3–6 mg versus 1–3 mg. These five comparisons were excluded from the meta-analysis.
473
474
8 Pharmacotherapy for Opioid Dependence Table 8.6a. Dose studies methadone. Outcome variable: abuse. 1 = 80–100 mg versus 50 mg; 2 = 50–80 mg versus 20–45 mg. Test of heterogeneity negative.
0.23 0.00 0.40 -0.24 0.35 0.03
0.46 1.05 0.68
0.28
0.10
0.46
0.52 -0.15 0.40 0.01 0.51 0.13 0.10 -0.38 0.46 0.14 0.54 0.01 0.25 -0.06 0.29 0.00
1.19 0.78 0.89 0.58 0.79 1.08 0.56 0.57
0.36
0.23
0.49
0.33
0.23
0.44
Table 8.6b. Dose studies methadone. Outcome variable: retention. 1 = 80–100 mg versus 50 mg; 2 = 50–80 mg versus 20–45 mg. Test of heterogeneity negative.
0.21 -0.02 0.33 -0.31 0.31 -0.02
0.44 0.98 0.63
0.25
0.07
0.43
0.13 0.26 1.13 -0.30 0.28 0.35 0.22 0.24
-0.53 -0.12 0.72 -0.78 -0.05 -0.19 -0.09 -0.05
0.79 0.64 1.54 0.19 0.60 0.88 0.53 0.52
0.30
0.17
0.43
0.28
0.18
0.39
16 mg versus 8 mg: Ling et al. compared 16 mg with 8 mg per day. They reported no effect differences between the doses [39]. 8–16 mg versus 1–4 mg: Johnson et al., Schottenfeld et al., and Ling et al. presented six comparisons of buprenorphine 8–16 mg versus 1–4 mg per day [23, 39, 58, 59]. Two of the comparisons by Ling et al. showed positive results with the higher dose on both abuse and retention [39]. Johnson et al. also compared 8 mg daily with 8 mg every second day. There were no effect differences between the two schedules concerning abuse and retention. The study by Johnson et al. is not included in the meta-analysis [24]. Meta-analysis Buprenorphine 16 mg per day is as effective as an 8 mg dose with respect to both abuse and retention. 8–16 mg is superior to 1–4 mg on abuse; d (fixed model) = 0.25
8.2 Agonists Table 8.7a. Dose studies buprenorphine. Outcome variable: abuse. 1 = 16 mg versus 8 mg; 2 = 8–16 mg versus 1–4 mg. Test of heterogeneity negative.
0.10 -0.10 0.10 -0.10
0.30 0.30
0.09 0.19 0.44 0.09 0.35 0.36
-0.36 -0.02 0.20 -0.11 0.14 -0.18
0.53 0.40 0.68 0.29 0.55 0.89
0.25
0.15
0.35
0.22
0.13
0.31
Table 8.7b. Dose studies buprenorphine. Outcome variable: retention. 1 = 16 mg versus 8 mg; 2 = 8–16 mg versus 1–4 mg. Test of heterogeneity negative.
Table 8.8.
0.18 -0.03 0.18 -0.03
0.38 0.38
-0.16 -0.60 0.21 0.00 0.43 0.22 0.03 -0.17 0.25 0.05 0.40 -0.13
0.29 0.42 0.64 0.23 0.45 0.94
0.21
0.12
0.31
0.21
0.12
0.30
Dose studies LAAM.
Does studies LAAM, 3 studies, n=369 Eissenberg [9] 1997 Oliveto [47] 1998 Jones [26] 1998 Buprenorphine, 6 studies, n=1179 1 study Ling [39] 1998 § 4 studies Johnson [23] 1995a Johnson [24] 1995b Schottenfeld [58, 59] 1997 Ling [39] 1998
330-340 mg versus 85-165 mg/w + [abuse] + [abuse] + [abuse]
16 mg versus 8 mg/d 0 8-16 mg versus 1-4 mg/d 0 0 0 0
(CI 0.15, 0.35). Test of heterogeneity negative. The higher dose interval was also superior concerning retention: d (fixed model) = 0.21 (0.12, 0.31). Test of heterogeneity negative (Tables 8.7a,b).
475
476
8 Pharmacotherapy for Opioid Dependence Table 8.9. Opioid agonists. Study
n
Agent
Psych. soc. Treat.
Treatment period (weeks)
Agonists versus control Methadone
Dole [8] 1969
28
1. Methadone 35 mg/d 2. Untreated control
*
50
Newman & Whitehill [42] 1979
100
1. Methadone 97 mg/d 2. Placebo
yes
156
Gunne & Grönbladh [15] 1981
34
1. Methadone, unknown* dose 2. Untreated control
104
1. 71%
Yancovitz [75] 1991
301
1. Methadone 80 mg/d 2. Untreated control
yes
64
Vanichseni [72] 1991
240
1. Methadone 74 mg/d 2. Methadone 58 mg/d [gradual withdrawal]
*
6
BDI = Becks depression inventory, BL = Base line, LAAM = Levo alpha acetyl methadol, OWRS = Opiate withdrawal rating scale, OWSC = Opiate withdrawal symptom checklist, WSC = Withdrawal symptom checklist, ( ) = Completers, * = Data missing or incompletely reported.
8.2 Agonists
Primary outcome measures Abuse Retention
477
Secondary outcome measures Psychatric/ Other withdrawal symptoms
Quality score
1. 75% 2. 6%
*
Work or school: 1. 50% 2. 0% Reincarceration 1. 25% 2. 94%
20
1. 56% 2. 2%
*
Deceased: 1. 14% 2. 0%
24
*
*
Deceased: 1. 0% 2. 12% Rehabilitated: 1. 76% 2. 6%
21
Pos u-tox 1. 29% 2. 60%
1. 72% 2. 56%
*
Cocaine-pos u-tox: 1. 68% 2. 70%
26
1. 28% 2. 53%
1. 76% 2. 34%
*
*
24
Readdicted 1. 0/12 2. 15/15
*
Drug free * 2. 6%
Table continues on next page
478
8 Pharmacotherapy for Opioid Dependence Table 8.9. (cont.) Study
n
Agent
Psych. soc. Treat.
Treatment period (weeks)
Strain [63–65] 1993, 1994
247
1. Methadone 50 mg/d 2. Methadone 20 mg/d 3. Methadone 0 mg/d
yes
26
Sees [60] 2000
179
1. Methadone 86 mg/d 2. Methadone 85 mg/d [gradual withdrawal]
yes
26
150 (103)
1. Buprenorphine 8 mg/d 2. Buprenorphine 2 mg/d 3. Placebo
yes
2
Buprenorphine Johnson [23] 1995
Agonists versus other agonists Methadone versus LAAM Jaffe & Senay [20] 1971
10
1. Methadone 68 mg/d * 2. LAAM 60 mg Saturdays, Methadone 50 mg/d week days
3
Jaffe [21] 1972
34
1. Methadone 30–80 mg/day 2. LAAM 36–80 mg
15
*
BDI = Becks depression inventory, BL = Base line, LAAM = Levo alpha acetyl methadol, OWRS = Opiate withdrawal rating scale, OWSC = Opiate withdrawal symptom checklist, WSC = Withdrawal symptom checklist, ( ) = Completers, * = Data missing or incompletely reported.
8.2 Agonists
479
Primary outcome measures Abuse Retention
Secondary outcome measures Psychatric/ Other withdrawal symptoms
Quality score
1. 56% 2. 68% 3. 74%
BDI: 1. (10 p) 2. (9 p) 3. (11 p) WSC: 1. (68 p) 2. (70 p) 3. (100 p)
Cocaine-pos u-tox: 1. 53% 2. 62% 3. 67%
26
*
HIV-risk behavior 1. 12 p–5 p 2. 10 p–7 p
w 20: 1. 52% 2. 42% 3. 21%
1. 67% 2. 88%
Median 1. 438 d 2. 174 d
1. (75%) 2. (80%) 3. (95%)
1. 73% 2. 80% 3. 67%
*
Patients who wanted a dose change: 1. (32%) 2. (27%) 3. (65%)
28
1. 20% 2. 20%
No group differences
*
*
23
Weeks with pos u-tox 1. 28% 2. 51%
1. 87% 2. 74%
*
Occupation BL–w 15: 27 1. 27%–67% 2. 27%–80% Table continues on next page
480
8 Pharmacotherapy for Opioid Dependence Table 8.9. (cont.) Study
n
Agent
Psych. soc. Treat.
Treatment period (weeks)
Ling [37] 1976
430
1. Methadone 100 mg/d 2. Methadone 50 mg/d 3. LAAM 80 mg 3 times/w
*
40
Savage [57] 1976
99
1. Methadone 2. LAAM Varied doses cross-over
*
26
Panell [49] 1977
60
1. Methadone 100 mg 2. Methadone 50 mg 3. LAAM 80 mg 3 times/w
*
40
Freedman & Czertko [12] 1981
48
1. Methadone 26 mg/d 2. LAAM 14 mg 3 times/w
yes
52
KarpGelernter [27] 1982
95
1. Methadone 2. LAAM Also randomized to two attendance schedules
*
40
Johnson [25] 2000
165
1. Methadone 60–100 mg/d 2. Methadone 20 mg/d 3. LAAM 75–115 mg, 3 times/w
*
17
BDI = Becks depression inventory, BL = Base line, LAAM = Levo alpha acetyl methadol, OWRS = Opiate withdrawal rating scale, OWSC = Opiate withdrawal symptom checklist, WSC = Withdrawal symptom checklist, ( ) = Completers, * = Data missing or incompletely reported.
8.2 Agonists
481
Primary outcome measures Abuse Retention
Secondary outcome measures Psychatric/ Other withdrawal symptoms
Quality score
Index forpos u-tox: 1. 23 p 1. 52% 2. 33 p 2. 42% 3. 21 p 3. 31% 1,3<2 (p<0.05/p<0.01)
*
Clinic visit/ expect. clin. visit: 1. 95% 2. 92% 3. 90%
24
1. 65% 2. 47%
*
*
22
Pos morphine score: 1. 12 p 1. 85% 2.18 p 2. 70% 3. 21 p 3. 60% 1<3(p<0.05)
*
*
23
1. 44% 2. 28%
1. 4% 2. 17%
*
*
24
Illegal drugs 1. 48% 2. 54%
1. 47% 2. 28%
*
*
24
1. 62% 2. 79% 3. 52%
1. 73% 2. 20% 3. 53%
*
>12 consecutive cocaine-neg urinalyses: 1. 38% 2. 14% 3. 36%
30
Pos u-tox 1. 5% 2. 8%
Table continues on next page
482
8 Pharmacotherapy for Opioid Dependence Table 8.9 (cont.) Study
n
Agent
Psych. soc. Treat.
Treatment period (weeks)
Methadone versus buprenorphine Bickel [2] 1988
45
1. Methadone 30 mg/d 2. Buprenorphine 2 mg/d
yes
3
Johnson [22] 1992
162
1. Methadone 60 mg/d 2. Methadone 20 mg/d 3. Buprenorphine 8 mg/d
yes
17
Kosten [32, 33] 1993, 1995
125
1. Methadone 65 mg/d 2. Methadone 35 mg/d 3. Buprenorphine 6 mg/d 4. Buprenorphine 2 mg/d
yes
26
Strain [66–68] 1994, 1996
164
1. Methadone mean 54 mg/d 2. Buprenorphine mean 9 mg/d
yes
16
Ling [38] 1996
225
1. Methadone 80 mg/d 2. Methadone 30 mg/d 3. Buprenorphine 8 mg/d
yes
52
Schottenfeld [58, 59] 1997, 1998
116
1. Methadone 65 mg/d 2. Methadone 20 mg/d 3. Buprenorphine 12 mg/d 4. Buprenorphine 4 mg/d
yes
24
BDI = Becks depression inventory, BL = Base line, LAAM = Levo alpha acetyl methadol, OWRS = Opiate withdrawal rating scale, OWSC = Opiate withdrawal symptom checklist, WSC = Withdrawal symptom checklist, ( ) = Completers, * = Data missing or incompletely reported.
8.2 Agonists
483
Primary outcome measures Abuse Retention
Secondary outcome measures Psychatric/ Other withdrawal symptoms
Quality score
Number of pos or 1. 80% missed u-tox w 3: 2. 92% 1. 1,5 2. 1,5
*
*
27
1. 56% 2. 71% 3. 47%
1. 32% 2. 20% 3. 42%
*
Cocaine-pos u-tox: 1. 64% 2. 57% 3. 52%
28
>70% opioid-free u-tox 1. 37% 2. 32% 3. 14% 4. 14%
1. 19 w 2. 21 w 3. 15 w 4. 17 w
OWRS: 1. 11 p 2. 14 p 3. 16 p 4. 19 p
$ heroin/month: 1. 180 2. 103 3. 225 4. 325
30
1. 47% 2. 55%
1. 56% 2. 56%
WSC: 1. (68 p–23 p) 2. (76 p–20 p)
Cocaine-pos u-tox: 1. 58% 2. 70%
29
Less craving 1<2,3
*
30
*
3 consecutive cocaine-free w: 1. 50% 2. 40% 3. 35% 4. 21%
30
% opioid-free u-tox 1. 62% 1. 31% 2. 45% 2. 19% 3. 45% 3. 20% Rates of pos u-tox 1. 45% 2. 72% 3. 58% 4. 77%
1. 64% 2. 47% 3. 55% 4. 35%
Table continues on next page
484
8 Pharmacotherapy for Opioid Dependence Table 8.9. (cont.) Study
n
Agent
Psych. soc. Treat.
Treatment period (weeks)
Fischer [11] 1999
60 (33)
1. Methadone max 80 mg/d 2. Buprenorphine max 8 mg/d
yes
24
Johnson [25] 2000
165
1. Methadone 60–100 mg/d 2. Methadone 20 mg/d 3. Buprenorphine 16–32 mg, 3 times/w = 7–14 mg/d
*
17
Methadone versus heroin Hartnoll [16] 1980
96
1. Methadone 60 mg/d 2. Heroin 60 mg/d
yes
52
Perneger [50] 1998
51
1. Methadone 2. Heroin iv 480 mg/d
yes
26
BDI = Becks depression inventory, BL = Base line, BZD = Bensodiazepines, LAAM = Levo alpha acetyl methadol, OWRS = Opiate withdrawal rating scale, OWSC = Opiate withdrawal symptom checklist, WSC = Withdrawal symptom checklist, ( ) = Completers, * = Data missing or incompletely reported.
8.2 Agonists
485
Primary outcome measures Abuse Retention
Secondary outcome measures Psychatric/ Other withdrawal symptoms
Quality score
1. 80% (73%) 2. 76% (37%)
1. 71% 2. 38%
*
*
28
Pos analyses/w: 1. 62% 2. 79% 3. 62%
*
>12 consecutive cocaine-neg urinalyses: 1. 38% 2. 14% 3. 30%
30
1. 73% 2. 20% 3. 58%
Regular illegal abuse: 1. 59% 2. 64%
1. 29% 2. 74%
*
Employment: 29 1. 23%–37% 2. 32%–38% Some time in prison: 1. 32% 2. 19% Failing health: 1. 33% 2. 33%
Self-reported daily illegal heroin w 26: 1. 48% 2. 4%
*
BL and w 26, respectively: Depression: 1. 48%, 14% 2. 48%, 30% Anxiety: 1. 43%, 43% 2. 82%, 44% Suicide attempt: 1. 14%, 19% 2. 22%, 4%
BL and w 26, respectively: Employment: 1. 19%, 14% 2. 15%, 22%
28
Table continues on next page
486
8 Pharmacotherapy for Opioid Dependence Table 8.9. (cont.) Study
n
Agent
Psych. soc. Treat.
Treatment period (weeks)
*
*
12
Agonists versus antagonists Methadone versus naltrexone Osborn [48] 1986
60
Agonists versus the same agonists Distribution principles Methadone Contingent versus non-contingent management Higgins [17] 1986
39
1. Methadone 30 mg/d [increased dose versus neg u-tox] 2. Methadone 30 mg/d [increased dose independent of u-tox] 3. Control
*
13
Stitzer [62] 1992
53
1. Methadone 51 mg/d [increased dose versus neg u-tox] 2. Methadone 51 mg/d [increased dose independent of u-tox]
*
52
BDI = Becks depression inventory, BL = Base line, LAAM = Levo alpha acetyl methadol, OWRS = Opiate withdrawal rating scale, OWSC = Opiate withdrawal symptom checklist, WSC = Withdrawal symptom checklist, ( ) = Completers, * = Data missing or incompletely reported.
8.2 Agonists
487
Primary outcome measures Abuse Retention
Secondary outcome measures Psychatric/ Other withdrawal symptoms
Quality score
1. 50% 2. 50%
1. 87% 2. 27%
*
*
25
w 8–11: 1. 14% 2. 38% 3. 50%
OWSC: 1. 25 p 2. 40 p 3. 50 p
Non-attendance: 1. 12% 2. 10% 3. 28%
23
1. 78 d 2. 75 d 3. 64 d
*
Drug-free after switch: 27 2) →1) 28%
4 consecutive drug-free w: 1. 32% 2. 8%
w 23: 1. 62% 2. 74%
Table continues on next page
488
8 Pharmacotherapy for Opioid Dependence Table 8.9. (cont.) Study
n
Agent
Psych. soc. Treat.
Treatment period (weeks)
Kidorf [28] 1994
25
1. Methadone, unknown dose a) with possibility for extra dose b) no possibility for an extra dose 2. Methadone, unknown dose a) with an extra dose after each therapy session b) with an extra dose after two consecutive therapy sessions
yes
12
Preston [53] 2000
120
1. Methadone 50 mg/d with enhancement in neg u-tox 2. Methadone 50 mg/d with dose increase to 70 mg/d and unconditional enhancement 3. 1 + 2 4. Methadone 50 mg/d with unconditional enhancement
yes
8
yes
12
Buprenorphine Outpatient care versus specialist clinic O’Connor [45] 1998
46 1. Buprenorphine Cocaine 22 mg Mon, Wed; Alcohol 40 mg Fri Outpatient care 2. Buprenorphine 22 mg Mon, Wed; 40 mg Fri Specialist care
BDI = Becks depression inventory, BL = Base line, LAAM = Levo alpha acetyl methadol, OWRS = Opiate withdrawal rating scale, OWSC = Opiate withdrawal symptom checklist, WSC = Withdrawal symptom checklist, ( ) = Completers, * = Data missing or incompletely reported.
8.2 Agonists
489
Primary outcome measures Abuse Retention
Secondary outcome measures Psychatric/ Other withdrawal symptoms
Quality score
*
*
*
Attendance at therapy sessions: 1a) 75% 1b) 7% 2a) 78% 2b) 51%
23
*
93% 87% 97% 96%
Craving: 1. 1.9 p–1.5 p 2. 2.1 p–1.4 p 3. 1.6 p–1.0 p 4. 1.8 p–1.3 p
*
Cocaine-pos u-tox: 1. 30.5% 2. 38.5%
Pos or missed u-tox: 1. 53% 2. 62% 3. 49% 4. 66%
1. 63% 2. 85% 3 consecutive drug-free w: 1. 43% 2. 13%
30
1. 78% 2. 52%
29
Table continues on next page
490
8 Pharmacotherapy for Opioid Dependence Table 8.9. (cont.) Study
n
Agent
Psych. soc. Treat.
Treatment period (weeks)
Ling [37] 1976
288
1. Methadone 100 mg/d 2. Methadone 50 mg/d
*
40
Panell [49] 1977
40
1. Methadone 100 mg 2. Methadone 50 mg
*
40
Johnsson [22] 1992
109
1. Methadone 60 mg/d 2. Methadone 20 mg/d
yes
17
Strain [63–65] 1993, 1994
166
1. Methadone 50 mg/d 2. Methadone 20 mg/d
yes
26
Kosten [32, 33] 1993, 1995
69
1. Methadone 65 mg/d 2. Methadone 35 mg/d
yes
26
Banys [1] 1994
38
1. Methadone 80 mg/d 2. Methadone 40 mg/d
yes
14
Dose level studies Methadone
BDI = Becks depression inventory, BL = Base line, LAAM = Levo alpha acetyl methadol, OWRS = Opiate withdrawal rating scale, OWSC = Opiate withdrawal symptom checklist, WSC = Withdrawal symptom checklist, ( ) = Completers, *= Data missing or incompletly reported.
8.2 Agonists
Primary outcome measures Abuse Retention
Index for pos u-tox 1. 23p 1. 52% 2. 33p 2. 42% (p<0.05)
Secondary outcome measures Psychatric/ Other withdrawal symptoms
*
491
Quality score
Clinic visit/expect. clin. visit: 1. 95% 2. 92%
24
*
1. 85% 2. 70%
*
*
23
1. 56% 2. 71%
1. 32% 2. 20%
*
Cocaine pos u-tox 1. 64% 2. 57%
28
w 20: 1. 52% 2. 42%
BDI 1. (10 p) 2. (9 p) WSC 1. (68 p) 2. (70 p)
Cocaine pos u-tox 1. 53% 2. 62%
26
1. 56% 2. 68%
>70% neg u-tox 1. 37% 2. 32%
1. 19w 2. 21w
OWRS 1. 11p 2. 14p
$ heroin/month 1. 180 2. 103
30
Withdrawal severity; Himmelsbach w 1, 14: 1. 7 p, 2 p 2. 7 p, 2 p
*
30
w 11–14: 1. 31% 2. 57%
1. 84% 2. 79%
Table continues on next page
492
8 Pharmacotherapy for Opioid Dependence Table 8.9. (cont.) Study
n
Agent
Psych. soc. Treat.
Treatment period (weeks)
Ling [38] 1996
150
1. Methadone 80 mg/d 2. Methadone 30 mg/d
yes
52
Schottenfeld [58, 59] 1997, 1998
58
1. Methadone 65 mg/d 2. Methadone 20 mg/d
yes
24
Rhoades et al. [55] 1998
150
1. Methadone 80 mg/d and 2 or 5 visit/w 2. Methadone 50 mg/d and 2 or 5 visit/w
yes
24
Strain [69] 1999
192
1. Methadone 80–100 mg/d 2. Methadone 40–50 mg/d
yes
30
Johnson [25] 2000
110
1. Methadone 60–100 mg/d 2. Methadone 20 mg/d
*
17
BDI = Becks depression inventory, BL = Base line, LAAM = Levo alpha acetyl methadol, OWRS = Opiate withdrawal rating scale, OWSC = Opiate withdrawal symptom checklist, WSC = Withdrawal symptom checklist, ( ) = Completers, *= Data missing or incompletly reported.
8.2 Agonists
Primary outcome measures Abuse Retention
Neg u-tox 1. 62% 2. 45%
1. 31% 2. 19%
493
Secondary outcome measures Psychatric/ Other withdrawal symptoms
Quality score
less craving 1<2
30
*
Rates of pos u-tox 1. 45% 2. 72%
3 consecutive cocaine-free weeks 1. 50% 2. 40%
1. 64% 2. 47%
*
1. 20% 2. 45%
1. 74% 2. 60%
*
*
27
1. 53% 2. 62%
1. 33% 2. 20%
*
Serious side effects: 1. 1.2% 2. 0.5%
30
1. 62% 2. 79%
1. 73% 2. 20%
*
>12 consecutive cocaine-neg urinalyses: 1. 38% 2. 14%
30
30
Table continues on next page
494
8 Pharmacotherapy for Opioid Dependence Table 8.9. (cont.) Study
n
Agent
Psych. soc. Treat.
Treatment period (weeks)
Eissenberg [9] 1997
180 (108)
LAAM 3 times/w: 1. 100 mg/100 mg/ 140 mg 2. 50 mg/50 mg/ 70 mg 3. 25 mg/25 mg/ 35 mg
no
17
Oliveto [47] 1998
9
1. LAAM 330 mg/w 2. LAAM 165 mg/w
yes
16
Jones [26] 1998
180 (149)
LAAM 3 times/w: 1. 100/100/140 mg 2. 50/50/70 mg 3. 25/25/35 mg
yes
4
Kosten [31] 1992
41
1. Buprenorphine 6+/ –2 mg/d 2. Buprenorphine 3 mg/d 3. Buprenorphine 2 mg/d
*
4
Kosten [32, 33] 1993, 1995
56
1. Buprenorphine 6 mg/d 2. Buprenorphine 2 mg/d
yes
26
LAAM
Buprenorphine
BDI = Becks depression inventory, BL = Base line, LAAM = Levo alpha acetyl methadol, OWRS = Opiate withdrawal rating scale, OWSC = Opiate withdrawal symptom checklist, WSC = Withdrawal symptom checklist, ( ) = Completers, * = Data missing or incompletly reported.
8.2 Agonists
Primary outcome measures Abuse Retention
1. 61% 2. 68% 3. 77% 4 consecutive opiate-free w: 1. 34% 2. 14% 3. 11%
Secondary outcome measures Psychatric/ Other withdrawal symptoms
Quality score
*
Cocaine-pos u-tox: 1. 62% 2. 61% 3. 63%
29
OWSC: 1. 14 p 2. 16 p
*
27
1. 59% 2. 66% 3. 55%
1. 22% 2. 53%
495
1. (71%) 2. (78%) 3. (82%)
1. 76% 2. 86% 3. 87%
*
Cocaine-pos u-tox: 1. (60%) 2. (61%) 3. (61%)
26
1. 37% 2. 27% 3. 37%
1. 82% 2. 70% 3. 63%
*
*
23
OWRS
$ Heroin/month
30
1. 16 p 2. 19 p
1. 225 2. 325
>70% opioid-free u-tox 1. 14% 2. 14%
1. 15 w 2. 17 w
Table continues on next page
496
8 Pharmacotherapy for Opioid Dependence Table 8.9. (cont.) Study
n
Agent
Psych. soc. Treat.
Treatment period (weeks)
Johnson [23] 1995
90
1. Buprenorphine 8 mg/d 2. Buprenorphine 2 mg/d 3. Placebo
yes
2
Johnson [24] 1995
99
1. Buprenorphine 8 mg/d 2. Buprenorphine 8 mg every second day, placebo every second day
yes
11
Schottenfeld [58, 59] 1997, 1998
58
1. Buprenorphine 12 mg/d 2. Buprenorphine 4 mg/d
yes
24
Ling [39] 1998
736 (375)
1. Buprenorphine 16 mg/d 2. Buprenorphine 8 mg/d 3. Buprenorphine 4 mg/d 4. Buprenorphine 1 mg/d
yes
16
BDI = Becks depression inventory, BL = Base line, LAAM = Levo alpha acetyl methadol, OWRS = Opiate withdrawal rating scale, OWSC = Opiate withdrawal symptom checklist, WSC = Withdrawal symptom checklist, ( ) = Completers, * = Data missing or incompletely reported.
8.2 Agonists
Primary outcome measures Abuse Retention
1. 75% 2. 80%
1. 73% 2. 80%
1. 57% 2. 69%
1. 72% 2. 57%
1. 58% 2. 77%
1. 55% 2. 35%
1. 62% 2. 67% 3. 71% 4. 82% 13 consecutive neg u-tox: 1. 27% 2. 18% 3. 14% 4. 9%
1. 61% 2. 52% 3. 51% 4. 40%
Secondary outcome measures Psychatric/ Other withdrawal symptoms
*
Patients who wanted a dose change 1. (32%) 2. (27%)
497
Quality score
28
OWSC: 1. 41 p 2. 48 p
Cocaine-pos u-tox: 1. 49% 2. 47% Not in meta-analysis
29
*
3 consecutive cocaine- 30 free w 1. 35% 2. 21%
Craving: 1. (39 p–23 p) 2. (37 p–21 p) 3. (42 p–18 p) 4. (45 p–28 p)
“Much better” [staff ratings]: 1. 42% 2. 38% 3. 38% 4. 21%
28
498
8 Pharmacotherapy for Opioid Dependence
LAAM Eisenberg et al., Oliveto et al., and Jones et al. reported a reduced abuse in treatment with 335±5 mg compared to 125±40 mg per week [9, 26, 47]. No effect differences concerning retention were noted. The studies are not reported in the meta-analysis (Table 8.8 on page 475).
8.3
Antagonists (see Tables 8.10–8.12)
Opioid antagonists block the opioid effect and thus eliminate opioid-induced euphoria. The advantage of antagonists is that they, as opposed to agonists, do not have the potential for abuse. The bond of naltrexone to an opioid receptor is 20 times stronger than that of morphine, which is the reason that naltrexone effectively overrides a bonded agonist. The duration is 72 h. A daily dose of 50 mg naltrexone can block the effect of 25 mg of heroin for 24 h. It may be difficult to initiate naltrexone treatment since it requires the user to be opioid free. Side effects have been reported; stomach pain, nausea, headache, dizziness, fatigue, and sleep problems [46]. 8.3.1
Antagonists versus Control Naltrexone versus control Curran & Savage, Hollister et al., Rawson et al., Mello et al., Ladewig, San et al., Lerner et al., Shufman et al., Gerra et al., and Cornish et al. studied the effect on opioid abuse [5, 6, 13, 18, 19, 34, 36, 41, 54, 56, 61]. Neither Curran & Savage nor Rawson et al. reported doses [6, 54]. Hollister et al. and Gerra et al. showed that naltrexone had a positive effect on abuse [13, 18]. Gerra et al. was excluded from the meta-analysis because of very high effect (d > 10). All authors studied the effect on retention [5, 6, 13, 18, 19, 34, 36, 41, 54, 56, 61]. Rawson et al. and Gerra et al. showed a positive naltrexone effect on retention [13, 54]. Hurzler et al. and Ladewig were excluded from the meta-analysis because of deviations in reporting of results [19, 34]. Hollister et al. and Lerner et al. showed that naltrexone had a positive effect on craving [18, 36]. Cornish et al. showed less criminality in the naltrexone group [5]. Meta-analysis The result of the meta-analysis was heterogeneous. Retention in the experimental group was identified as an important moderator variable. In most analyses, the retention rate differed significantly between those with high retention [5, 13, 36, 54, 61] and low retention [6, 18, 56]. Both groups were homogenous, and there was a significant difference in retention rates between the experimental and control groups. In the high retention group (retention ≥50%) d (fixed model) = 0.38 (CI 0.15, 0.65) and in the low retention group (<20%) d (fixed model) = –0.07 (–0.34, 0.20). There were no studies with retention rates between 20% and 50% (Tables 8.10a and 8.10b).
8.3 Antagonists Table 8.10a. Naltrexone versus control. Outcome variable: abuse. High = retention ≥ 50%; Low = retention < 20%. Test of heterogeneity negative. Gerra et al. 1995 were excluded because of high effect; d > 10.
0.59 0.19 0.45 0.36
-0.02 -0.55 0.92 -0.15 -0.37
0.42 0.10 0.74 0.45 -0.22 1.12 0.46 0.08 0.84 -0.19 -0.76 0.39 0.30 0.01 0.58 0.35 0.14 0.56
Table 8.10b. Naltrexone versus control. Outcome variable: retention. High = retention ≥ 50%; Low = retention < 20%. Test of heterogeneity negative. Naltrexone had better effect (p <0.05) in the high retention group compared with its effect in the low retention group.
0.32 0.43 0.19 0.82 -0.12
-0.28 0.09 -0.54 0.20 -0.84
0.93 0.77 0.93 1.44 0.61
0.38 0.15 0.62 0.00 -0.66 0.66 0.08 -0.28 0.44 0.07 -0.51 -0.07 -0.34 0.20 0.19 0.01 0.37
8.3.2
Antagonists versus the Same Antagonists Distribution Studies Naltrexone CM versus non-CM: Preston et al. studied 58 patients. Retention increased from 13% to 42% if, after each consecutive dose of naltrexone, the patients received a 8.3.2.1
Table 8.11. Distribution studies. Naltrexone – contingency management versus noncontingency
management. Distribution studies
Comparisons
Primary outcome measures
Naltrexone, 1 study, n = 58
CM versus non-CM
+ (retention)
Preston [52] 1999
499
500
8 Pharmacotherapy for Opioid Dependence Table 8.12.
Opioid antagonists.
Study
n
Agent
Psych. soc. Treat.
Treatment period (weeks)
Antagonists versus control Naltrexone versus control Curran & Savage [6] 1976
38
1. Naltrexone (no doses) 2. Placebo
*
36
Hurzeler [19] 1976
54
1. Naltrexone 350 mg/w 2. Placebo
*
42
Hollister [18] 1978
124
1. Naltrexone 350 mg/w 2. Placebo
*
32
Rawson [54] 1979
58
1. Naltrexone + behavioral therapy 2. Behavioral therapy
yes
40
Mello [41] 1981
12
1. Naltrexone 50 mg/d 2. Placebo
*
5
Ladewig [34] 1990
20
1. Naltrexone 350 mg/w 2. Control
yes
on-going
BSI = Brief symptoms inventory, CSS = Craving scale scores, HDRS = Hamilton depression rating scale, MMPI = Minnesota multifactorial personality inventory, * = Data missing or incompletely reported.
8.3 Antagonists
501
Primary outcome measures Abuse Retention
Secondary outcome measures Psychatric/ Other withdrawal symptoms
Quality score
Relapse including 1. 80.9 d intermittent abuse: 2. 92.1 d 1. 16% 2. 39%
*
*
22
*
5 months: 1. + 2. 32%
*
*
19
>5 samples delivered 2. 9% by patients 1. 65% 2. 59%
1. 12% 1. –22 p – > –38 p 2. –18 p – > –13 p
CSS:
*
25
24 weeks: 1. 63% 2. 13%
*
Reincarceration 1. 23% 2. 40%
23
1. 7% 2. 28% % intake of available heroin: 1. 5% 2. 90%
1. 100% 2. 100%
*
*
24
ITT-analyses 6 weeks: 1. 47% 2. 100%
1. 70±25d 2. 50-d±20 d
*
*
21
Table continues on next page
502
8 Pharmacotherapy for Opioid Dependence Table 8.12.
(cont.)
Study
n
Agent
Psych. soc. Treat.
Treatment period (weeks)
San [56] 1991
50
1. Naltrexone 350 mg/w 2. Placebo
yes
26
Lerner [36] 1992
31
1. Naltrexone 350 mg/w 2. Placebo
yes
8
Shufman [61] 1994
32
1. Naltrexone 150 mg/w 2. Placebo
yes
12
Gerra [13] 1995
152
1. Naltrexone 50 mg/d 2. Placebo
yes
12
Cornish [5] 1997
51
1. Naltrexone 250 mg/w 2. Control
yes
26
BSI = Brief symptoms inventory, CSS = Craving scale scores, HDRS = Hamilton depression rating scale, MMPI = Minnesota multifactorial personality inventory, * = Data missing or incompletely reported.
8.3 Antagonists
503
Primary outcome measures Abuse Retention
Secondary outcome measures Psychatric/ Other withdrawal symptoms
Quality score
1. 57% 2. 55%
1. 17% 2. 40%
MMPI – depressive symptoms: 1. 74 p 2. 65 p
Cocaine-pos u-tox: 1. 15% 2. 20%
30
Self-report: 1. 47% 2. 50%
Severe craving: 1. 20% 2. 81%
*
28
1. 60% 2. 50% 1. 50% 2. 56%
BSI-score improved: 1. 1.3 2. 0.4
*
30
w 12: 1. 6% 2. 56%
*
Participation in meetings: 1. 67% 2. 3%
27
1. 91% 2. 75%
1. 52% 2. 33%
Reincarceration: 1. 26% 2. 56%
28
1. 8% 2. 30%
w 12: 1. 64% 2. 81%
*
Table continues on next page
504
8 Pharmacotherapy for Opioid Dependence Table 8.12.
(cont.)
Study
n
Agent
Psych. soc. Treat.
Treatment period (weeks)
yes
12
Antagonists versus the same antagonists Distribution studies Naltrexone Contingent versus non-contingent management Preston [52] 1999
58
1. Naltrexone 350 mg/w [1 coupon for each consecutive dose] 2. Naltrexone 350 mg/w [coupon independent of dose] 3. Naltrexone 350 mg/w [control]
BSI = Brief symptoms inventory, CSS = Craving scale scores, HDRS = Hamilton depression rating scale, MMPI = Minnesota multifactorial personality inventory, * = Data missing or incompletely reported.
8.3 Antagonists
505
Primary outcome measures Abuse Retention
Secondary outcome measures Psychatric/ Other withdrawal symptoms
Quality score
1. 14% 2. 27% 3. 24%
*
27
1. 42% 2. 22% 3. 4%
30 naltrexone doses picked up: 1. 47% 2. 21% 3. 5%
506
8 Pharmacotherapy for Opioid Dependence
reward supporting a drug-free life style. The patients in the CM group also took the naltrexone doses to a greater extent than did the latter group. CM and non-CM were equivalent with respect to abuse [52]. The study is not reported in the meta-analysis (Table 8.11).
8.4
Adjunctive Treatment with Antidepressants for Depressive Disorders (see Tables 8.13a–c and 8.14)
The studies discussed below investigated the treatment effect in psychiatric comorbidity. The patients were treated with both antidepressants and methadone. In one study, however, patients were treated with naltrexone instead of methadone [35]. 8.4.1
Antidepressants versus Control Tricyclic antidepressants and selective serotonin reuptake inhibitors, respectively, versus control Woody et al., Titievsky et al., Kleber et al., and Nunes et al. evaluated the effect of tricyclic antidepressants (TCA) [30, 44, 70, 74]; Petrakis et al. studied the effect of selective serotonin reuptake inhibitors (SSRI) [51]. Woody et al., Kleber et al., Nunes et al., and Petrakis et al. studied the effect on abuse [30, 44, 51, 74]. No study showed that antidepressants had any positive effect. All five authors studied the effect on retention [30, 44, 51, 70, 74]. No study showed that active medication was better than placebo. All authors also studied the effect on depressive symptomatology [30, 44, 51, 70, 74]. Titievsky et al. and Nunes et al. both reported a positive effect for TCA [44, 70]. Landabaso et al. evaluated the effect of SSRI on opioid-dependent individuals treated with naltrexone. Landabaso and collaborators reported an increased retention for fluoxitine patients [35]. The article is not presented in Table 8.13 or in the meta-analysis. Meta-analysis Antidepressants were not superior to placebo with respect to abuse or retention. Tricyclics, however, were better than placebo for reducing depressive symptoms; d (fixed model) = 0.64 (CI 0.39, 0.90). Test of heterogeneity negative (Tables 8.13a, 8.13b, 8.13c).
8.5
Meta-Analyses
In their meta-analysis, Caplehorn et al. included 5 cohort studies of 296 patients. The main finding was that methadone treatment reduced the mortality risk to one-
8.5 Meta-Analyses Table 8.13a. Antidepressants versus placebo. Outcome variable: abuse. SSRI = selective serotonin reuptake inhibitors; tricyc = tricyclic antidepressants. Test of heterogeneity negative.
0.00 -0.61 0.00 -0.61
0.61 0.61
0.00 -0.59 0.38 -0.06 0.50 -0.24 0.29 -0.02
0.59 0.81
0.23 -0.05
0.50
0.60
Table 8.13b. Antidepressants versus placebo. Outcome variable: retention. SSRI = selective serotonin reuptake inhibitors; tricyc = tricyclic antidepressants. Test of heterogeneity negative.
0.16 -0.45 0.16 -0.45 0.17 -0.20 -0.31 0.50 -0.09
0.77 0.77
-0.43 0.76 -0.54 0.14 -0.77 0.15 -0.20 -0.32 -0.14
-0.06 -0.27 -0.16
Table 8.13c. Antidepressants versus placebo. Outcome variable: depressive symptoms. SSRI = selective serotonin reuptake inhibitors; tricyc = tricyclic antidepressants. Test of heterogeneity negative.
-0.158 -0.711 0.395 -0.158 -0.711 0.395 0.167 -0.428 0.763 0.646 0.298 0.994 1.120 0.472 0.784 -0.103 0.644 0.387 0.900 0.497 0.266 0.729
fourth [3]. Marsch et al. included not only RCTs to study the effect of methadone on opioid abuse, HIV risk behavior, and criminality (43 studies, 11 026 patients). Marsch et al. concluded that if 200 opioid-dependent patients were treated with methadone, an estimated 67% would reduce their abuse, 61% would reduce their HIV risk behavior, and 61% would reduce their drug- and theft-oriented behavior [40]. Glans et al. compared methadone and LAAM. He included 12 studies with 1788 patients. Glans et al. showed no difference between the agents concerning abuse, but reported better retention in the methadone patients [14].
507
508
8 Pharmacotherapy for Opioid Dependence Table 8.14. Study
Adjunctive therapy with antidepressants. n
Agent
Psych. soc. Treat.
Treatment period (weeks)
Antidepressants versus control in methadone treated patients Tricyclic antidepressants
Woody [74] 1975
35 (24)
1. Doxepin 100–150 mg/d 2. Placebo
yes
16
Titievsky [70] 1982
76 (46)
1. Doxepin 200 mg/d 2. Placebo
*
5
Kleber [30] 1983
46
1. Imipramine 150/ 225 mg/d 2. Placebo
yes
8
ASI = Addiction severity index, BDI = Becks depression inventory, CGI = Clinical global impressions scale, HDRS = Hamilton depression rating scale, POMS = Profile of mood states, SCL = Symptom check list, ( ) = Completers, * = Data missing or incompletely reported.
8.5 Meta-Analyses
Primary outcome measures Abuse Retention
509
Secondary outcome measures Psychatric/ Other withdrawal symptoms
Quality score
w 8–16: 1. 59% 2. 33%
HDRS, symptom reduction: 1. (18 p–7 p) 2. (18 p–15 p) Craving: 1. (2.2 p–0.3 p) 2. (2.2 p–1.3 p)
*
21
w 2–5: 1. 57% 2. 69%
HDRS, symptom reduction: 1. (28 p–19 p) 2. (27 p–23 p) POMS: 1. (104 p–89 p) 2. (111 p–106 p)
CGI- response: 1. (75%) 2. (31%)
25
Number of pos 1. 57% u-tox of unallowed 2. 48% substances/number of days in the study w 8: 1. 0.3 2. 0.2
BDI: 1. 15 p–10 p 2. 13 p–10 p HDRS, symptom reduction: 1. 20 p–10 p 2. 20 p–11 p SCL-90: 1. 226 p–174 p 2. 221 p–177 p
*
33
Neg u-tox > 50% of the time 1. 69% 2. 49%
*
Table continues on next page
510
8 Pharmacotherapy for Opioid Dependence Table 8.14.
(cont.)
Study
n
Agent
Psych. soc. Treat.
Treatment period (weeks)
Nunes [44] 1998
137
1. Imipramine 300 mg/d 2. Placebo
yes
12
*
12
yes
26
Selective serotonin reuptake inhibitors Petrakis [51] 1998
44
1. Fluoxetine 50 mg/d 2. Placebo
Antidepressants versus control in naltrexone treated patients Selective serotonin reuptake inhibitors Landabaso [35] 1998
112
1. Fluoxetine 20 mg/d 2. Control
ASI = Addiction severity index, BDI = Becks depression inventory, CGI = Clinical global impressions scale, HDRS = Hamilton depression rating scale, POMS = Profile of mood states, SCL = Symptom check list, ( ) = Completers, * = Data missing or incompletely reported.
8.5 Meta-Analyses
511
Primary outcome measures Abuse Retention
Secondary outcome measures Psychatric/ Other withdrawal symptoms
Quality score
Abstinent: 1. 14% 2. 2%
*
CGI- response: 1. 35% 2. 6% (p<0.001)
31
Number of days 1. 87% with heroin abuse, 2. 81% pre-post treatment: 1. 2 d – 2 d 2. 6 d – 3 d
HDRS, symptom reduction: 1. 14 p–8 p, 2. 15 p–7 p,
ASI: 1. 0.17 p–0.11 p 2. 0.21 p–0.15 p
28
*
*
*
28
6 w: 1. 57% 2. 67%
1. 71% 2. 48%
512
8 Pharmacotherapy for Opioid Dependence
Kirchmayer discussed the naltrexone literature based on 11 studies, two of which were nonrandomized studies. Because of the heterogeneity in, e.g., study design and reporting of study results, the review included only a small number of metaanalyses. The result of the quantitative analysis was considered to be statistically weak, as was the methodological quality of the studies. Kirchmayer concluded that the available material did not allow a thorough assessment of the effect of naltrexone as a preventive drug [29].
8.6
Reviews
Farrell et al. concluded that methadone was superior to controlled conditions for several outcome measures, e.g., abuse and criminality. Methadone >50 mg per day yielded lower abuse and increased retention [10]. The NIH summary (JAMA 1998) reported that methadone was the most common treatment alternative in opioid dependence. Buprenorphine was considered a future treatment option [43]. Ward et al. reported that methadone >60 mg per day reduced heroin abuse and yielded better retention. LAAM and buprenorphine were considered as effective as methadone in reducing abuse. Naltrexone was considered to be a good option for certain groups [73]. Valmaña highlighted buprenorphine because of its long duration and high level of safety. The advantages compared to methadone included the reduced potential for abuse due to enhanced withdrawal symptoms, the reduced risk of overdosing, and the fact that detoxification from the agent was easier. Advantages associated with LAAM included the slow onset of action and its long duration. No difference between LAAM and methadone was shown as regards abuse. However, the LAAM patients were found to interrupt treatment more often [71].
8.7
Conclusion
Some weaknesses of the meta-analyses may be argued, e.g., the different methods of the studies as regards the documentation of abuse. The analyses are mainly based on the ITT material. 8.7.1
Agonists, Including Partial
Maintenance treatment with opioid agonists is successful in opioid dependence. The effect of methadone is well documented. The substance has a positive effect on abuse and retention. The treatment effect is associated with the size of the dose. The daily dose of methadone should not fall below 60 mg.
8.7 Conclusion
LAAM is as effective as methadone in reducing abuse, but poorer at retaining patients in treatment. The advantage of LAAM is the dosage of 3 times per week. The treatment effect is associated with the size of the dose. The weekly dose should not fall below 300 mg. LAAM has been withdrawn from the European market. Buprenorphine is as effective as methadone with regard to both abuse and retention. The advantages of buprenorphine are a smaller potential for abuse and a smaller risk for overdosing. However, the evidence is based on a small amount of data. The substance can be administered every second day. The treatment effect is associated with the size of the dose. The daily dose should be at least 8 mg. 8.7.2
Antagonists
Maintenance treatment with naltrexone in opioid dependence yields a reduction in abuse and increased retention in treatment. The result of the initial meta-analysis was strongly heterogeneous. The retention turned out to be an important moderator variable. It appears that 50 mg per day is a suitable dosage, but the optimum dose has not been studied. 8.7.3
Antidepressants
Adjunctive treatment with antidepressants for opioid-dependent patients with depression has an effect on the depressive symptomatology, but does not cause any reduction in abuse or any improvement in retention. 8.7.4
Other Illegal Drugs
No randomized controlled trials were found which analyze long-term pharmacological treatment for cannabis and amphetamine dependence.
513
514
8 Pharmacotherapy for Opioid Dependence
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8.8 Appendix
8.8
Appendix
Since our search in MEDLINE (April 2000), 13 RCTs with 1331 patients have been published. The primary outcome measures in most of the studies have been abuse and retention. Three meta-analyses have been published. In this section, metaanalysis has not been conducted. The material is presented in Tables A-8.1–8.5. Significances are reported by + or – under the heading “primary outcome measure”. Plus (+) implies that the experimental substance is superior to the control (p < .05), while minus (–) implies the opposite. Zero indicates a nonsignificant effect. The material is also presented in Tables A and B, where data from the studies are reported more thoroughly. 8.8.1
Agonists 8.8.1.1 Agonists (Including Partial) versus Control Burprenorphine versus placebo Krook et al. randomized 106 patients to either buprenorphine (112 mg per week) or placebo in a 12-week study. All patients were waiting for methadone-assisted rehabilitation. The retention rate after 12 weeks was 29% in the buprenorphine group and 2% in the placebo group (p < 0.05). The buprenorphine group had a larger decrease in reported opioid abuse (p < 0.001) [13].
Agonists versus Other Agonists Methadone plus heroin versus methadone Van den Brink et al. randomized 549 treatment-resistant, methadone-treated, heroin-dependent patients to methadone plus heroin or to methadone alone in a 12month study. Supervised co-prescription of heroin was more effective than the continuation of methadone alone and yielded clinically relevant health benefits [19]. 8.8.1.2
Agonists versus the Same Agonists Distribution studies Methadone CM versus non-CM: Robles et al. included 48 methadone patients randomized to either abstinence or attendance reinforcement condition. The abstinence group could receive vouchers for providing opioid-negative urine while the subjects in the attendance group received vouchers of equal value for attending the clinic regardless of urinalysis results. Over 80% of the participants in both groups remained in treatment through week 20. The subjects in the abstinence group, compared with the attendance group, had lower rates of opioid use during the maintenance (weeks 5–10) and detoxification (weeks 11–23) phases [17].
8.8.1.3
519
n
Agent
106
Van den Brink [18] 2002
549
Treatment period (weeks)
1) Methadone + Heroin 2) Methadone
52
1) Buprenorphine 112 mg/w 12 2) Placebo
Agonists vs other agonists Methadone + Heroin vs Methadone
Krook [13] 2002
Agonists Agonists (including partial) vs control Buprenorphine vs Placebo
Study
Appendix Table A.
Multi-domain Methadone + Heroin better than Methadone alone to reduce abuse. OR = 2.99 for injection and OR = 2.77 for inhalation abuse
Self-report Larger decrease in the Buprenorphine group (p<0.001)
Abuse
Average number of days 1) 42 days 2) 14 days (p<0.001)
1) 29% 2) 2% (p<0.05)
Retention
Outcome measures
Patients treated with Buprenorphine reported better well-being (p <0.01) and a higher self-satisfaction (p <0.05) than patients in the placebo group.
Others
520
8 Pharmacotherapy for Opioid Dependence
n
(cont.)
48
Fiellin [7] 2001
46
Treatment period (weeks)
1) MMT by primary care physicians 2) MMT by NTP
26
1. Abstinence reinforcement 26 2. Attendance reinforcement
Agent
Outpatient care versus specialist clinic
Robles [16] 2002
Agonists vs the same agonists Distribution studies Methadone CM vs non-CM
Study
Appendix Table A.
Ongoing illicit drug abuse 1) 18% 2) 21% (ns)
Self report or utox 1) 50% 2) 38% (ns)
The abstinence reinforcement group had less abuse than the attendance reinforcement group (p <0.01)
Abuse
1) 82% 2) 79% (ns)
> 80% in both groups remained in treatment through week 20.
Retention
Outcome measures
Self-satisfaction 1) 73% 2) 13% (p=0.001)
No group differences concerning withdrawal symptoms including craving
Others
8.8 Appendix 521
73
King [9] 2002
16
92
Bickel [3] 1999
Schottenfeld [17] 2000
Dose level studies Buprenorphine
n
(cont.)
Study
Appendix Table A.
Buprenorphine 1) 16 mg/70 kg/24h 2) Tuesday 44 mg/70 kg Friday & Sunday 34 mg/70 kg
Buprenorphine 1) 6+2 mg/70 kg/24h 2) Double dose/48h Placebo day 2 3) Triple dose/72h Placebo day 2&3
1) MMT – physician office 2) MMT – clinic based 3) Routine Methadone care
Agent
12
Each condition 3 weeks
52
Treatment period (weeks)
Pos utox 1) 57% 2) 58% (ns)
Pos utox – illegal drugs, 6 months 1) 0% 2) 1% 3) 2% (ns)
Abuse
1) 71% 2) 77% (ns)
6 months 1) 92% 2) 89% 3) 90% (ns)
Retention
Outcome measures
Medical compliance 1) 92% 2) 91% (ns) Concealing attendance 1) 82% 2) 82% (ns)
Withdrawal effects No group difference
Opioid agonist effects No group differences
New vocational or social activities 1) 96% 2) 71% 3) 33% (p<0.001) CSQ 1) 31p 2) 29p 3) 27p (p<0.05)
Others
522
8 Pharmacotherapy for Opioid Dependence
n
60
33
105
Perez de los Cobos [14] 2000
Petry [15, 16] 1999, 2001
Ahmadi [1] 2002
(cont.)
Study
Appendix Table A.
Buprenorphine 1) 1 mg/d 2) 2 mg/d 3) 4 mg/d
A) 4 mg or 8 mg/24h B) 12 mg or 24 mg/72h. Placebo day 1+2 C) 20 mg or 40 mg/120h. Placebo day 1-4
Buprenorphine 1) 4 mg/70 kg/d 2) 8 mg/70 kg/d
Buprenorphine 1) 8 mg/d 2) Monday & Wednesday 16 mg Friday 24 mg
Agent
17
8
12
Treatment period (days)
No differences between dosing conditions
No differences between dosing conditions
Pos utox 1) 47% 2) 58% (p=0.0001)
Abuse
1) 34% 2) 43% 3) 63% (p=0.017) 1 vs 3
–
1) 63% 2) 70% (ns) Average number of days 1) 70 days 2) 72 days (ns)
Retention
Outcome measures
–
Agonist effects None of the higher doses induced agonist effects.
Opioid withdrawal Increased during every 5th day dosing regimes.
Craving, VAS 1) 2.9±2.3 2) 4.3±2.9 (p = 0.045)
Others
8.8 Appendix 523
n
(cont.)
CM CSQ MMT NTP VAS
26
1) Buprenorphine 8 mg+ Naloxone 2 mg/24h 2) Buprenorphine 8 mg + Naloxone 2 mg/48h, placebo every 2nd day 3) Buprenorphine 16 mg + Naloxone 2 mg/48h, placebo every 2nd day
Agent
Contingency Management Client Satisfaction Questionnaire Methadone Maintenance Treatment Narcotic Treatment Program Visual Analog Scale
Abbreviations
Amass [2] 2000
Buprenorphine + naloxone
Study
Appendix Table A.
3 (triple cross-over)
Treatment period (weeks)
1) 53% 2) 60% 3) 54% (ns)
Abuse
Dropouts 1) 5 2) 5 3) 2 (ns)
54% completed
Retention
Outcome measures
Medication compliance No group differences Completers analysis
Opioid effects No group differences
Others
524
8 Pharmacotherapy for Opioid Dependence
8.8 Appendix Table A-8.1. Agonists (including partial) versus control or other agonists.
Comparisons
Buprenorphine, 1 study, n=106 Krook et al. [13] 2002
Placebo
Methadone + heroin, 1 study, n=549 Van den Brink et al. [19] 200
Methadone
Primary outcome measures
+ [abuse, retention]
Not evaluated
Table A-8.2. Distribution studies. Methadone: Contingency management versus noncontingency management and outpatient care versus specialist clinic.
Comparisons
Methadone, 1 study, n=48 Robles et al. [17] 2002 Methadone, 2 studies, n=119 Fiellin et al. [7] 2001 King et al. [9] 2002
Primary outcome measures
CM vs non-CM 0 Outpatient care vs specialist clinic 0 0
Outpatient care versus specialized clinic: Fiellin et al. included 47 patients in methadone maintenance treatment (MMT) either by primary care physicians or by narcotic treatment programs. The two groups had the same overall efficacy [7]. King et al. reported 73 patients randomized to either (1) MMT at a physicians office, (2) clinic-based MMT, or (3) routine methadone care. The results are presented for the first 6 months during a one-year trial. Only 1% of the urine specimens were positive for illegal drugs, and 90% of the patients remained in treatment with no differences between the groups [9]. Dose level studies Buprenorphine Bickel et al. randomized 16 patients to buprenorphine 4±2 mg every 24 h, the double dose every 48 h, and the triple dose every 72 h under placebo-controlled conditions. There were no differences of measures of opioid-agonist and withdrawal effects between the conditions [3]. Bickel et al. only report suboptimal doses, and therefore the study does not appear in Table A-8.3. Schottenfeld et al. reported 92 patients randomized to either daily or thrice-weekly sublingual buprenorphine at an equivalent weekly dose of 112 mg. No differences with respect to the primary outcome measures were observed between the groups [18]. Péres de los Cobos et al. randomized 60 patients to either daily or thrice-weekly sublingual buprenorphine at an equivalent weekly dose of 56 mg. The daily regime
525
526
8 Pharmacotherapy for Opioid Dependence Table A-8.3. Dose level studies. Buprenorphine and buprenophine + naloxone in different doses.
Comparisons
Primary outcome measures
Buprenorphine, 3 studies, n=185 Schottenfeld et al. [18] 2000* Péres de los Cobos et al. [14] 2000** Petry et al. [15, 16] 1999, 2001***
Daily vs every 3rd d Daily vs every 3rd d Daily vs every 3rd or 5th d
0 + [abuse] Not evaluated
Buprenorphine + naloxone, 1 study, n=26 Amass et al. [2] 2000 ***
Daily vs every 2nd d
0
* ** ***
weekly dose 112 mg weekly dose 56 mg weekly dose 28 mg or 56 mg
with respect to abuse was better than 3 times per week. No differences with respect to retention [14]. Petry et al. included 33 patients randomized to either buprenorphine 4 mg or 8 mg/24 h, 12 mg or 24 mg/72 h, or 20 mg or 40 mg/120 h. Opioid withdrawal increased during every fifth day dosing regimes [15, 16]. Ahmadi randomized 105 patients to either buprenorphine 1, 2, or 4 mg per day in a 17-week treatment period. Retention in the 4 mg group (63%) was significantly better than in the 1 mg group (34%) (p = 0.017). None of the other comparisons was significant [1]. Ahmadi reports suboptimal doses only, and therefore the study does not appear in Table A-8.3. Buprenorphine plus naloxone Amass et al. evaluated the efficacy of tablets with buprenorphine 8 mg, and naloxone 2 mg for every day and every second day treatment in 26 patients. The daily dosage results in a weekly dose twice as high as every second day dosage. Rates of compliance and abuse were the same for daily and alternate-day treatments among completers (n=14) [2]. 8.8.2
Antagonists
Antagonists versus Control Naltrexone versus placebo Guo et al. randomized 49 detoxified heroin addicts to either naltrexone or placebo in a 6-month treatment course. At the end of the study, 31% in the naltrexone group and 7% in the placebo group were abstinent. The retention rates were 29% and 7%, respectively [8]. 8.8.2.1
49
n
1) Naltrexone 2) Placebo
Agent
127
1) Naltrexone 3 times/w. 2) Naltrexone + CM 3) Naltrexone + CM + SO
Abbreviations CM Contingency Management SO Significant Other Involvement
Carroll [4] 2001
Antagonists vs the same antagonists Distribution studies Naltrexone Contingent vs non-contingent management
Guo [8] 2001
Antagonists Antagonists vs control Naltrexone vs placebo
Study
Appendix Table B.
12
26
Treatment period (weeks)
Number of opioid-free utox 1) 13.5 2) 18.9 3) 20.2 (p=0.04)
Abstinent 1) 31% 2) 7% (p<0.05)
Abuse
–
Others
Number of weeks Number of Naltrexone in treatment doses 1) 5.6 No group differences 1) 7.4 2) 7.4 (p=0.05)
1) 29% 2) 7% (p<0.05)
Retention
Outcome measures
8.8 Appendix 527
528
8 Pharmacotherapy for Opioid Dependence Table A-8.4. Antagonists versus control.
Comparisons
Naltrexone, 1 study, n=49
Primary outcome measures
Placebo
Guo et al. [8] 2001
+ [abuse, retention]
Table A-8.5. Distribution studies. Naltrexone: Contingency management versus non-contingency management.
Comparisons
Naltrexone, 1 study, n=127 Carroll et al. [4] 2001
Primary outcome measures
CM versus non-CM + [abuse, retention]
8.8.2.2 Antagonists versus the Same Antagonists Distribution studies Naltrexone CM versus non-CM: Carroll et al. randomized 127 patients to naltrexone three times per week, naltrexone + CM, or to naltrexone + CM + significant other involvement (SO). Subjects who complied with the naltrexone regimen and whose urinanalyses were all negative could earn the equivalent of a maximum of $561 worth of items during the 12-week trial. Naltrexone + CM was more successful than naltrexone alone with respect to both abuse (19 vs 14 drug-free urine) and retention (7.4 vs 5.6 weeks) [4].
Meta-Analysis Farré et al. assessed the efficacy of methadone maintenance treatment (MMT). MMT was compared with buprenorphine and LAAM. Data for 1944 opioid-dependent patients from 13 RCTs studied were analyzed. Methadone doses ≥ 50 mg per day were more effective than lower methadone doses in the reduction of abuse, OR=1.72 (95% CI 1.26, 2.36). Methadone doses ≥ 50 mg per day were similar to buprenorphine ≥ 8 mg per day for both retention and abuse. Methadone-treated patients had better retention than patients treated with LAAM, OR=1.92 (95% CI 1.32, 2.78). The authors proposed that in agonist-maintenance programs, oral methadone at doses of 50 mg per day or higher is the drug of choice for opioid dependence [6]. Clark et al. reviewed the literature on LAAM versus methadone for the Cochrane Library. Fifteen RCTs were included. Of these studies only 5 were double-blind, and 2 studies were single-blind. LAAM appears to be more effective than methadone at reducing heroin use. More LAAM patients ceased their allocated medication, but many transferred to methadone, so the significance is unclear. No difference in safety was observed [5]. This is the first review showing that LAAM is better than 8.8.2.3
8.8 Appendix
methadone in reducing abuse. Glans et al., Valmaña, and Ward et al. did not report this (see main text). Kirchmeyer et al. re-reviewed the naltrexone literature from 1999 for the Cochrane Library and concluded that the 11 trials included (both RCTs and CTs) did not allow a final evaluation of maintenance treatment with naltrexone. The results are not statistically significant for the successful completion of treatment, OR = 0.78 (95% CI 0.34, 1.75) for the use of opioids under treatment, OR = 0.85 (95% CI 0.45, 1.62) when comparing naltrexone versus placebo. Use of naltrexone in addition to behavioral treatment significantly decreased the probability of (re-) incarceration, OR = 0.30 (95% CI 0.12, 0.76) [10–12]. Conclusion The results from the additional studies do not change the general conclusion. 8.8.2.4
529
530
8 Pharmacotherapy for Opioid Dependence
Appendix References 1 Ahmadi J. Buprenorphine mainte-
2
3
4
5
6
7
nance treatment of heroin dependence: the first experience from Iran. J Subst Abuse Treat 2002; 22:157-159. Amass L, Kamien JB, Mikulich SK. Efficacy of daily and alternate-day dosing regimens with the combination buprenorphine-naloxone tablet. Drug Alcohol Depend 2000; 58:143-152. Bickel WK, Amass L, Crean JP, Badger GJ. Buprenorphine dosing every 1, 2, or 3 days in opioid-dependent patients. Psychopharmacol 1999; 146:111-118. Carroll KM, Ball SA, Nich C, O’Connor PG, Eagan DA, Frankforter TL, Triffleman EG, Shi J, Rounsaville BJ. Targeting behavioral therapies to enhance naltrexone treatment of opioid dependence. Arch Gen Psychiatry 2001; 58:755-761. Clark N, Lintzeris N, Gijsbers A, Whelan G, Dunlop A, Ritter A, Ling W. LAAM maintenance vs methadone maintenance for heroin dependence. (Cochrane Review). In: The Cochrane Library, Issue 2, 2002. Oxford: Update Software. Farré M, Mas A, Torrens M, Moreno V, Cami J. Retention rate and illicit opioid use during methadone maintenance interventions: a meta-analysis. Drug Alcohol Depend 2002; 65:283290. Fiellin DA, O’Connor PG, Chawarski M, Pakes JP, Pantalon MV, Schottenfeld RS. Methadone maintenance in primary care. A randomized controlled trial. JAMA 2001; 286:1724-1731.
8 Guo S, Jiang Z, Wu Y. Efficacy of nal-
9
10
11
12
13
14
trexone hydrocholoride for preventing relapse among opiate-dependent patients after detoxification. Hong Kong J Psychiatry 2001; 11(4):2-8. King VL, Stoller KB, Hayes M, Umbricht A, Currens M, Kidorf MS, Carter JA, Schwartz R, Brooner RK. A multicenter randomized evaluation of methadone medical maintenance. Drug Alcohol Depend 2002; 65:137148. Kirchmayer U, Davoli M, Verster A. Naltrexone maintenance treatment for opioid dependence. (Cochrane Review). In: The Cochrane Library, Issue 4, 2001. Oxford: Update Software. Kirchmayer U, Davoli M, Verster A. Naltrexone maintenance treatment for opioid dependence. (Cochrane Review). In: The Cochrane Library, Issue 2, 2002. Oxford: Update Software. Kirchmayer U, Davoli M, Verster A, Amato L, Ferri M, Perucci CA. A systematic review on the efficacy of naltrexone maintenance treatment in opioid dependence. Addiction 2002; 97:1241-1249. Krook AL, Brors O, Dahlberg J, Grouff K, Magnus P, Roysamb E, Waal H. A placebo-controlled study of high dose buprenorphine in opiate dependents waiting for medication-assisted rehabilitation in Oslo, Norway. Addiction 2002; 97:533-542. Pérez de los Cobos J, Martin S, Etcheberrigaray A, Trujols J, Batlle F, Tejero A, Queralto JM, Casas M. A
Appendix References controlled trial of daily versus thriceweekly buprenorphine administration for the treatment of opioid dependence. Drug Alcohol Depend 2000; 59:223-233. 15 Petry NM, Bickel WK, Badger GJ. A comparison of four buprenorphine dosing regimens in the treatment of opioid dependence. Clin Pharmacol Ther 1999; 66:306-314. 16 Petry NM, Bickel WK, Badger GJ. Examining the limit of the buprenorphine interdosing inter-daily, everythird-day and every-fifth-day dosing regimens. Addiction 2001; 96:823834.
17 Robles E, Stitzer ML, Strain EC,
Bigelow GE, Silverman K. Voucherbased reinforcement of opiate abstinence during methadone detoxification. Drug Alcohol Depend 2002; 65:179-189. 18 Schottenfeld RS, Pakes J, O’Connor P, Chawarski M, Oliveto A, Kosten TR. Thrice-weekly versus daily buprenorphine maintenance. Biol Psychiatry 2000; 47:1072-1079. 19 Van den Brink W, Hendriks VM, Blanken P, Huijsman IA, van Ree JM. Medical prescription of heroin. Two randomized controlled trials. Central Committee on the Treatment of Heroin Addicts (CCBH), Utrecht, 2002.
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9
Pharmacotherapy for Cocaine Dependence Björn Axel Johansson
9.1
Background and Pharmacological Principles
In the central nervous system, cocaine mainly affects the activity of dopamine and noradrenalin. The inhibition of reuptake greatly increases signal transmission [9, 40]. Three pharmacological principles have been studied to deal with cocaine dependence: antidepressants, dopamine agonists, and antiepileptics. The concept of antidepressive treatment has been to restore dysregulated reward mechanisms and to treat existing depression [16]. The reward effect of cocaine is probably due to the blocking of dopamine reuptake. The increased concentration of dopamine is also thought to cause cocaine-induced euphoria and the addictive effect of the drug. Cocaine withdrawal inhibits function in the target area for dopamine. The neurotransmitter level decreases, resulting in anxiety, anhedonia, craving, and depression. Dopamine agonist treatment is mainly intended to address these symptoms. Dopamine agonists are otherwise used in treating, e.g., Parkinson’s syndrome [22]. Craving can be understood as a kindling phenomenon. In animal models, a successful anti-kindling effect with carbamazepine has been achieved and serves as the theoretical basis of studies in humans [9, 12]. Aim The aim of this systematic literature review is to attempt to answer the following question: Does pharmacological treatment have an effect on cocaine dependence and on cocaine abstinence? Search strategy and methods The MEDLINE database (1966–2000) was searched using the index terms: alcohol, substance use, and RCT (randomized controlled trials). This search was followed by a manual selection of the studies found. The Cochrane Library was also searched, adding the index term cocaine. Reference lists in published articles and reviews have been studied. The result is based exclusively on randomized and double-blind, controlled studies.
Treating Alcohol and Drug Abuse. Edited by M. Berglund, S. Thelander, E. Jonsson Copyright c 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 3-527-30682-X
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9 Pharmacotherapy for Cocaine Dependence
Diagnostic criteria Cocaine dependence according to DSM-IV or ICD-10. Included studies Forty randomized controlled studies with 2328 patients were included. Most of these studies are placebo-controlled. The quality of the studies, which usually run 12 weeks (pharmacological long-term treatment), is generally high. The articles include three studies describing withdrawal treatment and five interaction studies. Finally, a study discussing long-term pharmacological treatment for methamphetamine dependence is included. Apart from the randomized studies, two review articles are included. Four studies compared antidepressants with dopamine agonists and placebo [25–27, 29, 40–42]. The two drugs have been analyzed separately under the respective sections. Three authors, Arndt [2, 3], Carroll [6–8], and Ziedonis [26, 27, 29, 41, 42] used the same patients in their different studies. The articles have been clustered into one study for each author. Excluded studies Thirty-one studies were excluded. None of these studies were clinical trials. Outcome measures The primary outcome measures were cocaine-positive urinalyses and retention in treatment. Depressive symptoms and craving were used as secondary outcome measures. In the withdrawal studies, the primary outcome measures were withdrawal severity and retention. Cocaine-positive urinalyses and craving were secondary outcome measures. In the methamphetamine study, the primary outcome measures were methamphetamine-positive urinalyses and retention in treatment. Tables The material is presented in 14 tables. The primary outcome measures and existing significances (p<0.05) are shown by + or –. Plus (+) implies that the experimental substance is superior to the control, and minus (–) implies the opposite. A nonsignificant effect is marked by a zero. The outcome measures are reported in greater detail in the Tables 9.7, 9.9, and 9.11. Meta-analyses Effect estimates concerning long-term pharmacological treatment for cocaine dependence have been made for antidepressants, dopamine agonists, and antiepileptics. Only the effects on the primary outcome measures have been analyzed.
9.2 Long-term Pharmacotherapy in Cocaine Dependence
9.2
Long-term Pharmacotherapy in Cocaine Dependence (see Tables 9.1–9.7)
9.2.1
Antidepressants
Fifteen studies with 1245 patients were included. 9.2.1.1 Tricyclic antidepressants Desipramine The patients in four studies were both cocaine-and-opioid dependent and opioid dependent, and were treated with methadone [2, 3, 25, 26, 27, 29, 41, 42]. Gawin et al. found that desipramine had a positive effect on abuse, retention, and craving [16]. Weddington et al. did not report any positive results [40]. In the material by Ziedonis et al., patients with comorbid depression and antisocial personality disorder (ASP) were studied and compared with patients without comorbidity. The depressive subgroup was less troubled by depressive symptoms and craving compared with the depressed patients receiving placebo. The number of patients with depression and ASP was small. Hence, significance levels could not be shown and firm conclusions could not be drawn. Desipramine showed no effect in the group without psychiatric comorbidity [26, 27, 29, 41, 42]. Kolar et al. reported an improvement with respect to abuse for completers, with cocaine-free urine the last 2 weeks [25]. The study by Arndt et al. investigated, e.g., how ASP affected treatment. Desipramine had a positive effect on retention. Among the non-ASP patients, desipramine had a positive effect on psychiatric symptoms [2, 3]. Hall reported no effect from desipramine [21]. Campbell et al. found an equivalent effect with active substance and placebo [5]. A study by Carroll et al. investigated patients with comorbid depression and compared them with patients without comorbidity. Carroll et al. noted no difference between desipramine and placebo. In a depressive subgroup, the depressive symptoms were alleviated [6–8].
Imipramine A study by Galloway et al. compared the effects of 150 mg and 10 mg of imipramine. Better retention was reported in the first group, but no other positive effects were observed [14]. A study by Nunes et al. examined the effect of imipramine in, e.g., concurrent depression. Good response was defined as three consecutive, cocaine-free weeks. This was achieved by 19% of the imipramine patients and 7% of the placebo patients, which was not a significant difference. Depressed patients on imipramine treatment did not use less cocaine than the depressed patients receiving placebo [34].
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9 Pharmacotherapy for Cocaine Dependence
SSRI Fluoxetine Grabrowski et al. did not report any positive results [18]. Covi et al. showed that fluoxetine 60 mg was less effective than placebo in reducing abuse. There were no significant differences after Hedges’ correction [11]. Batki et al. reported longer retention among the fluoxetine patients [4]. 9.2.1.2
Other antidepressants Bupropion Margolin et al. studied 149 patients and reported no differences in abuse between active substance 300 mg/day and placebo during the 12-week treatment period [30]. 9.2.1.3
Lithium Gawin et al. studied 48 patients. He found no differences between lithium 600 mg/d and placebo during 6 weeks of treatment [16]. Table 9.1. Antidepressive treatment in cocaine dependence. Agent and studies
Placebo
Primary outcome measures
Desipramine, n=493 Gawin [16] 1989 Weddington [40] 1991 Ziedonis [26, 27, 29, 41, 42] 1991 Kolar [25] 1992 Arndt [2,3] 1992 Hall [21] 1994 Campell [5] 1994 Carroll [6, 7, 8]1994
X X X X X X X X
+ [abuse, retention] 0 0 + [abuse] 0 0 0 0
Imipramine, n=296 Galloway [14] 1994 Nunes [34] 1995
X X
+ [retention] 0
Fluoxetine, n=259 Grabowski [18] 1995 Covi [11] 1995 Batki [4] 1996
X X X
0 0 + [retention]
Buproprion, n=149 Margolin [30] 1995
X
0
Lithium, n=48 Gawin [16] 1989
X
0
9.2 Long-term Pharmacotherapy in Cocaine Dependence Table 9.2a. Meta-analysis: Antidepressants versus placebo, abuse. -0.19 -0.10 0.01 0.87 0.16
0.35 0.50 0.39
-0.03 0.09
-0.72 -0.70 -0.37 0.26 -0.25 0.14 -0.69 -0.42
0.13
-0.05
0.31
0.00 -0.87 0.00 0.00 -0.34 -0.37
-0.72 -0.86 -0.83 -0.93 -0.96
0.72 0.03 0.86 0.83 0.25 0.21
-0.27
-0.55
0.01
0.08 0.32
-0.23 -0.06
0.38 0.70
0.17
-0.06
0.41
0.06
-0.07
0.19
0.57 0.63 0.60
Table 9.2b. Meta-analysis: Antidepressants versus placebo, retention. -0.46 0.14 0.68 0.23 -0.26 -0.33
-0.94 -0.24 0.09 -0.18 -0.12 -0.93 -0.84
0.03 0.52 1.28 0.65 2.11 0.40 0.19
0.05 0.08
-0.14 -0.25
0.24 0.40
0.88
0.12
0.88 0.88
0.12 0.12
0.37 0.00
0.07 -0.37
0.68 0.37
0.22 0.20
-0.01 -0.16
0.46 0.57
0.15 0.16
0.01 -0.09
0.29 0.41
Meta-analysis Effects on abuse and retention for active medication and placebo were not different. Abuse (Hedges’ correction) d=0.06 (95%CI –0.07, 0.19) fixed model, test of heterogeneity negative. Retention d=0.16 (95%CI –0.09, 0.41) random model, test of heterogeneity positive. There were no differences between the different antidepressant drugs.
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9 Pharmacotherapy for Cocaine Dependence
9.2.2
Dopamine Agonists
Eight studies with 365 patients were included. Amantadine The patients in four studies were both cocaine-and-opioid dependent and opioid dependent, and were treated with methadone [22, 25–27, 29, 41, 42]. Weddington et al. reported no positive results [40]. Ziedonis et al. reported equivalent results between amantadine and placebo [26, 27, 29, 41, 42]. Kolar et al. did not report any positive results [25]. Handelsman et al. noted that amantadine was not superior to placebo in reducing abuse [22]. Likewise, Kampman et al. did not report any positive findings [24]. 9.2.3
Other Dopamine Agonists Bromocriptine The study by Handelsman et al. investigated 50 patients treated for 6 weeks with bromocriptine 5 mg/day or placebo. No positive results were reported [23]. Mazindol Margolin et al. treated 37 patients for 12 weeks with mazindol 1 mg/day or placebo [31]. Stine et al. treated 43 patients for 6 weeks with mazindol 2 mg/day or placebo [38]. None of the authors reported any positive results.
Table 9.3.
Dopamine agonist treatment in cocaine dependence.
Agent and studies
Placebo
Primary outcome measures
Amantadine, n=235 Weddington [40] 1991 Ziedonis [26, 27, 29, 41, 42] 1991 Kolar [25] 1992 Handelsman [22] 1995 Kampman [24] 1996
X X X X X
0 0 0 0 0
Bromocriptine, n=50 Handelsman [23] 1997
X
0
Mazindol, n=80 Margolin [31] 1995 Stine [38] 1995
X X
0 0
9.2 Long-term Pharmacotherapy in Cocaine Dependence Table 9.4a. Meta-analysis: Dopamine agonists versus placebo, abuse.
-0.03 -0.15 0.17 0.00 -0.03 -0.03
-0.65 -0.76 -0.34
0.59 0.47 0.68
-0.53 -0.53
0.47 0.47
0.00
-0.24
0.23
Table 9.4b. Meta-analysis: Dopamine agonists versus placebo, retention.
0.02 0.26 -0.35 -0.28
-0.49 -0.96
0.53
-0.78
0.33 0.23
-0.15
-0.45
0.15
Meta-analysis Both analyses were homogenous. Fixed model; abuse d=0.00 (95%CI –0.24, 0.23). Retention d= –0.15 (95%CI –0.45, 0.15). Dopamine agonists are not superior to placebo in reducing abuse or improving retention in cocaine dependence. 9.2.4
Antiepileptics
Six studies with 468 patients were included. Carbamazepine The study by Campbell et al. did not give any support for treatment with carbamazepine [5]. Likewise, Montoya et al. did not report any positive results [32]. Kranzler et al. and Cornish et al. found no difference between active substance and placebo [9, 28]. Halikas et al. found that both 400 mg and 800 mg of carbamazepine were more effective than placebo, and that the lower dose had a greater effect than the higher dose [20]. Phenytoin Crosby et al. reported that the cocaine abuse was lower in the phenytoin group [12].
539
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9 Pharmacotherapy for Cocaine Dependence Table 9.5. Antiepileptic treatment in cocaine dependence. Agent and studies
Placebo
Primary outcome measures
Carbamazepine, n=408 Campbell [5] 1994 Montoya [32] 1995 Kranzler [28] 1995 Cornish [9] 1995 Halikas [20] 1997
X X X X X
0 0 0 0 0
Phenytoin, n=60 Crosby [12] 1996
X
+ [abuse]
Table 9.6a. Meta-analysis: Antiepileptics versus placebo, abuse.
-0.28 -0.20 0.27 -0.05 0.33 0.36
-0.93 -0.64 -0.10 -0.40 -0.32 -0.16
0.37 0.24 0.63 0.30 0.97 0.87
0.07
-0.11
0.25
0.64
0.01
0.64
0.01
0.12
-0.06
0.29
Table 9.6b. Meta-analysis: Antiepileptics versus placebo, retention.
0.23 0.15 -0.22 -0.20 0.11
-0.22 -0.21 -0.57 -0.84 -0.40
0.67 0.51 0.14 0.45 0.62
0.02
-0.17
0.21
-0.01
-0.62
0.62
-0.01
-0.62
0.60
0.02
-0.17
0.20
Meta-analysis Both analyses were homogenous. Fixed model; abuse d=0.12 (95%CI –0.06, 0.29). Retention d=0.02 (95%CI –0.17, 0.20). The results of treatment from antiepileptics and placebo are equivalent in treating cocaine dependence.
Table 9.7 see page 542–551.
9.3 Withdrawal Treatment in Cocaine Dependence
9.3
Withdrawal Treatment in Cocaine Dependence (see Tables 9.8 and 9.9) 9.3.1
Dopamine Agonist Amantadine Alterman et al. reported no effect with respect to the primary outcome measures. With respect to abuse, 7% of the amantadine patients versus 40% of the placebo patients had positive urinalyses upon completion of treatment, which was a significant difference. The difference was unchanged at the followup 1 month later [1]. Bromocriptine Eiler et al. reported no differences between bromocriptine and placebo [13]. 9.3.2
Partial Serotonin Agonist Buspirone Giannini et al. showed that buspirone 30 mg/day had a positive effect on withdrawal from day 5 (p=0.04), but had no effect on retention [17]. Table 9.8. Dopamine agonist and partial serotonin agonist treatment in cocaine withdrawal. Agent and studies
Placebo
Primary outcome measures
Dopamine agonists Amantadine, n=42 Alterman [1] 1992
X
0
Bromocriptin, n=63 Eiler [13] 1995
X
0
Partial serotonin agonists Buspirone, n=32 Giannini [17] 1993
X
+ [withdrawal]
Summary Buspirone showed a positive effect on withdrawal in a small study.
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9 Pharmacotherapy for Cocaine Dependence Table 9.7. Long-term pharmacotherapy in cocaine dependence. Study
n
Agent
Treatment period (weeks)
Antidepressants Tricyclic antidepressants Desipramine versus placebo
Gawin [16] 1989
48
1. Desipramine 2.5 mg/kg/day 2. Placebo
6
Weddington [40] 1991
38
1. Desipramine 200 mg/day 2. Placebo
12
Ziedonis [26, 27, 29, 41, 42] 1991, 1992, 1994
61
1. Desipramine 150 mg/day 2. Placebo
12
Kolar [25] 1992
17
1. Desipramine 200 mg/day 2. Placebo
12
ASP = Antisocial personality disorder; BPRS = Brief psychiatric rating scale; CCR = Cocaine craving scale; dep sub grp = Depressive subgroup; GSI = Global severity index; SCL = Symptom checklist; SSRI = Selective serotonin reuptake inhibitor; 0 = No treatment effect. + = Significant treatment effect; – = Control significantly better than active substance; ( ) = Completers, * = Data missing or incompletely reported.
9.3 Withdrawal Treatment in Cocaine Dependence
Primary outcome measures Abuse Retention
Abstinence 3-4 consecutive weeks 1. 59% 1. 38 d 2. 17% 2. 31 d (p<0.01) (p<0.02)
Secondary outcome measures Depressive Craving symptoms
543
Quality score
CCR *
1. –6.3±0.8 2. –3.3±1.0 (p<0.001) w. 4
29
Abstinence last week 1. 42% 2. 43%
1. 29% 2. 43%
0
0
28
Abstinence any two weeks 1. 28% 2. 24%
1. 73% 2. 87%
0 [+dep sub grp]
0 [+dep sub grp]
28
0
0
28
Negative u-tox last two weeks 1. 88% 1. 100% 2. 22% 2. 44% (p<0.01) (p<0.05)
Table continues on next page
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9 Pharmacotherapy for Cocaine Dependence Table 9.7. (cont.) Study
n
Agent
Treatment period (weeks)
Arndt [2, 3] 1992, 1994
79
1. Desipramine 300 mg/day 2. Placebo
12
Hall [21] 1994
94
1. Desipramine 200 mg/day 2. Placebo
12
Campell [5] 1994
46
1. Desipramine (no doses) 2. Placebo
26
1. Desipramine 300 mg/day + psychosocial treatment 2. Placebo + psychosocial treatment
12
Carroll [6, 7, 8] 1994, 1995
110
Imipramine versus placebo
Galloway [14] 1994
183
1. Imipramine 150 mg/day 2. Dito 10 mg = active placebo
26
Nunes [34] 1995
113
1. Imipramine 300 mg/day 2. Placebo
12
ASP = Antisocial personality disorder; BPRS = Brief psychiatric rating scale; CCR = Cocaine craving scale; dep sub grp = Depressive subgroup; GSI = Global severity index; SCL = Symptom checklist; SSRI = Selektive serotonin reuptake inhibitor; 0 = No treatment effect; + = Significant treatment effect; – = Control significantly better than active substance; ( ) = Completers, * = Data missing or incompletely reported.
9.3 Withdrawal Treatment in Cocaine Dependence
Primary outcome measures Abuse Retention
Average pos u-tox 1. (78%) 2. (70%)
Secondary outcome measures Depressive Craving symptoms
Quality score
+ [Psychiatric symptoms: non-ASP]
0
27
*
*
27
1. 15 w 2. 11 w
*
*
29
1. 44% 2. 37%
0 [+ dep sub grp]
*
29
0
0
29
0
0
27
1. 68% 2. 88% (p<0.05)
% abstinence 1. 69% 2. 61%
Mean duration 1. 74 d 2. 58 d
Average pos u-tox 1. 58% 2. 51%
Mean duration
% pos u-tox 1. 33% 2. 34%
1. 10% 2. 12%
545
Median duration 1. 34 d 2. 17 d (p=0.0015)
Three consecutive weeks of abstinence 1. 19% 15% 2. 7% completed
Table continues on next page
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9 Pharmacotherapy for Cocaine Dependence Table 9.7. (cont.) Study
n
Agent
Treatment period (weeks)
SSRI Fluoxetine versus placebo
Grabowski [18] 1995
155 (70)
1. Fluoxetine 20 mg/day 2. Fluoxetine 40 mg/day 3. Placebo
12
Covi [11] 1995
72 (45)
1. Fluoxetine 20 mg/day 2. Fluoxetine 40 mg/day 3. Fluoxetine 60 mg/day 4. Placebo
12
Batki [4] 1996
32
1. Fluoxetine 40 mg/day 2. Placebo
12
Dopamine agonists Amantadine versus placebo
Weddington [40] 1991
37
1. Amantadine 400 mg/day 2. Placebo
12
Ziedonis [26, 27, 29, 41, 42] 1991, 1992, 1994
64
1. Amantadine 300 mg/day 2. Placebo
12
ASP = Antisocial personality disorder; BPRS = Brief psychiatric rating scale; CCR = Cocaine craving scale; dep sub grp = Depressive subgroup; GSI = Global severity index; SCL = Symptom checklist; SSRI = Selektive serotonin reuptake inhibitor; 0 = No treatment effect; + = Significant treatment effect; – = Control significantly better than active substance; ( ) = Completers, * = Data missing or incompletely reported.
9.3 Withdrawal Treatment in Cocaine Dependence
Primary outcome measures Abuse Retention
Opioid pos u-tox week 12 1. (82%) 2. (78%) 3. (62%) Opioid pos u-tox 1 and 2 = 4 3 > 4 (p =0.04)
Average values week 1-6 0
Abstinence last week 1. 31% 2. 43%
547
Secondary outcome measures Depressive Craving symptoms
Quality score
1. intermediate rate 2. lowest rate 3. highest rate
0
0
29
*
0
0
30
0
0
28
0
0
28
0
0
28
Median duration 1. 50% 2. 6% (p<0.001)
1. 25% 2. 43%
Abstinence any two weeks 1. 21% 1. 76% 2. 24% 2. 87%
Table continues on next page
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9 Pharmacotherapy for Cocaine Dependence Table 9.7. (cont.) Study
n
Agent
Treatment period (weeks)
Kolar [25] 1992
14
1. Amantadine 200 mg/day 2. Placebo
12
Handelsman [22] 1995
59
1. Amantadine 200 mg/day 2. Amantadine 400 mg/day 3. Placebo
9
Kampman [24] 1996
61
1. Amantadine 300 mg/day 2. Placebo
4
Antiepileptics Carbamazepine versus placebo
Campbell [5] 1994
44
1. Carbamazepine (no doses) 2. Placebo
26
Montoya [32] 1995
62
1. Carbamazepine 800 mg/day 2. Placebo
8
Kranzler [28] 1995
40
1. Carbamazepine 600 mg/day 2. Placebo
12
Cornish [9] 1995
82
1. Carbamazepine 200 mg/day 2. Placebo
10
Halikas [12] 1997
183
1. Carbamazepine 400 mg/day 2. Carbamazepine 800 mg/day 3. Placebo
12
ASP = Antisocial personality disorder; BPRS = Brief psychiatric rating scale; CCR = Cocaine craving scale; dep sub grp = Depressive subgroup; GSI = Global severity index; SCL = Symptom checklist; SSRI = Selektive serotonin reuptake inhibitor; 0 = No treatment effect; + = Significant treatment effect; – = Control significantly better than active substance; ( ) = Completers. * = Data missing or incompletely reported.
9.3 Withdrawal Treatment in Cocaine Dependence
Primary outcome measures Abuse Retention
549
Secondary outcome measures Depressive Craving symptoms
Quality score
1. 60% 2. 44%
0
0
28
1. (59%) 2. (60%) 3. (56%)
*
0
0
28
1. 54% 2. 60%
1. 63% 2. 61%
0
0
30
Average pos u-tox 1. 62% 2. 51%
Mean lenght of stay 1. 9 w 2. 11 w
*
*
29
W 1-8, mean % neg u-tox 1. 47-56% 2. 65-65%
1. 25% 2. 21%
0
0
29
% pos u-tox 1. 66% 2. 76%
1. 55% 2. 65%
0
*
28
% pos u-tox 1. 36% 2. 25%
1. 46% 2. 33%
*
0
28
% pos u-tox 1. 41% 2. 57% 3. 55%
1. 40% 2. 22% 3. 32%
*
0
29
Neg u-tox last two weeks 1. 20% 2. 22%
Table continues on next page
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9 Pharmacotherapy for Cocaine Dependence Table 9.7. (cont.) Study
n
Agent
Treatment period (weeks)
1. Phenytoine 300 mg/day 2. Placebo
12
Phenytoine versus placebo
Crosby [12] 1996
60 (44)
ASP = Antisocial personality disorder; BPRS = Brief psychiatric rating scale; CCR = Cocaine craving scale; dep sub grp = Depressive subgroup; GSI = Global severity index; SCL = Symptom checklist; SSRI = Selektive serotonin reuptake inhibitor; 0 = No treatment effect; + = Significant treatment effect; – = Control significantly better than active substance; ( ) = Completers. * = Data missing or incompletely reported.
9.3 Withdrawal Treatment in Cocaine Dependence
Primary outcome measures Abuse Retention
Rate of pos u-tox 1. 38% 2. 49% (p=0.037)
1. 21% 2. 19%
551
Secondary outcome measures Depressive Craving symptoms
Quality score
*
28
0
552
9 Pharmacotherapy for Cocaine Dependence Table 9.9. Withdrawal treatment in cocaine dependence. Study
n
Agent
Treatment period (days)
1. Amantadine 200 mg/day 2. Placebo
14
1. Bromocriptine 10 mg/day 2. Placebo
18
1. Buspirone 30 mg/day 2. Placebo
28
Dopamine agonists Amantadine versus placebo Alterman [1] 1992
42
Bromocriptine versus placebo Eiler [13] 1995
63
Partial serotonin agonist Buspirone versus placebo Giannini [17] 1993
32
BPRS = Brief psychiatric rating scale; CCR = Cocaine craving scale; GSI = Global severity index; SCL = Symptom checklist. * = Data missing or incompletely reported.
9.3 Withdrawal Treatment in Cocaine Dependence
Primary outcome measures Withdrawal Retention severity
SCL-90 1. 60–31p 2. 50–18p
1. 76% 2. 76%
GSI of SCL-90-R 1. 0.6–0.05p 2. 1.3–0.35p
1. 24% 2. 22%
BPRS d 1-5-10-20-30 1. 65–60–57– 46–37p 2. 66–67–64– 58–54p
1. 94% d 1–5–10–20–30
Secondary outcome measures Abuse Craving
553
Quality score
*
28
*
CCR 3.2–1.5p 5.3–1.2p
28
* 2. 81%
*
28
1. 7% 2. 40%
554
9 Pharmacotherapy for Cocaine Dependence
9.4
Interaction Studies 9.4.1
Antidepressants
Walsh et al. (n=5) showed that fluoxetine treatment did not cause any negative physiological interactions in cocaine dependence [39]. 9.4.2
Dopamine Agonists
A study by Moscovitz et al. (n=29) reported no serious side effects or interaction effects between bromocriptine and cocaine [33]. Preston et al. (n=12) showed that cocaine and mazindol each resulted in increased heart rate and blood pressure. Concurrent administration of these substances resulted in a further increase in these parameters [36]. 9.4.3
Antiepileptics
Halikas et al. (n=30) showed that cocaine along with carbamazepine did not have any cardiovascular effects [19]. 9.4.4
Partial Opioid Agonist
Rosen et al. (n=5) showed that buprenorphine caused increased cocaine-induced well-being and an increase in heart rate [37].
9.5
Review Articles
O’Brien et al. reported that antidepressants, dopamine agonists, and antiepileptics have been used in pharmacological treatment of cocaine dependence, but the results have been inconsistent. He concluded that the cornerstone of treatment is psychotherapeutic intervention [35]. Cornish & O’Brien discussed the development of peripheral cocaine blocking agents. Two areas were reported: cocaine vaccine and attempts to modify the pharmacokinetics of cocaine [10].
9.6
Long-term Pharmacotherapy in Methamphetamine Dependence (see Tables 9.10 and 9.11)
9.7 Conclusion
9.6.1
Antidepressants 9.6.1.1 Tricyclic Antidepressants Imipramine 1 study, 32 patients. Galloway et al. reported no effect on abuse but a positive effect on retention (p=0.04) [15]. Table 9.10.
Antidepressive treatment in methamphetamine dependence.
Agent and studies
Placebo
Primary outcome measures
Imipramine, n=32 Galloway [15] 1996
X
+ [retention]
Table 9.11 see page 556/557.
Summary One small study showed a positive effect on retention.
9.7
Conclusions 9.7.1
Long-term Pharmacological Treatment in Cocaine Dependence
The primary material used in the meta-analyses contains some weaknesses. For example, the authors did not always use the same principles to classify a urine test as positive for narcotics. Some studies report the average number of positive analyses during the episode of care, while others report the number of analyses during a specified period, e.g., the last week of treatment. Some data have not been reported in the text, but have secondary origins based on figures in the articles. Antidepressive treatment is not superior to placebo in reducing cocaine abuse or to retain patients in treatment. Cocaine addicts with concurrent depression reduce their depressive symptomatology by antidepressive treatment. Four studies compared antidepressants (desipramine) with dopamine agonists (amantadine) [25–27, 29, 40–42]. No effect differences between the agents were reported. Dopamine agonists do not have a better effect than placebo as measured by positive urinalyses and retention in treatment. Likewise, the antiepileptic studies do not report any positive results.
555
556
9 Pharmacotherapy for Cocaine Dependence Table 9.11.
Long-term pharmacotherapy in methamphetamine dependence.
Study
n
Agent
Treatment period (weeks)
1. Imipramine 150 mg/day 2. Dito 10 mg/day
26
Antidepressants Tricyclic antidepressants Imipramine versus control Galloway [15] 1996
32
0 = No treatment effect.
9.7 Conclusion
557
Primary outcome measures Abuse Retention
Secondary outcome measures Depressive Craving symptoms
Quality score
1. 5% 2. 10%
0
29
1. 33 d 2. 10 d
0
558
9 Pharmacotherapy for Cocaine Dependence
9.7.2
Withdrawal Treatment in Cocaine Dependence
A small study showed that buspirone, a partial serotonin agonist, has a positive effect on withdrawal. 9.7.3
Interactions
No serious interaction effects between cocaine and antidepressants, dopamine agonists, or antiepileptics have been noted. 9.7.4
Long-term Pharmacological Treatment in Methamphetamine Dependence
A small study showed that imipramine has a positive effect on retention.
References
References 1 Alterman AI, Droba M, Antelo RE,
2
3
4
5
6
7
Cornish JW, Sweeney KK, Parikh GA, O’Brien CP. Amantadine may facilitate detoxification of cocaine addicts. Drug Alcohol Depend 1992; 31:19–29. Arndt IO, Dorozynsky L, Woody GE, McMellan AT, O’Brien CP. Desipramine treatment of cocaine dependence in methadone-maintained patients. Arch Gen Psychiatry 1992; 49:888–893. Arndt IO, McLellan AT, Dorozynsky L, Woody GE, O’Brien CP. Desipramine treatment for cocaine dependence. Role of antisocial personality disorder. J Nerv Ment Dis 1994; 182:151–156. Batki SL, Washburn AM, Delucchi K, Jones RT. A controlled trial of fluoxetine in crack cocaine dependence. Drug Alcohol Depend 1996; 41:137–142. Campbell JL, Thomas HM, Gabrielli W, Liskow BI, Powell BJ. Impact of desipramine or carbamazepine on patient retention in outpatient cocaine treatment: preliminary findings. J Addict Dis 1994; 13:191–199. Carroll KM, Rounsaville BJ, Gordon LT, Nich C, Jatlow P, Bisighini RM, Gawin FH. Psychotherapy and pharmacotherapy for ambulatory cocaine abusers. Arch Gen Psychiatry 1994; 51:177–187. Carroll KM, Rounsaville BJ, Nich C, Gordon LT, Wirtz PW, Gawin F. One-year follow-up of psychotherapy and pharmacotherapy for cocaine dependence. Delayed emergence of
8
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15
psychotherapy effects. Arch Gen Psychiatry 1994; 51:989–997. Carroll KM, Nich C, Rounsaville BJ. Differential symptom reduction in depressed cocaine abusers treated with psychotherapy and pharmacotherapy. J Nerv Ment Dis 1995; 183:251–259. Cornish JW, Maany I, Fudala PJ, Neal S, Poole SA, Volpicelli P, O’Brien CP. Carbamazepine treatment for cocaine dependence. Drug Alcohol Depend 1995; 38:221–227. Cornish JW, O’Brien CP. Developing medications to treat cocaine dependence: a new direction. Curr Op Psychiatry 1998; 11:249–251. Covi L, Hess JM, Kreiter NA, Haertzen CA. Effects of combined fluoxetine and counselling in the outpatient treatment of cocaine abusers. Am J Drug Alcohol Abuse 1995; 21:327–344. Crosby RD, Pearson VL, Eller C, Winegarden T, Graves NL. Phenytoin in the treatment of cocaine abuse: a double-blind study. Clin Pharmacol Ther 1996; 59: 458–468. Eiler K, Schaefer MR, Salstrom D, Lowery R. Double-blind comparison of bromocriptine and placebo in cocaine withdrawal. Am J Drug Alcohol Abuse 1995; 21:65–79. Galloway GP, Newmeyer J, Knapp T, Stalcup SA, Smith D. Imipramine for the treatment of cocaine and methamphetamine dependence. J Addict Dis 1994; 13:201–216. Galloway GP, Newmeyer J, Knapp T, Stalcup SA, Smith D. A controlled trail of imipramine for the treatment of
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16
17
18
19
20
21
22
23
24
metham-phetamine dependence. J Subst Abuse Treat 1996; 13:493–497. Gawin FH, Kleber HD, Byck R, Rounsaville BJ, Kosten TR, Jatlow PI, Morgan C. Desipramine facilitation of initial cocaine abstinence. Arch Gen Psychiatry 1989; 46:117–121. Giannini AJ, Loiselle RH, Graham BH, Folts DJ. Behavioral response to buspirone in cocaine and phencyclidine withdrawal. J Subst Abuse Treat 1993; 10:523–27. Grabowski J, Rhoades H, Elk R, Schmitz J, Davis C, Creson D, Kirby K. Fluoxetine is ineffective for treatment of cocaine dependence or concurrent opiate and cocaine dependence: two placebo-controlled doubleblind trials. J Clin Psychopharmacol 1995; 15:163–174. Halikas JA, Corsby RD, Koop LP, Crea F, Nugent SM, Carlson GA. Daily monitored cardiovascular effects of carbamazepine in chronic crack cocaine users. Psychopharmacol Bull 1991; 27:345–351. Halikas JA, Corsby RD, Pearson VL, Graves NL. A randomized doubleblind study of carbamazepine in the treatment of cocaine abuse. Clin Pharmacol Ther 1997; 62:89–105. Hall SM, Tunis S, Triffleman E, Banys P, Clark HW, Tusel D, Stewart P, Presti D. Continuity of care and desipramine in primary cocaine abusers. J Nerv Ment Dis 1994; 182:570–575. Handelsman L, Limpitlaw L, Williams D, Schmeidler J, Paris P, Stimmel B. Amantadine does not reduce cocaine use or craving in cocaine-dependent methadone maintenance patients. Drug Alcohol Depend 1995; 39:173–180. Handelsman L, Rosenblum A, Palij M, Magura S, Foote J, Lovejoy M, Stimmel B. Bromocriptine for cocaine dependence. A controlled clinical trial. Am J Addict 1997; 6:54–64. Kampman K, Volpicelli JR, Alterman A, Cornish J, Weinrib R, Epperson L, Sparkman T, O’Brien CP. Amantadine in the early treatment of cocaine dependence: a double-blind, placebo-
25
26
27
28
29
30
31
32
33
controlled trial. Drug Alcohol Depend 1996; 41:25–33. Kolar AF, Brown BS, Weddington WW, Heartzen CC, Michaelson BS, Jaffe JH. Treatment of cocaine dependence in methadone maintenance clients: a pilot study comparing the efficacy of desipramine and amantadine. Int J Addict 1992; 27:849–868. Kosten TR, Morgan CH, Schottenfeld RS. Amantadine and desipramine in the treatment of cocaine-abusing methadone maintained patients. NIDA Res Monogr 1991; 105:510–511. Kosten TR, Morgan CM, Falcione J, Schottenfeld RS. Pharmacotherapy for cocaine-abusing methadone–maintained patients using amantadine or desipramine. Arch Gen Psychiatry 1992; 49:894–898. Kranzler HR, Bauer LO, Hersh D, Klinghoffer V. Carbamazepine treatment of cocaine dependence: a placebo-controlled trial. Drug Alcohol Depend 1995; 38:203–211. Leal J, Ziedonis D, Kosten T. Antisocial personality disorder as a prognostic factor for pharmacotherapy of cocaine dependence. Drug Alcohol Depend 1994; 35:31–35. Margolin A, Kosten TR, Avants SK, Wilkins J, Ling W, Beckson M, Arndt IO, Cornish J, Ascher JA, Li SH. A multicenter trial of bupropion for cocaine dependence in methadonemaintained patients. Drug Alcohol Depend 1995; 40:125–131. Margolin A, Avants SK, Kosten TR. Mazindol for relapse prevention to cocaine abuse in methadone-maintained patients. Am J Drug Alcohol Abuse 1995; 21:469–481. Montoya ID, Levin FR, Fudala PJ, Gorelick DA. Double-blind comparison of carbamazepine and placebo for treatment of cocaine dependence. Drug Alcohol Depend 1995; 38:213–219. Moscovitz H, Brookoff D, Nelson, L. A randomized trial of bromocriptine for cocaine users presenting to the emergency department. J Gen Intern Med 1993; 8:1–4.
References 34 Nunes EV, McGrath PJ, Quitkin FM,
35
36
37
38
Ocepek-Welikson K, Stewart JW, Koenig T, Wager S, Klein DF. Imipramine treatment of cocaine abuse: possible boundaries of efficacy. Drug Alcohol Depend 1995; 39:185–195. O’Brien CP. Recent developments in the pharmacotherapy of substance abuse. J Consult Clin Psychol 1996; 64:677–686. Preston KL, Sullivan JT, Berger P, Bigelow GE. Effects of cocaine alone and in combination with mazindol in human cocaine abusers. J Pharmacol Exp Ther 1993; 267:296–307. Rosen MI, Pearsall HR, McDougle CJ, Price LH, Woods SW, Kosten TR. Effects of acute buprenorphine on responses to intranasal cocaine: a pilot study. Am J Drug Alcohol Abuse 1993; 19:451–464. Stine SM, Krystal JH, Kosten TR, Charney DS. Mazindol treatment for
39
40
41
42
cocaine dependence. Drug Alcohol Depend 1995; 39:245–252. Walsh SL, Preston KL, Sullivan JT, Fromme R, Bigelow GE. Fluoxetine alters the effects of intravenous cocaine in humans. J Clin Psychopharmacol 1994; 14:396–407. Weddington WW Jr, Brown BS, Haertzen CA, Hess JM, Mahaffey JR, Kolar AF, Jaffe JH. Comparison of amantadine and desipramine combined with psychotherapy for treatment of cocaine dependence. Am J Drug Alcohol Abuse 1991; 17:137–152. Ziedonis DM, Kosten TR. Pharmacotherapy improves treatment outcome in depressed cocaine addicts. J Psychoactive Drugs 1991; 23:417–425. Ziedonis DM, Kosten TR. Depression as a prognostic factor for pharmacological treatment of cocaine dependence. Psychopharmacol Bull 1991; 27:337–343.
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9.8
Appendix
Since our search in MEDLINE in April 2000, further RCT studies have been published. These were found in a new search in April 2002. Ten randomized controlled studies with 1213 patients were included. Six new drugs, disulfiram, neuroleptics, serotonin antagonists, opioid antagonists, stimulants, and beta blockers, have been studied. In general, high rates of alcohol abuse are found among cocaine-dependent patients. Alcohol may potentiate the effects of cocaine euphoria, produce disinhibition, and impair judgement and function as conditioned cue leading to cocaine use [1]. This has been the theoretical basis behind the trials with disulfiram. The material is presented in Appendix Tables A-9.1 and A-9.2. Table A-9.1. Long-term pharmacotherapy for cocaine dependence. Studies published after the publication of the SBU report in Sweden, August 2001. Agent and studies
Placebo
Primary outcome measures
Dopamine agonists Pergolide, n=464 Malcolm [8, 9] 2000, 2001
X
– [abuse]
Disulfiram Disulfiram, n=183 George [3] 2000 Petrakis [10] 2000 Carroll [1] 2000
X X –
+ [abuse] + [abuse] + [abuse]
Neuroleptics Risperidon, n=125 Grabowski [4] 2000
X
0
Serotonin antagonists Ritanserin, n=80 Cornish [2] 2001
X
0
Opioid antagonists Naltrexone, n=85 Schmitz [11] 2001
X
+ [abuse]
Stimulants Dextroamphetamine, n=128 Grabowski [5] 2001
X
0
β-Blockers Propranolol, n=198 Kampman [7] 2001
X
0
Table A-9.2 see page 564–569.
9.8 Appendix
9.8.1
Long-term Pharmacotherapy in Cocaine Dependence
Antidepressants No studies. 9.8.1.1
Dopamine Agonists Amantadine Kampman et al. randomized 61 patients to either amantadine or placebo. Subjects with severe cocaine withdrawal symptoms (high CSSA) who received amantadine had more negative urine analyses than the placebo group (p=0.002) [6]. This article is not presented in Table A-9.1. In the ITT analysis (Kampman et al., 1996) there were no differences between the groups. 9.8.1.2
Pergolide Malcolm et al. randomized 464 patients to pergolide 0.05 mg bid, 0.25 mg bid or to placebo. The study duration was 12 weeks. Placebo was significantly better than active medication [8, 9]. Antiepileptics No studies. 9.8.1.3
Disulfiram George et al. randomized 20 buprenorphine-maintained patients to either disulfiram or placebo. Study duration was 12 weeks. All subjects were cocaine and opioid dependent. The number of weeks abstinent from cocaine were significantly higher for the disulfiram-treated patients (7.8±2.6 and 3.3±0.5, respectively, p<0.05). Retention was high in both groups, 73% and 78% respectively. There was a negligible use of alcohol in both groups at the baseline [3]. Petrakis et al. randomized 67 methadone-maintained patients to either disulfiram or placebo. Study duration was also 12 weeks here. He found a disulfiram effect on both frequency (p=0.04) and quantity (p=0.02) of cocaine use compared with placebo. Alcohol consumption was minimal regardless of medication [10]. Carroll et al. randomized 96 participants who met the DSM-III-R criteria for cocaine dependence and alcohol dependence or abuse to either disulfiram and psychosocial treatment or to psychosocial treatment alone in a 1-year followup study. The psychosocial methods were cognitive-behavioral treatment, 12-step facilitation, and clinical management. Carroll et al. show a clear medication effect (p<0.001). The main effects of disulfiram were sustained during the followup period [1]. 9.8.1.4
563
564
9 Pharmacotherapy for Cocaine Dependence Table A-9.2. Study
n
Agent
Treatment period (weeks)
464
1. Pergolide 0.05 mg, bid 2. Pergolide 0.25 mg, bid 3. Placebo
12
George [3] 2000
20
1. Disulfiram 250 mg/d 2. Placebo
12
Petrakis [10] 2000
67
1. Disulfiram 250 mg/d 2. Placebo
12
Carroll [1] 2000
96
1. CBT + disulfiram 260 mg/d 2. 12-step + disulfiram 260 mg/d 3. CM + disulfiram 4. CBT 5. 12-step
12
125
1. Risperidon 2 mg/d 2. Risperidon 4 mg/d 3. Risperidon 8 mg/d 4. Placebo
12
Dopamine agonists Pergolide vs Placebo Malcolm [8, 9] 2000, 2001
Disulfiram Disulfiram vs control
Neuroleptics Risperidone vs Placebo Grabowski [4] 2000
Legend see page 568
9.8 Appendix
565
Outcome measures Abuse
Retention
Others
Neg utox 1. 3 ± 3.6 2. 3 ± 3.3 3. 4 ± 3.5 (ns)
1. 28% 2. 29% 3. 42%
Craving No group differences
TES 1. 25p 2. 14p 3. 32p (p=0.002)
Sub-analysis, n=255, only coc depend pat
Study completion 1. 33% Sub-analysis, 2. 21% n=255, 3. 49% only coc (p<0.001) depend pat
Neg urines 1. 80% 2. 42% 3. 46% (p=0.02)
No of weeks abstinent 1. 7.8 ± 2.6 2. 3.3 ± 0.5 (p<0.05)
1. 73% 2. 78% (ns)
Disulfiram effect Frequency (p = 0.04) Quantity (p = 0.02)
78% completed
Craving No group differences
1. 23% 2. 8% 3. 0% 4. 7% (ns)
SEQ Side-effects pomarily associated with the 8 mg dose
% days of levels of cocaine use during one year follow-up Main effect of disulfiram on cocaine use were sustained (p<0.001)
Proportion pos utox month 3 1. 0.62 2. 0.39 3. No data 4. 0.66 (ns)
Table continues on next page
566
9 Pharmacotherapy for Cocaine Dependence Table A-9.2. (cont.) Study
n
Agent
Treatment period (weeks)
80
1. Ritanserin 10 mg/d 2. Placebo
4
1. Naltrexone 0 mg + RP 2. Naltrexone 50 mg + DC 3. Naltrexone 0 mg + DC 4. Naltrexone 50 mg + RP
12
1. Dextroamphetaminesulfate 15 – 30 mg/d 2. Dextroamphetaminesulfate 30 – 60 mg 3. Placebo
12
Serotonin antagonist Ritanserin vs Placebo Cornish [2] 2001
Opioid antagonists Naltrexone and psychosocial intervention Schmitz [11] 2001
85
Stimultans Dextroamphetamine vs Placebo Grabowski [5] 2001
Legend see page 568
128
9.8 Appendix
567
Outcome measures Abuse
Retention
Others
Mean pos utox 1. 5.9 ± 4.7 2. 4.5 ± 4.3 (ns)
1. 75% 2. 78% (ns)
Craving w.1, w.4 1. 21.0, 18.9 2. 18.6, 15.9 (ns) BDI BL, w.4 1. 2.4, 6.3 2. 10.8, 6.4 (ns)
% neg utox w. 1-4 w. 9-12 1. 78% 70% 2. 79% 65% 3. 65% 69% 4. 86% 100% (p= 0.03)
Pos utox month 3 1. 58% 2. 33% 3. 80% (ns)
At least 6 weeks 1. 50% 2. 50% 3. 50% 4. 46% (ns)
1. 40% 2. 9% 3. 23% (p=0.0012)
Craving No group differences
BDI 1. Increasing 2. Declining 3. Stable
Table continues on next page
568
9 Pharmacotherapy for Cocaine Dependence Table A-9.2. (cont.) Study
n
Agent
Treatment period (weeks)
108
1. Propranolol 40 – 100 mg/d 2. Placebo
8
β-Blockers Propranolol vs Placebo Kampman [7] 2001
Abbrevations BDI Beck’s Depression Inventory bid Twice a day BL Baseline CBT Cognitive Behavior Therapy CM Clinical management CSSA Cocaine Selected Severity Assessment DC Drug concealing RP Relapse prevention SEQ Side Effects Questionnaire TES Treatment effectiveness scores
9.8 Appendix
569
Outcome measures Abuse
Retention
Others
Pos utox No group differences
1. 52% 2. 54% (ns)
Craving No group differences
Subjects with high CSSA at BL had fewer pos urines when treated with propranolol (p=0.01)
High BL CSSA 1. 69% 2. 29% (p=0.015)
Withdrawal Less symptoms with propranolol (p=0.05)
570
9 Pharmacotherapy for Cocaine Dependence
Neuroleptics Risperidon Grabowski et al. randomized 125 patients to risperidon 2 mg, 4 mg, 8 mg, or to placebo in a 12-week study. Risperidon did not have a positive effect on abuse or retention [4]. 9.8.1.5
Serotonin Antagonists Ritanserin Cornish et al. randomized 80 patients to either ritanserin or placebo. Ritanserin was not superior to placebo [2]. 9.8.1.6
Opioid Antagonist Naltrexone Schmitz et al. reported 85 patients who were randomized to naltrexone 50 mg or placebo and to drug counseling with and without CBT in a 12-week study. Participants receiving a combination of naltrexone 50 mg and relapse prevention had significantly fewer positive urine analyses than participants receiving other treatment combinations [11]. 9.8.1.7
Stimulants Dextroamphetamine Grabowski et al. randomized 128 patients to dextroamphetamine 15–30 mg and 30–60 mg respectively or to placebo in a 12-week study. The lower dextroamphetamine dose was superior to the high dose and placebo respectively for increasing retention [5]. 9.8.1.8
9.8.1.9 β-Blockers Propranolol Kampman et al. randomized 108 patients to either propranolol or placebo in an 8-week study. Cocaine withdrawal symptoms were less intense among the propranolol-treated patients (p=0.05). Those with initially more severe CSSA scores showed the strongest decrease in positive urines (p=0.01) [7].
Summary Disulfiram reduced cocaine abuse among cocaine-dependent patients, independently of comorbid alcohol dependence or changes in alcohol consumption. In one study, CBT in combination with naltrexone has shown positive effects. Studies of neuroleptics, dopamine agonists, serotonin antagonists, and stimulants were not successful.
Appendix References
Appendix References 1 Carroll KM, Nich C, Ball SA, McCance
2
3
4
5
6
E, Frankforter TL, Rounsaville BJ. One-year follow-up of disulfiram and psychotherapy for cocaine-alcohol users: sustained effects of treatment. Addiction 2000; 95:1335–1349. Cornish JW, Maany I, Fudala PJ, Ehrman RN, Robbins SJ, O’Brien CP. A randomized, double-blind, placebocontrolled study of ritanserin pharmacotherapy for cocaine dependence. Drug Alc Depend 2001; 61:183–189. George TP, Chawarski MC, Pakes J, Carroll KM, Kosten TR, Schottenfeld RS. Disulfiram versus placebo for cocaine dependence in Buprenorphine-maintained subjects: a preliminary trial. Biol Psychiatry 2000; 47:1080–1086. Grabowski J, Rhoades H, Silverman P, Schmitz JM, Stotts A, Creson D, Bailey R. Risperidone for the treatment of cocaine dependence: randomized, double-blind trial. J Clin Psychopharmacol 2000; 20:305–310. Grabowski J, Rhoades H, Schmitz JM, Stotts A, Daruzska LA, Creson D, Moeller FG. Dextroamphetamine for cocaine-dependence treatment: a double-blind randomized clinical trial. J Clin Psychopharmacol 2001; 31:522–526. Kampman KM, Volpicelli JR, Alterman AI, Cornish J, O’Brien CP.
7
8
9
10
11
Amentadine in the treatment of cocaine-dependent patients with severe withdrawal symptoms. Am J Psychiatry 2000; 157:2052–2054. Kampman KM, Volpicelli JR, Mulvaney F, Alterman AI, Cornish J, Gariti P, Cnaan A, Poole S, Muller E, Acosta T, Luce D, O’Brien CP. Effectiveness of propranolol for cocaine dependence treatment may depend on cocaine withdrawal symptom severity. Drug Alcohol Depend 2001; 63:69–78. Malcolm R, Kajdasz DK, Herron J, Anton RF, Brady KT. A double-blind, placebo-controlled outpatient trial of pergolide for cocaine dependence. Drug Alcohol Depend 2000; 60: 161–168. Malcolm R, Herron J, Sutherland SE, Brady KT. Adverse outcomes in a controlled trial of pergolide for cocaine dependence. J Addict Dis 2001; 20:81–92. Petrakis IL, Carroll KM, Nich C, Gordon LT, McCance-Katz EF, Frankforter T, Rounsaville BJ. Disulfiram treatment for cocaine dependence in methadone-maintained opioid addicts. Addiction 2000; 95:219–228. Schmitz JM, Stotts AL, Rhoades HM, Grabowski J. Naltrexone and relapse prevention treatment for cocainedependent patients. Addict Behav 2001; 26:167–180.
571
1 Kolumnentitel
10
Pregnancy, Neonatal Period, and Substance Abuse Ulf Rydberg
10.1
Introduction
Since most women are aware of the dangers of consuming alcohol or illegal narcotics during pregnancy, the use of addictive agents by pregnant women has been relatively low. However, problems do exist and have become apparent in western nations during recent decades [34]. Effective detection and treatment interventions have been difficult to document since no particular medical specialty comprehensively addresses this problem. Hence, it has not been possible to base clinical management on comprehensive knowledge, and the approaches to collaboration among caregivers vary widely. Treatment research is difficult since abuse associated with pregnancy is relatively uncommon. Controlled studies in the field are considered by many to be impossible or unethical. However, it cannot be considered unethical to perform randomized studies if the control group is given routine care and is not left untreated. The number of cases is small for each hospital, region, and country. Generally, the methods and structures of cooperation required to develop knowledge, methods, and needed treatment studies are lacking. Furthermore, harm to the individual may be severe and lifelong in some cases, and may involve structural changes, deformity, and functional, social, psychological, or legal injury with major economic consequences [33]. 10.1.1
Aim
The primary aim of this chapter is to review the literature on the detection and treatment of women exposed to hazardous alcohol or drug consumption during pregnancy. The secondary aim is to summarize the literature on the diagnosis of alcohol-induced fetal injuries. Since fully developed fetal alcohol syndrome is rare, the review aims to evaluate whether surrogate endpoints can be used in treatment studies.
Treating Alcohol and Drug Abuse. Edited by M. Berglund, S. Thelander, E. Jonsson Copyright c 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 3-527-30682-X
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10 Pregnancy, Neonatal Period, and Substance Abuse
10.2
Search Strategy and Methods
The MEDLINE database was searched for literature published from 1966 through 2000. The Cochrane Library Issue 4, year 2000, was also searched for both complete reviews and individual studies. Review articles, monographs, reference lists, and manual searches were also used. Active researchers in the field were contacted to acquire information about any unpublished studies. The database searches on alcohol used the search terms “pregnancy and alcohol” and “fetal alcohol syndrome”. The text words “fetal alcohol effects” were also used. Furthermore, the search was limited to randomized trials concerning treatment studies. In the area of narcotics, the following search terms were used: “pregnancy and dependence-producing drugs”, “pregnancy and opiates”, “pregnancy and central stimulants”, “pregnancy and sedatives”, “pregnancy and hypnotics”, “pregnancy and cannabis”, “pregnancy and hallucinogens”, “pregnancy and solvents”. These terms were also combined with the terms “controlled clinical trial” and “randomized clinical trial”. The number of reliable studies on the occurrence and severity of abuse during pregnancy is quite limited, as are data on the risks for alcohol- or drug-related fetal injuries. Only 11 randomized controlled studies were found. Of these, 4 concerned areas unrelated to the effects of alcohol or drugs in pregnancy [24, 26, 27, 32]. The 6 remaining studies mainly concerned limited issues and rarely evaluated entire treatment programs. Long-term studies of treatment effects have not been performed.
10.3
Incidence and Prevalence of Alcohol and Drug Use in Pregnant Women
A study from the United States reported that 20–25% of American women consumed alcohol during pregnancy [33]. Another study reported that 5% (230 000) of all babies born in the United States are to women who used illegal drugs during pregnancy [5]. A more recent study of nearly 6000 pregnant women in the United States (Georgia) found that 14% consumed alcohol during pregnancy and 2% drank alcohol on a regular basis [9]. Data from 1980 in Sweden [21] show that 4% of pregnant women consumed alcohol at a rate exceeding the equivalent of 30 cl of strong liquor per day, and that drugs were abused during pregnancy. The same study showed that an additional 7% consumed the equivalent of 8–30 cl of strong liquor per day during pregnancy [20]. More recent data are not available. A study by Palinkas reports disturbing figures [27]. According to a federal report, every fourth American teenager is estimated to have a very high risk of problems with alcohol and drugs. Three million are estimated to be problem drinkers, and 400 000 adolescents need help for drug abuse. It is also reported that the percent-
10.4 Treatment Research – Alcohol and Pregnancy
age of pregnant teenagers is higher in the United States than in any other western nation. The occurrence of a fully developed fetal alcohol syndrome appears to vary according to geography, differences in alcohol habits, and differences in diagnostics. The fact that the initial studies on fetal alcohol syndrome came from France – the country where the consumption of alcohol per person was highest at the time – indicates a probable correlation between the total consumption level and the level of injury, but individual vulnerability factors probably also exist [22]. Fetal alcohol syndrome (FAS) has now been reported in most countries where statistics are available. Abel reports FAS in approximately 1 child per 1000 births: higher in the United States than in Europe [1]. A survey from 1985–1986 of 50 pediatric departments in Sweden showed that among 200 abusing mothers 18 children diagnosed with FAS were born from January 1983 to December 1984, while 41 children were born with partially developed syndrome, corresponding to an incidence of 0.5 per thousand [25]. It was claimed that an intensive information campaign conducted around 1980 caused the rate to decrease, but no data were presented to support this claim. In an area so sensitive and difficult to study, the design of the variables, and how studies have been designed and implemented are decisive factors, and therefore exact figures must be viewed with skepticism. Since the mechanisms behind fetal alcohol effects and fetal alcohol syndrome are so unclear, it is extremely difficult to assess treatment effects. The effect on consumption levels appears to be the most realistic parameter to measure.
10.4
Treatment Research – Alcohol and Pregnancy
In a study by Chang, women were screened in gestational week 16 and assigned to two groups [7]. One group was given brief intervention and the other was simply examined. ASI (Addiction Severity Index, which gives a reliable measure of consumption levels) and other instruments were used. No significant differences between the two groups were observed. However, those who decided to abstain from alcohol before the examination continued to abstain at a significantly higher rate. Self-motivation appears to be just as important as treatment interventions. A later publication, using the Timeline Followback Interview, reported on followup of the results after delivery [6, 31]. However, a specific treatment effect cannot be determined from that study since the control group was not followed up. Forty-two pregnant problem drinkers were studied and compared with 36 control patients who received standard treatment [29]. The women were poor, and availability to treatment was limited, so the study can be called a low-budget program. The women were offered 10 minutes of counseling/education and a cognitively oriented self-help manual with nine steps. Alcohol abstinence was achieved in 88% of the self-help group versus 69% of the control group, which was not a significant difference. Nevertheless, the authors interpreted the study to mean that self-help pro-
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grams were more effective for those consuming small or moderate amounts of alcohol. It can be argued that the followup time of the study was too short and it did not report the rate of delivery complications or the condition of the children. A study from the United States (New Mexico) compared a trial group that received motivational interviews with a control group that received only written information about the risks of alcohol and were referred to their regular physician as needed [16]. Both groups were given the same extensive questionnaire. The patient group consisted of only 43 women, and the study is referred to as a pilot study. The dropout rate at followup after 2 months was 19%. Of the control patients, 67% continued drinking during pregnancy in contrast to 56% in the “motivational interview” group, although average consumption was low. The difference between the groups was not significant. The authors concluded that the current intervention should be sufficient for low consumers, but more extensive and specialized treatment interventions are needed for women with alcohol problems. A followup (after 4 years) of the effects of a brief intervention against hazardous drinking described the effects in women aged between 18 and 40 years [23]. The primary aim of the study was not to influence drinking during pregnancy. Of the 205 women with hazardous drinking who were identified at screening, 103 were randomized to the intervention group and 102 to the control group. The intervention consisted of two 15-minute medical visits including counseling, education, and agreements to reduce consumption. The women in the control group received only general health counseling. The followup after 4 years included 85% of those participating in the original study. The reduction in consumption achieved in the intervention group persisted, measured both as total consumption and as the frequency of intoxication. A particularly pronounced reduction in drinking was observed among the 41 women who experienced at least one pregnancy during followup, but mainly among the 22 women in the treatment group. The difference was significant, despite the limited number of individuals studied. The quality of this study is high. Although the results are promising, they need to be confirmed by further studies.
10.5
Narcotics and Pregnancy
Few treatment centers in the world have brought together a sufficiently large group of pregnant narcotic abusers with a comprehensive team of treatment personnel and strong research. Hence, the area has not been well researched, and randomized studies have not been conducted. Only recently have researchers performed controlled treatment studies. Social factors and concurrent mental illness probably play a greater role here than in patients with alcohol problems. From a standpoint of direct hazard to the fetus, alcohol presents a greater risk factor than narcotics. Structural changes and malformations can be linked to psychological and motor function impairment, but this is not always the case.
10.5 Narcotics and Pregnancy
10.5.1
Cannabis and Pregnancy
No treatment studies on cannabis abuse during pregnancy were found. A metaanalysis of ten observational studies did not identify any effect on birth weight if the mother had used cannabis during pregnancy [11]. However, transient irritability has been observed during the neonatal period when the mother used cannabis [13]. Impaired night sleep persisted until the examination at age 3 years in children whose mothers had abused cannabis during pregnancy [8]. In a longitudinal and multifactorial study (from Pittsburgh) of 763 children from families with low socioeconomic status, a correlation was found between exposure to cannabis prior to birth and hyperactivity, attention deficit problems, and impulsiveness at age 10 years [14]. This correlation persisted after adjusting for a large number of other feasible risk factors. 10.5.2
Amphetamine, Other Central Stimulants, and Pregnancy
No treatment studies were found. However, studies from Sweden found that amphetamine abuse during the pregnancy led to poorer care of the children, lower birth weight, and increased rates of malformation. It was also associated with neurological complications [12, 21]. 10.5.3
Cocaine and Pregnancy
The association of cocaine with pregnancy has been difficult to interpret. Metaanalysis of five studies showed that cocaine abuse yielded a lower birth weight [17]. However, it is uncertain whether it was the drug per se or a generally unhealthy life style that was responsible for the lower birth weight. Although the literature is extensive, much is of dubious quality, and research has been unable to distinguish the effects of cocaine per se from the effects of the drug addict’s lifestyle in general [35]. To date, most researchers have not shown that it is the cocaine per se that harms the fetus. Most women who have used cocaine during pregnancy have given birth to children who are normal in appearance and show normal neurological development. In this perspective, skepticism is warranted toward the claim of greater harmful effects from the cocaine variant “crack” and the so-called “crack babies”. A review study notes that although subtle injuries do occur, cocaine is not shown to cause serious morphological damage to the growing brain [35]. The damage that does occur manifests itself in the form of increased irritability and concentration problems, believed to be caused by preventing the uptake of neurotransmitters and by impairing the growth of dendrites. The long-term effects are unclear. A study from Miami investigated 905 pregnant women exposed to cocaine. They were analyzed in four groups on the basis of the treatment they had received. The study was not randomized. A linear decline in the children’s birth weights was
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noted. Birth weights of children were as follows: of mothers who were nonusers, 3140 g; of mothers with extensive care, 3031 g; of mothers who only received care during pregnancy, 2880 g; and of mothers who only received minimal care, 2650 g [4]. 10.5.4
Opiates and Pregnancy
A meta-analysis has shown that heroin abuse during pregnancy resulted in lower birth weight [18]. Finnegan and Kandall present a rating scale to assess withdrawal symptoms in newborns of opiate abusers and hence the need for medication [13]. The association between heroin withdrawal during pregnancy and high risk of miscarriage is well recognized. Therefore, the usual treatment involves methadone substitution, which aims to maintain levels of the agent in the blood that are as stable as possible. For ethical reasons, it has not been possible to conduct controlled studies of this method [30]. The only randomized study that was found was aimed at influencing injection behavior that increased the risk for infection [28]. The study was successful in this respect, but yielded no information about the effects on the fetus or the mother’s ability to care for the child. 10.5.5
Benzodiazepines and Pregnancy
There is no evidence that benzodiazepines at doses used clinically cause fetal injury [3, 28]. However, a small case-control study found an association between the intake of very high doses of benzodiazepines during pregnancy and developmental and behavioral impairments in the children [20]. The study had major methodological weaknesses, and similar results have not been reported in other studies. Obviously, the same reasons for caution apply as in treatment with other pharmaceuticals during pregnancy. 10.5.6
Other Narcotics and Pregnancy
No studies of the effects of either hallucinogens or solvents on pregnancy were found.
10.6
Studies of the Treatment of Drug Abuse in Pregnancy
A study from the United States (Cleveland, Ohio) randomized 179 pregnant women who had used cocaine during pregnancy to an intervention group and a control group [2]. The control group received an extensive basic program with case man-
10.8 Summary
agement and outpatient and inpatient care resources for drug treatment. In addition to access to the same program, the experimental group also had access to voicemail, health information via the Internet, electronic notifications of self-help groups, and intercessions and testimonials from individuals who had become drugfree. The study showed that the members of the experimental group participated more in different treatment activities, but that this did not have any positive effects on drug abuse. A small study compared the effects of two interventions, both aimed at maintaining self-imposed abstinence from cocaine [10]. Both groups received behavioral therapy-based counseling, but the experimental group also received financial compensation if they attained certain treatment goals. Abstinence was high in both groups, but more women in the control group experienced complications during delivery. Since only six patients were included in each group, the difference may be due entirely to chance. Since the study concerned women who had decided themselves to abstain from cocaine during pregnancy, the positive results cannot be generalized to other groups.
10.7
Staff Training
Questions about alcohol and drug habits are still not routinely asked in many health care settings. It is probably even less common for such questions to be asked of a pregnant woman. To the extent that data about the consumption of alcohol or narcotics are available, most staff members involved in maternal health services lack the knowledge of how counseling and treatment should be offered. A randomized study from the United States investigated whether a brief educational program for maternal health services’ staff could influence the capacity for empathy and the skills for motivational interviewing [15]. Subjects in a mixed group of 30 caregivers were randomized to view either a 20minute training video tape or a video tape of the same length containing a documentary about a female alcoholic. Before and after viewing the video, all participants were given the opportunity to role-play, with the help of an actress who played the role of a female alcoholic. Those in the experimental group improved significantly in expressing empathy and in performing a motivational interview compared with those in the control group. The study has limitations in that real patients were not used, and the study did not investigate whether the skills were maintained over time.
10.8
Summary
The direct, harmful effects of alcohol on the fetus are well documented. A nonhazardous level of consumption has not been found, and many caregivers believe that
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pregnant women should totally abstain from consuming alcohol. Few treatment studies have used acceptable methodology. A well-executed study has shown general effects on alcohol consumption obtained from a brief treatment intervention against hazardous drinking in women in the fertile age group. The effects remained after 4 years and were particularly pronounced in the women who became pregnant during the followup period. Larger controlled studies are essential. Another well-executed study demonstrated that limited educational programs for maternal health care staff had effects on their capacity for empathy and on their skills for conducting motivational and supportive interventions for pregnant women with alcohol problems. Injuries and problems from using narcotics are usually related to the unhealthy lifestyle that most drug addicts have. No studies have documented any effects from any particular treatment method in pregnant drug addicts, but this area needs further investigation.
References
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Appendix Appendix 1. Project Group Authors and Scientific Reviewers
Project Group
Sven Andréasson Associate Professor, Senior Consultant, Department of Public Health Sciences, Karolinska Institute, Stockholm Mats Berglund Professor, Senior Physician, Department of Clinical Alcohol Research, Malmö, Lund University (Chair of the Project Group) Johan Franck Associate Professor, Senior Physician, Department of Clinical Neuroscience, Section for Clinical Alcohol and Drug Research, Karolinska Institute, Stockholm Mats Fridell Associate Professor, Department of Psychology, Lund University, Lund Ingrid Håkanson Project Assistant, SBU, Stockholm Björn Axel Johansson Senior Physician, Department of Clinical Alcohol Research, Malmö, Lund University Anna Lindgren PhD, Senior Consultant, Centre for Mathematical Sciences, Lund University, Lund
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Ulf Rydberg Professor, Senior Physician, Department of Clinical Neuroscience, Occupational Therapy and Elder Care, Division of Psychiatry, Karolinska Institute, Huddinge University Hospital Mikko Salaspuro MD, Professor of Substance Abuse Medicine, University of Helsinki, Helsinki, Finland Sten Thelander MD, Psychiatrist, SBU, Stockholm (Project Manager) Agneta Öjehagen Associate Professor, Department of Clinical Neuroscience, Division of Psychiatry, Lund University Hospital, Lund
Scientific Reviewers
Fanny Duckert Professor, Institution for Psychology, Oslo University, Oslo, Norway Lars Gunne Professor Emeritus, Stockholm Peter Gøtzsche MD, Director, Nordic Cochrane Centre, Copenhagen, Denmark Marcus Heilig MD, PhD, Director of Research and Development, Division of Psychiatry, NEUROTEC, Karolinska Institute, Huddinge University Hospital, Huddinge Matti Hillbom Professor, Department of Neurology, University of Oulu, Finland Onni Niemelä MD, PhD, Department of Laboratory Medicine, Tampere University and Seinäjoki Central Hospital, Finland Barbro Westerholm Professor Emeritus, Stockholm
Appendix 2. Quality Checklist
Appendix 2. Quality Checklist Study
Fully Some Not acceptable = 3 deficiencies = 2 acceptable = 1
Meta-analyses
A. Article selection, search method B. Diagnosis, analysis of heterogeneity C. Treatment description D. Outcome measures
Randomized controlled trials
A. Randomization method B. Blinding C. Patient recruitment, selection D. Diagnosis E. Control treatment F. Basis for calculating effect size G. Outcome measure H. Multicenter study I. Treatment delivery J. Total treatment situation K. Side effect reporting L. Statistical methods
Cohort studies
Management of bias
Case-control studies
Management of bias
Experimental group
Control group I
Control group II
Number of patients Men/women Age, range Age, mean Diagnosis Dropouts, side effects Dropouts, no effects Treatment duration Followup time Treatment Symptom reduction > 50% improvement A manual, detailing how to score the different items, was developed, and interrater reliability tested on a random sample of trials. Interrater reliability was consistently higher than 0.7 (intraclass correlation). Treating Alcohol and Drug Abuse. Edited by M. Berglund, S. Thelander, E. Jonsson Copyright c 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 3-527-30682-X
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Appendix
Appendix 3. Guidelines for Estimating Effect Size
Common methods for estimating responsiveness, i.e., sensitivity to change, are distribution based. Figure 1 illustrates some of these methods. They are explained further in the literature [4, 5]. If variance is not reported, a simple relative change can be estimated by using the difference in the mean between the baseline and the followup divided by the mean value at the baseline. To calculate the effect size (ES), the difference in the means between measurement points (e.g., between baseline and followup) is divided by a measure of variance (e.g., the standard deviation at the baselin: Effect Size I). This formula can be directly transferred to comparisons between groups (i.e., difference in means between groups divided by the summed standard deviation for the groups). To calculate the Standardized Response Mean (SRM), the difference between two measurement points is divided by the standard deviation for the difference in a group. The formula can be directly generalized to comparisons between groups (i.e., the difference in means between two measurement points in the groups divided by the summed standard deviation for this difference). These methods provide information about the importance of an identified difference when using different types of instruments with different scoring and ranges of variation, i.e., how well one can distinguish the “signal” from the “noise”. To achieve more uniform assessments, the methodology is appearing more often in scientific reporting of treatment effects. General rules for estimating the magnitude of ES or SRM: [2] • < 0.20: trivial effect • 0.20-0.50: small effect • 0.50-0.80: moderate effect • > 0.80: large effect
Method • Relative change [3] • Relative effect size [1] • Effect size I (ES) [4,7] • Effect size II (SRM) [6] • Effect size III (t-test) & Relative effect size (t/t) [8] • Effect size IV (t-test) [5] Figure 1. Common methods for evaluating responsiveness.
Treating Alcohol and Drug Abuse. Edited by M. Berglund, S. Thelander, E. Jonsson Copyright c 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 3-527-30682-X
Formula
Appendix 4. Glossary
Appendix 4. Glossary Absolute Risk Reduction (ARR)
Measuring the treatment effect in absolute numbers (e.g., 1 bottle of wine less in the experimental group than in the control group).
Adrenergic
Influenced by the neurotransmitters adrenaline and noradrenaline.
Adrenergic receptors
Two main types of alpha-receptors (most common in the lungs and nervous system) and beta-receptors (most common in the circulatory organs).
Agonist
Substance which has the same effect as the body’s own neurotransmitter on a certain receptor.
Anhedonia
Pathological inability to feel pleasure.
Antagonist
Opposite of agonist.
Axis
The Diagnostic and Statistical Manual of Mental Disorders. (DSM) uses a multiaxial system to describe a patient’s condition: Axis I (the mental disorder that has been identified), Axis II (personality disorder) Axis III (physical disorders), Axis IV (degree of stress the patient has been exposed to), and Axis V (functional level of the patient).
Bias
Systematic error in a study.
Booster session
Extra treatment session after completed psychotherapy to enhance skills and insight.
Cardiomyopathy
Disease of the heart muscle. (Alcoholic cardiomyopathy refers to disease of the heart muscle due to alcohol consumption.)
Case-control study
Individuals with a particular disease are compared with others who, in various ways, are similar but do not have the disease. The aim is to retrospectively identify differences in the degree to which they were exposed to potential risk factors to determine possible causes underlying the origin of the disease.
Case management
A structured treatment approach that focuses on the substance abuse and may involve several different methods.
Cluster randomization
Randomization of treatment units, not individual patients.
Cohort study
Groups (cohorts) of individuals in a population are identified and followed up (prospectively) over a period of time.
Compliance
The extent to which patients adhere to the prescribed treatment.
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The interval within which the true effect is located with a high degree of probability (95 or 99 percent).
Controlled study
All studies where the treatment group is compared with a control group of some type.
Craving
Need for a drug because previous drug abuse has caused lasting psychological and biological changes in the brain.
Cross-over study
The same patient group is randomly given both of the compared treatments in the same study. Requires that the condition being treated is relatively chronic and stable, and that the effect from the first treatment does not last long enough to influence the second treatment.
Cut-off level
The severity determined in a certain study to be required for the patients to be allowed to participate or be excluded.
Dissociation
The rate at which a drug separates from the receptor it attached to.
Dopamine
Neurotransmitter in the brain that affects processes controlling movement, emotional response, and will. The system most influenced by cocaine and amphetamine.
DSM system
DSM = Diagnostic and Statistical Manual of Mental Disorders. The official psychiatric diagnostic system used in the United States, and the predominant means for establishing diagnoses in research. The first version, DSM-III, which used operational criteria, appeared in 1980. Currently, the prevailing version is DSM-IVTR which appeared in 2000. The system uses five dimensions, i.e., Axis I – IV (see Axis).
Double-blind
A way to design a study so that neither the patient, the caregiver, nor the person evaluating the treatment results knows which treatment was given.
Effect size
A way to estimate treatment results (see Appendix III).
Empiric
Knowledge based on observations and experiments.
Epidemiology
Research field that investigates risk factors and the occurrence and spread of disease.
Epigastralgia
Pain in the region over the pit of the stomach.
Euphorizing
Provoking a desired, positive state of intoxication.
Exclusion criteria
Rules established in a study that identify the type of patients who may not participate. Also rules when making a diagnosis.
Appendix 4. Glossary Habilitation
Training for new skills – as opposed to rehabilitation where training focuses on retraining previously acquired skills.
Heterogeneity
Used in statistical contexts to describe the degree of difference within a group of studies with the same aim.
Hypnotic
Sleeping agent.
Hypertension
High blood pressure.
Hypotension
Low blood pressure.
Inclusion criteria
Rules defining which type of patients may participate in a study. Also rules when making a diagnosis.
Interaction
(a) Any positive or negative effects from giving more than one drug at the same time. (b) The corresponding effects from giving more than one type of psychological or social treatment.
Kindling
Repeated stimulation of the nervous system – reduces the stimulation required henceforth to cause a reaction.
Locus ceruleus
Structure of the brain involved in substance abuse mechanisms.
Manual-based
The treatment method is standardized and structured so that everyone using the method will implement it in the same manner.
Matching
Used in substance abuse research to identify qualities of the patient which make a certain treatment more or less suitable.
Mesolimbic system
Structures of the brain central to the development of dependence.
Meta-analysis
Statistical method to increase precision in assessing a treatment effect by pooling several similar studies. The confidence interval (see above) becomes narrower.
Naturalistic study
Also called “observational study” to emphasize that this is not an experiment which the researcher can influence.
Noradrenaline
A neurotransmitter, e.g., in the brain.
Number needed to treat (NNT)
Number of patients who need to be treated in order to for one patient to benefit from the effect of treatment.
Nystagmus
Involuntary rapid oscillation of the eyeballs in a horizontal, vertical, or rotary direction.
Opioid receptors
Receptors for the body’s own opioids (endorphins) but also for morphine, heroin, etc. Exist in two forms: µ and κ.
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Abnormally severe and long-lasting drop in blood pressure occurring from a rapid change in position.
Parenteral
Usually indicates the way of administering a drug when it is not given by mouth or rectally. The most common methods are subcutaneous (under the skin), intramuscular (in a muscle), or intravenously (into the blood stream).
Peroral
By mouth.
Placebo
Biologically inactive control treatment.
Power
(Statistical power) Reflects the size of a study in relation to the reliability of the conclusions that can be drawn from it.
Potentiation
Enhancement. The synergic action of two substances, e.g., drugs, in which their total effects are greater than the sum of their independent effects.
Prospective study
See cohort study.
Randomization
Method of chance allocation of patients to different treatment alternatives.
Rebound
Very intense form of a normal physical reaction. In some cases, observed after sudden discontinuation of drug treatment.
Receptor
Receiver on cell surfaces for neurotransmitters and drugs.
Relative risk reduction (RRR)
Treatment effect expressed as a percent or proportion.
Retention
To remain in treatment. See compliance.
Retrospective
To look back, e.g., retrospective study. (see Case-control Study).
Seponation
Interruption of a drug treatment.
Serotonin
A neurotransmitter, e.g., in the brain (also called 5-HT).
Single-blind
The study is designed so that the caregiver, but not the patient, knows which treatment is given. Considered to be less reliable than double-blind studies.
SSRI
Selective Serotonin Reuptake Inhibitors. Group of drugs affecting serotonin metabolism and used in treating many mental disorders.
Appendix 4. Glossary Statistical significance
A scientific convention for the level of uncertainty one accepts when relying on the results of a measurement. Usually the level of statistical significance is stated by the P value. In most cases one accept that a false measurement occurs once in 20 cases, which is the same as p=0.05.
Subarachnoid bleeding
Sudden bleeding between the brain and the membranes surrounding it.
Tachyarrhythmia
Abnormally rapid heart rhythm.
Weighted effect size
Statistical method in meta-analyses to give different weights to different studies depending on their size (or in some cases other aspects of the study).
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Treating Alcohol and Drug Abuse – An Evidence Based Review The SBU Board of Directors and the SBU Scientific Advisory Committee have reviewed and approved the summary and conclusions of this report. Report prepared by Sven Andréasson, Stockholm Mats Berglund (Chair), Malmö Johan Franck, Stockholm Mats Fridell, Lund Ingrid Håkanson (Project Assistant), Stockholm Björn Axel Johansson, Malmö Anna Lindgren, Lund Björn Lindgren, Lund Lars Nicklasson, Lund Ulf Rydberg, Huddinge Mikko Salaspuro, Helsinki, Finland Sten Thelander (Project Manager), Stockholm Agneta Öjehagen, Lund Manuscript reviewed by Fanny Duckert, Oslo, Norway Lars Gunne, Uppsala Peter Gøtzsche, Copenhagen, Denmark Markus Heilig, Huddinge Matti Hillbom, Uleåborg, Finland Onni Niemelä, Uleåborg, Finland Barbro Westerholm, Stockholm English translation by Ron Gustafson (Publisher Liaison), Hörby
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Treating Alcohol and Drug Abuse – An Evidence Based Review
Summary written by Mats Berglund, Malmö Egon Jonsson, Stockholm Sten Thelander, Stockholm Treating Alcohol and Drug Abuse – an Evidence Based Review The report is presented in two volumes (Swedish version is 850 pages) with 1600 references.
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Conclusions by SBU (September 2001) Main Conclusions
Alcohol-related problems can be prevented Most physicians and nurses have contact with patients who consume hazardous levels of alcohol. Well-documented scientific studies show that brief intervention – based on identifying hazardous consumption and providing information, motivation, and support – leads to a reduction in alcohol consumption and alcohol-related problems. This simple but effective method to prevent the physical and psychological damage caused by alcohol is, however, not as widely applied as it could be. Effective methods are available to treat alcohol and drug problems Many specific psychosocial treatment methods and pharmaceuticals have been scientifically documented as effective in treating alcohol and drug abuse and dependence. Several other methods currently used to treat alcohol and drug problems have no documented effects, or are shown to be ineffective in scientific studies. Consequently, treatment for alcohol and drug problems can be improved by (a) shifting resources away from ineffective treatment methods and into treatment methods that have been documented as effective and (b) committing more resources to treatment programs that apply evidence-based methods. Information, education, and research are needed Treatment programs for alcohol and drug problems should rest on a foundation of evidence-based knowledge. This requires a commitment to information, education, and research. Informational and educational efforts should encompass the findings presented in this report and should be pursued by all appropriate health care and social service providers in the public and private sectors.
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Conclusions by SBU
Important research topics include: • the effectiveness of psychosocial and pharmacological methods to treat the abuse of cannabis and amphetamines, • integrated psychosocial and pharmacological treatment, • optimal intensity and duration of different treatment interventions, • studies on substance abuse during pregnancy, • the cost-effectiveness of different treatment methods.
Alcohol – Hazardous Consumption, Abuse, and Addiction • Short-term preventive interventions by health care providers that target hazardous levels of alcohol consumption are shown to be effective in reducing alcohol consumption for up to 2 years. • Many psychosocial treatment methods with a clear structure and well-defined interventions have favorable effects on alcohol dependence. These methods include cognitive behavioral therapy, 12-step treatment, structured interactional therapy, structured modern therapy with dynamic reference frameworks, motivationenhancing treatment, partner therapy, and strategies that involve the family in treatment. • The effects of many psychosocial treatment methods (e.g., general counseling) have not been scientifically documented. • Benzodiazepines are the most thoroughly documented medication for alcohol withdrawal. The routine practice of supplementing this treatment with antiepileptic therapy does not have satisfactory scientific support. • In long-term treatment of alcohol addiction, acamprosate and naltrexone have confirmed effects, as does disulfiram when delivered under supervision. • The scientific evidence shows that treatment with antidepressants and buspirone relieves depression and anxiety in alcoholics, but it does not show any positive effects on alcohol dependence. Narcotics – Dependence and Abuse • Reeducative therapies targeted at the behaviors of substance abusers are the most effective among the psychosocial methods for treating heroin and cocaine dependence. These methods are generally based on behavioral therapy. Dynamic psychotherapy appears to have a positive effect on heroin abuse. Nonspecific, supportive therapy is often used to treat drug abuse, but its effectiveness has not been confirmed. • The psychosocial therapies that have been used to address other drugs have no proven effects (e.g., cannabis) or are insufficiently studied (e.g., amphetamines, etc.). • Clonidine can be used successfully to treat heroin withdrawal, and it does not cause addiction. Morphine-like substances, i.e., methadone and buprenorphine, have effects that are similar to clonidine.
Conclusions by SBU
• Methadone and buprenorphine used in maintenance therapy for heroin addiction reduces heroin use and improves participation in treatment programs. Naltrexone also reduces abuse. • No well-executed, controlled studies have shown that medication is effective in treating cocaine, amphetamine, or cannabis dependence.
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SBU Summary (September 2001) Introduction
Alcohol-related problems are common in society. Large population studies from the United States have shown that 10–15% of all men and approximately 5% of all women suffer from chronic alcohol dependence. In these groups, approximately one fourth are in a phase of active abuse. Dependence results from consuming hazardous levels of alcohol for a prolonged period. Alcohol dependence often leads to major adverse social and economic consequences for individuals and their families. Suicide, violence, drunken driving, social isolation, and criminal acts often follow dependence and abuse. Alcohol abuse often leads to serious health disorders that mainly affect the brain and nervous system, but also cause serious damage to the liver, muscles, heart, and blood vessels. A large share of the total health care expenditure is for alcohol-related disorders. The social services allocate substantial economic and human resources toward managing the social and economic consequences of alcohol-related problems. Drug addiction and abuse are a less common, but no less serious, problem. Addiction to narcotics is becoming more widespread, particularly among young people. The use of narcotics is generally illegal, with the exception of narcotics used in medical treatment. The most commonly used narcotics include heroin, cocaine, amphetamines, and cannabis. Each of these agents can lead to psychological problems, anxiety, and depression, and some drugs can create long-term or incurable brain disorders. In recent years, several other substances have appeared which some people claim are relatively harmless. This is not the case. Many studies have documented the serious effects of, e.g., ecstasy, which can damage the neurotransmitter system in the brain. The use of both alcohol and drugs may result in physical dependence and greater tolerance levels, i.e., increasingly greater doses are needed to become intoxicated. The nervous system adapts to the intake level, and withdrawal may cause extreme suffering and in some cases may be life-threatening. Alcohol and drug problems often become chronic conditions, even though longer periods of sobriety are common. The dependent individual may often suffer from other physical and/or mental disorders. Hence, treatment must aim both at the Treating Alcohol and Drug Abuse. Edited by M. Berglund, S. Thelander, E. Jonsson Copyright c 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 3-527-30682-X
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SBU Summary
dependency itself and at concurrent disorders, and it may need to be repeated, with the goal of preventing relapse and reducing injury. This is similar to the goals of treating chronic somatic diseases, e.g., diabetes and cardiovascular diseases. “Treating Alcohol and Drug Abuse – An Evidence Based Review” presents the methods available to intervene against harmful levels of alcohol consumption and the methods used to treat and prevent relapse of alcohol and drug dependence and abuse. Furthermore, it presents the findings from scientific studies concerning the effectiveness of different treatment methods. Definitions Dependence Dependence implies that alcohol or drugs have come to play a major role in an individual’s life, to the point that these substances lead to substantial functional impairment or suffering. The internationally accepted criteria for dependence are, e.g., that the individual loses control over intake, that withdrawal problems develop, and that a higher intake is needed to become intoxicated. Most of the studies reviewed in this report have used a system of diagnostic criteria for dependence that was developed in the United States, i.e., the Diagnostic and Statistical Manual of Mental Disorders (DSM system). The DSM system includes the following 7 criteria, 3 of which must be met for a period of one year to establish a diagnosis of dependence:
1. Increased tolerance, e.g., a marked increase in consumption is needed to achieve intoxication. 2. Withdrawal symptoms when use is discontinued. 3. Substances often taken in larger amounts or over a longer period than intended. 4. Persistent desire or unsuccessful efforts to cut down or control substance use. 5. Much time spent acquiring and consuming alcohol and drugs, or recovering from their effects. 6. Neglect of important social, occupational, or recreational activities. 7. Continued substance use despite physical or psychological problems. Abuse
Many of the reviewed studies based their definition of substance abuse on criteria from the DSM system mentioned above. According to DSM-IV, an individual who meets one or more of the following 4 criteria for a period of one year is defined as suffering from substance abuse: 1. Repeated use of alcohol or drugs that leads to problems fulfilling ones obligations at work, school, or home. 2. Repeated use of alcohol or drugs in risk situations, e.g., driving or working with mechanical equipment.
Project Design and Scope
3. Repeated contact with the judicial system as a result of substance abuse. 4. Continued use despite recurring problems. Hazardous alcohol consumption
There is no scientifically established definition of hazardous alcohol consumption, but there is general agreement on a definition within the research community. It suggests that one glass of wine per day for women and two glasses of wine per day for men do not carry a risk, and indeed may have a prophylactic effect against cardiovascular disease. The following limits have often been applied in studies of hazardous alcohol consumption: • Three bottles of wine per week, or 9 to 12 cans of strong beer per week, or 75 centiliters of distilled spirits per week for men. • Two bottles of wine per week, or 6 to 9 cans of strong beer per week, or 50 centiliters of distilled spirits per week for women. Project Design and Scope
This project is limited to reviewing the methods used to intervene against hazardous levels of alcohol consumption and the methods used to treat established alcohol and drug abuse and dependence. Dependence on benzodiazepines and other sedatives was not investigated, nor does the report address preventive work, e.g., campaigns, information directed at different target groups, legislation, pricing policies, and other primary prevention. The report was prepared by a project group of 11 experts. The group identified relevant scientific studies by searching databases covering the international scientific literature in the field. The literature search covered all studies published from the 1950s to the summer of 2000. The MEDLINE database alone yielded 23 000 studies on alcohol problems. The project group selected studies of high scientific quality. The selection focused on randomized controlled trials (RCTs), i.e., studies that randomly assign patients to different types of treatments to determine which treatments yield the best results. This assessment approach is the most reliable, but is often conducted under relatively ideal conditions. Hence, not all of the conclusions are directly applicable to routine, day-to-day health care delivery. Ultimately, the group identified 641 relevant studies, most of which were RCTs. The report presents an assessment of numerous methods and combinations of methods, including medications. It covers pharmacological treatment for alcohol and drug dependence and alcohol detoxification. It also covers psychosocial treatment of alcohol and drug problems and the long-term course of alcohol dependence.
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SBU Summary
The project group considered the following questions to be fundamental in analyzing the various treatment methods: • Does the treatment method have a better effect than no treatment? • Is the treatment method more effective than other methods? • Is the treatment method more effective in a particular type of patient? • Do substance abusers with mental illness require special treatment? • Is inpatient care more effective than outpatient care? The following summary presents the main results of the report.
Preventive Interventions against Hazardous Alcohol Consumption
The intent of various types of interventions is to detect and treat, at an early stage, individuals with excessively high alcohol consumption to prevent them from developing dependence and damaging various organs in the body. The interventions are simple but relatively effective. Most of the methods are based on the following principles: 1. To identify hazardous alcohol consumption by asking a few simple questions. 2. To provide information about the risks and empathetically challenge, advise, and motivate people to reduce or cease alcohol consumption. In total, nearly 500 studies were identified in this area, 27 of which met the standards for high scientific quality and relevance. These studies are presented in detail in Chapter 1 of the report. In most of the studies, primary care physicians and nurses carried out the interventions described above. Many of the studies reported similar outcomes, regardless of whether a physician or a nurse managed the intervention. Generally, those who perform the intervention should participate in a brief educational program (1 or 2 days). The overwhelming majority of studies reported significantly better results with active intervention against hazardous alcohol consumption. Approximately 30% in the group who received advice/counseling reduced their alcohol consumption to risk-free levels compared to approximately 20% in the control group. This is a substantial effect compared to the interventions used in preventive programs for other disorders. For example, 18 patients with an enlarged prostate must be treated by medication for 4 years to avoid surgery in 1 individual, and 128 middle-aged patients with moderately elevated blood pressure must be treated by medication for 5 years to avoid cardiovascular disease in 1 individual. However, in 10 persons who are given counseling and motivation to reduce their alcohol consumption, 1 individual will cease or lower their consumption to a risk-free level.
Psychosocial Treatment for Alcohol Dependence
Psychosocial Treatment for Alcohol Dependence
The wide range of treatment methods covered by the concept of psychosocial treatment can be classified into the following categories: 1. 2. 3. 4. 5.
Methods intended to motivate change Methods aimed at changing the abusive behavior itself Methods that focus on the presumed factors that lead to abuse Methods that offer general support Methods that focus on partners and family
This section of the report identifies 139 randomized controlled trials, of which 14 compared psychosocial treatment to no treatment. The outcomes were generally favorable and were comparable with results achieved in treating other health problems and diseases within the health care system. A comparison of different types of psychosocial treatment reveals that several specific treatment methods have similar effects. These treatment methods are distinguished by a clear structure and well-defined interventions that are often based on detailed protocols. Examples include different types of cognitive behavioral therapy such as a 12-step treatment program (e.g., the Minnesota model) often combined with self-help programs (e.g., Alcoholics Anonymous) and motivational programs. Several studies have shown that structured interactional therapy and structured modern therapy with psychodynamic reference frameworks have effects similar to cognitive behavioral therapy. The studies on partner therapy and family intervention show positive results. Several studies use the term “standard treatment” when referring to the control group. This concept is often poorly defined. Standard treatment usually refers to supportive discussions in combination with input from social services. In the studies reviewed, such treatment showed no effects when compared to specific treatment methods. Furthermore, this type of treatment does not focus as clearly on abusive behavior as specific therapies do. The evidence that a specific treatment method has better effects in certain categories of patient is weak. In patients with less serious alcohol dependence it appears that limited treatment has the same effects as more comprehensive treatment. However, people with more severe alcohol problems have better results with more comprehensive treatment. Although a few treatment programs have been aimed specifically at women, several studies have analyzed the effects of treatment in both genders without finding any distinct differences. The scientific evidence shows that treatment of psychologically disturbed substance abusers and homeless substance abusers must concurrently address both the psychological problems and other lifestyle problems. Positive effects in treating homeless substance abusers have been achieved when applying behavioral methods and structured, consistent patient support. Supportive housing and inpatient care do not appear to yield better results than outpatient treatment.
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SBU Summary
Pharmacotherapy for Alcohol Withdrawal Syndrome
The main goal with this treatment is to prevent and treat life-threatening delirium tremens, epileptic seizures, and other withdrawal symptoms. Agents commonly used for this purpose are benzodiazepines and chlormethiazole. The literature search identified 82 randomized controlled trials of medications for alcohol withdrawal. An additional 13 studies assessed treatment of manifest delirium tremens. These studies show that benzodiazepine treatment is the best documented. This treatment reduces the risks for developing both delirium and withdrawal seizures. It also reduces symptoms of hyperactivity, e.g., perspiration, tremors, and palpitations. Differences between short-acting and long-acting benzodiazepines have not been confirmed. There is no scientific evidence to support other drugs alone as treatment for withdrawal seizures or delirium tremens. The documentation for chlormethiazole – which has more potentially serious side effects than benzodiazepines – is substantially weaker, even though 3 smaller studies found similar effects for benzodiazepines and chlormethiazole. In treating severe cases of alcohol withdrawal, a common intervention is to combine benzodiazepines or similar agents with specific agents for treating epilepsy to prevent withdrawal seizures. Scientific support for this routine is inadequate. Pharmacotherapy for Alcohol Dependence
Since the 1950s, many psychopharmacological drugs have been used to treat alcohol dependence. Earlier drugs were less specifically targeted at alcohol dependence compared to the drugs developed in recent decades. In total, 122 published and 14 unpublished randomized controlled trials assessed the effects of medication on alcohol dependence. Essentially all drugs used at different periods to treat alcohol dependence are covered by these assessments. The agents studied and approved by the Swedish Medical Products Agency to treat alcohol dependence (acamprosate - Campral and naltrexone - Revia) have welldocumented effects. Acamprosate significantly increases the rate of complete recovery, while naltrexone significantly reduces alcohol abuse when the drug is combined with effective psychosocial interventions such as cognitive behavioral therapy. Antabuse (disulfiram), which causes nausea and discomfort during alcohol consumption, is also documented as an effective method to reduce alcohol intake, but only when used under supervision. Drugs (antidepressants / buspirone) are effective in treating depression or anxiety in alcoholics. However, they have no confirmed effects on alcohol dependence. Scientific studies have not confirmed the effects of other medications on alcohol dependence.
Psychosocial Treatment for Drug Dependence
Psychosocial Treatment for Drug Dependence
In total, 112 randomized controlled trials were found on the psychosocial treatment of drug addiction. These studies can be classified into the following categories: 1. Supportive treatment, which is often based on attempts to organize a functioning network among patients, caregivers, and family members. The treatment is not based on protocols, and the structure is usually inadequately described in the studies currently available. 2. Re-education, which usually includes behavioral therapy to change the behaviors behind abuse. This usually involves common behavioral therapy or behavioral interventions targeted at the abuse itself. Hence, this approach requires uniform standards for adequate education of the caregiver. Some reeducative treatment methods, e.g., to prevent the relapse of substance abuse, are based on written protocols and can be administered by individuals without special qualifications. 3. Psychotherapy methods that include family therapy, cognitive therapy, and dynamic-oriented treatments. Interventions that involve re-education are effective in treating heroin and cocaine addiction. However, all of the studies involved patients who were also treated with methadone. Dynamic psychotherapies are effective in treating heroin, but not cocaine, abuse. They are also the only methods shown to have the effect of keeping people in treatment, a primary measure of treatment effectiveness. Supportive interventions have not been effective in treating addiction or keeping people in treatment. The negative findings on supportive therapy and the positive findings on reeducative therapy have many similarities with the corresponding findings on psychosocial treatment methods in alcohol dependence. In the latter case, the scientific literature shows positive effects for specific treatments (which correspond to reeducative therapy in drug dependency) and a lack of positive effects for standard, nonspecific treatment (which corresponds to supportive therapy in drug dependency). Seven randomized controlled trials assessed the effects of different psychosocial treatment methods on cannabis dependence. None of the methods tested had any confirmed treatment effects. Amphetamine abuse is a common problem in some countries. Yet, there are no randomized controlled trials of psychosocial treatment methods for amphetamine dependence.
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Pharmacotherapy for Drug Dependence Long-term Treatment of Heroin Addiction Many randomized controlled trials (70) have assessed different types of drugs to treat heroin addiction. The four studies that assessed the effects of methadone treatment, compared to an untreated control group, reported significant positive effects: reduced heroin abuse and good compliance with treatment. One of the studies also reported a lower mortality rate in the treatment group compared to the control group. The dose of methadone is important. Studies show that doses exceeding 50–60 mg are usually required to achieve favorable treatment results. An alternative to methadone is buprenorphine, which was compared to placebo in only a single study. This study shows significant positive effects from buprenorphine in treating heroin addiction. Another agent which can be used to treat heroin addiction is the methadone derivative, levomethadyl acetate hydrochloride (ORLAAM). This drug has not been assessed in relation to placebo. Comparative studies show similar treatment effects from methadone, buprenorphine, and ORLAAM. The effects have been measured in terms of reduced addiction and continued participation in treatment programs. Buprenorphine is generally described as having certain advantages, e.g., less addiction and lower risk of overdosing, but these effects were insufficiently documented in the studies reviewed. Another alternative is naltrexone, which blocks the receptors for heroin, i.e., the drug user does not experience a “high” from the narcotic. In contrast to what is commonly reported, this review clearly shows that naltrexone has an effect on heroin abuse. It is common for heroin addicts to suffer from depression in conjunction with methadone treatment. Six controlled studies have been conducted on the effects of antidepressants. Two of these studies reported definite effects on depression but not on narcotic addiction. Long-term Treatment of Cocaine Addiction Forty studies have evaluated the effects of several different drugs on cocaine addiction. No effects were documented in these studies. Long-term Treatment of Amphetamine and Cannabis Addiction No studies have demonstrated that pharmaceuticals are effective in treating amphetamine or cannabis addiction.
Overview of the Effects of Different Methods
Pharmacotherapy in Heroin Detoxification
The pharmaceuticals used in heroin detoxification have been assessed in 33 randomized controlled trials. Detoxification can be achieved with some antihypertensive drugs or with morphine-like agents such as methadone and buprenorphine. Among the antihypertensive drugs, clonidine is the agent that has been most studied. Clonidine is more effective than placebo and demonstrates the same effects as morphine-like substances in most of the studies. The effects of methadone treatment are similar to treatment with other morphine-like substances, including buprenorphine. Using naltrexone in combination with clonidine or buprenorphine can shorten the withdrawal period. Inpatient and Outpatient Treatment
The studies that compare the effects of inpatient and outpatient care show that no confirmed conclusions can be drawn on the value of institutional treatment for alcohol dependence, even though the care setting should be appropriate to the level of dependence. In drug addicts, institutional care has effects on social functioning and continued participation in treatment, but such effects are temporary. However, superior results are reported for some drug abuse groups, specifically those who are mentally ill and/or homeless. Among these groups, institutional care results in lower alcohol and drug use and fewer mental symptoms compared to treatment delivered by psychiatric outpatient care or general social services.
Substance Abuse and Pregnancy
There is growing knowledge about the injury to the fetus that can be caused by a mother's use of alcohol and drugs. However, there are no controlled trials that show the effects of prevention or treatment interventions.
Overview of the Effects of Different Methods
The following table provides an overview of several of the important findings from the literature review. With few exceptions, this study is based on randomized controlled trials of high and moderate scientific quality. Hence, the only treatment methods included here are those where the effects have been substantiated by several studies, or treatment methods where the lack of effect has been substantiated by several studies.
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SBU Summary Intervention Against:
Is treatment effective?
Which therapies are best?
No. of studies
Hazardous alcohol consumption
Yes
Identify hazardous consumption, inform about risks, give advice and motivation on how to cut back or quit
25
Yes
Acamprosate Naltrexone Disulfiram (treatment under supervision) Specific methods
80
Yes No
Benzodiazepines
95
Heroin dependence Pharmacological treatment
Yes
70
Psychosocial treatment Withdrawal treatment
Yes Yes
Methadone Buprenorphine ORLAAM Naltrexone Re-educative therapy Clonidine Buprenorphine Methadone
Nonspecific supportive treatment
No
No Yes
None Re-educative therapy
40 44
Not studied
Not studied
0
Not studied No
Not studied No
0 7
Alcohol dependence
Pharmacological treatment Psychosocial treatment focused on addiction Withdrawal treatment Nonspecific supportive treatment
Cocaine dependence Pharmacological treatment Psychosocial treatment Amphetamine dependence Cannabis dependence Pharmacological treatment Psychosocial treatment
Yes
SBU Board of Directors
Kjell Asplund (Chairman) Norrland University Hospital Eva Fernvall Markstedt The Swedish Association of Health Professionals
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SBU Scientific Advisory Committee
Bernhard Grewin Swedish Medical Association Tore Löwstedt Federation of Swedish County Councils Nina Rehnqvist-Ahlberg National Board of Health and Welfare Madeleine Rohlin Faculty of Dentistry, Malmö Olle Stendahl The Medicial Research Council Birgitta Strandvik Swedish Society of Medicine Marie Åsberg The Karolinska Institute Ulla Åhs The Swedish Association of Local Authorities
SBU Scientific Advisory Committee
Peter Aspelin, Chairman Huddinge University Hospital Hans-Olof Adami The Karolinska Institute Björn Beermann Medical Products Agency David Bergqvist Uppsala University Hospital Birgitta Bernspång Umeå University Cecilia Björkelund Vasa Hospital, Gothenburg
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Kurt Boman Skellefteå Hospital Ann-Kathrine Granéus Linköping University Hospital Kerstin Hagenfeldt Karolinska University Hospital Anna-Karin Holm School of Dentistry, Umeå Bengt Jönsson Stockholm School of Economics Anders Lindgren Ministry of Health and Social Affairs Dag Lundberg Lund University Hospital Måns Rosén National Board of Health and Welfare Lil Träskman-Bendz Lund University Hospital Giggi Udén Malmö University
Index a AA – see: Alcoholics Anonymous Absenteeism 22 Absolute Risk Reduction (ARR) 3, 26 Abstinence 318 – drug 359 Abusive behavior 330 Acamprosate 47, 249, 268ff – abstinent days 269 – effect size 281 – Europe 268 – meta-analysis 269 – odds ratio 280 – sobriety 269 – study 268 Acupuncture 326 Addiction Severity Index (ASI) 75, 339, 394ff, 508ff, 575 Adjunctive treatment 466 Administration 386 Adrenergic agent – Baclofen 458 – buprenorphine 418ff – clonidine 418ff – doxepin 418ff – non-rapid detoxification 419 – opioid withdrawal 418ff – other adrenergic agonists 418ff Adrenergic agonist 417, 460, 462 – anesthesia 460 – buprenorphine 438, 458 – clonidine 417, 438f, 455, 458 – lofexidine 458 – methadone 417, 438, 455 – methohexital 460 – naloxone 438, 458 – naltrexone 438f, 458 – non-rapid 460 – opioid antagonist 458, 460 – placebo 438
– propofol 460 – ultra-rapid 460 Affective disorders 362 Aftercare study – homeless alcohol-dependent 73 Aftercare – daycare 73 – Duration 74 – extent of treatment 73ff – Inpatient care – duration 73 – intensity 73 – outpatient care 73f – types of care 73ff Agonist 469, 472, 519 – antagonist 472 – buprenorphine 468, 470ff, 519ff – Contingency Management (CM) 472ff – control 467ff, 519ff – distribution study 472, 519 – dose level study 473 – heroin 471f, 519ff – LAAM 469, 498 – maintenance treatment 467, 512 – meta-analysis 467, 469ff – methadone 467ff, 470ff, 519 – naltrexone 472 – non-CM 472ff – opioid dependence 467ff, 470ff, 512ff, 519ff – outpatient care 472ff – partial agonist 467ff, 512, 519ff – placebo 519ff – RCT 469 – retention 470ff – specialist clinic 472ff – unpublished study 471 Akonline 336 ALAT 38 Albuquerque 320 Alcohol abuse
Treating Alcohol and Drug Abuse. Edited by M. Berglund, S. Thelander, E. Jonsson Copyright c 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 3-527-30682-X
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Index – chronic condition 321 Alcohol consumption – Hazardous 1ff – early phase 20 – intervention 1ff – primary prevention 1ff – screening 38 – secondary prevention 1ff Alcohol counseling 38 Alcohol dependence – 3-grade scale 50 – 5-HT system 270ff – 12-step treatment 71, 118 – abstinence 295 – acamprosate (odds ratio) 268, 274, 280, 302 – aftercare 150ff, 158, 162 – Antabuse 252 – Antabuse supervision – non-manual-based study 256 – antidepressive treatment 296 – anxiety treatment 63 – aversion technique 68 – aversive agent 295 – behavioral therapy 65ff – bibliotherapy 59 – bromocriptine 260ff – buspirone 268, 300, 302 – calcium carbimide 252, 260 – CBT 71 – self-control training 112 – similar technique 288 – treatment 58 – CBT-based study – broad spectrum treatment 106 – CRA-treatment 110 – cue exposure 116 – other methods 116 – CES 44 – changing 45ff – chronic 318 – chronic condition 313 – cognitive behavioral therapy (CBT) 56, 59, 71 – comorbidity 313 – comparability 44ff, 65ff, 68 – Counseling – supportive contact 68 – craving 260 – cross-sectional study 313, 316 – D2 dopamine receptor 260 – depression 294 – Dipsan 252, 260 – disulfiram 252 – dose 295
– – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – –
– – – – – – –
– – – – – – –
duration 315 dynamically oriented therapy 120 effect size 86 environmental therapy 65 epidemiological study 313, 315 epidemiologically defined group 317ff factors behind alcohol dependence 66 factors behind drinking problem 45ff family 45ff family involvement 136 flupenthixol decanoate 260 gender 315, 322 gender distribution 50 gender related effect 176 group therapy 65 homeless abuser 170ff homeless man 68 hours in treatment 158 inpatient care 150ff intensity 150ff, 158, 262 interactional therapy 122 interpretation 44ff intervention partner 138 literature search 50 longitudinal study 318 long-term course 313 long-term effect 322 long-term followup 322 long-term treatment strategy 322 manual-based treatment 266, 272 marital therapy 71, 132 Matching – intensity 146 – specific treatment method 140 Matching effect 70 Matching hypothesis 70ff Matching partner 144 Matching result 148 Matching study 47 MEDLINE – other searches 50 MET 71 – CBT-oriented 98 – primary care 100 – self-help manual – bibliotherapy 102 meta-analysis 44, 80ff, 280ff method 45ff mortality 315ff motivation enhancing treatment (MET) 104 motivation to change 45ff nalmefene 288, 302 naltrexone 288
Index – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – –
– – – – – – – – – – –
non manual-based treatment 270, 274ff ondasetron 268 oral administration 252 outcome 86 outpatient care 150ff partner 45ff patient characteristics 72 pharmacotherapy 247 placebo 252, 288 placebo study 290 problem behavior 45ff psychiatric comorbidity 294, 296, 300 psychiatric disorder 71 psychosocial treatment 43, 264, 270ff psychotherapy 124 Q-score 50 randomized CBT 288 randomized controlled trial 50 randomized placebo-controlled study 260 randomized study 260 relapse prevention 59, 71 result 72 result protocol 50 schizophrenia 260 search strategy 50 self confrontation 63 self-control training 112 similar technique 288 specific therapy 65ff specific treatment 68 SSRI 264 structure 146 Study 67ff – overview 252 Subgroups of patients – co-existing psychiatric disorders 75 – compulsive disorder 75 – homeless 76 – integrated treatment 75 – randomized controlled study 75 – standard case management 75 – treatment study of homeless 77 supervision 260 supportive counseling 45ff supportive measures 146 supportive network 86 supportive therapy 288 therapeutic approach 174 therapist-managed 59 tianeptine 268 tiapride 260 Transaction Analysis (TA) 65 Treatment 58, 295 – study 90ff
– treatment goal 86, 313 – twelve-step treatment 68, 288 – vitamin tablet 252 – younger age groups 315 Alcohol problem – brief intervention 1ff – early detection 1 – secondary prevention 1 – severity 84ff – Study – no significant effects 34 – treatment 1 Alcohol-related mortality 27 Alcohol syndrome – fetal 573 Alcohol treatment method – changing drinking behavior 46 – family 46 – motivation 46 – partner 46 – supportive counseling 46 – underlying factor 46 Alcohol treatment study – basic requirement 45 Alcohol withdrawal syndrome – benzodiazepine 196 – beta-receptor antagonist 222ff – diagnostic criteria 190 – Drugs tested – delirium tremens 192 – withdrawal seizure 192 – meta-analysis 191 – other treatment 226 – outcome measure 190 – pharmacological treatment 189 – pharmacotherapy 189 – psychological treatment 226 – randomized controlled trial 191 – risk factor 189 – symptom 189 – thiamine 226 Alcohol withdrawal treatment 191 Alcohol withdrawal – anti-epileptic drug 238ff – benzodiazepine 235, 238ff – beta-receptor antagonist 238ff – calcium antagonist 239 – phenytoin 238ff Alcoholics Anonymous (AA) 63, 73ff, 86, 327ff Alcohol-related mortality 27 Alconline 336 alpha-2-agonist 189 Amantadine 458, 538, 541, 555, 563ff
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Index Amphetamine 513 Anesthesia 449, 452 Antabuse 52, 65ff Antagonist 498f, 526, 528 – CM 499, 528 – control 498, 526 – distribution study 499, 528 – effect on opioid abuse 498 – maintenance treatment 513 – meta-analysis 498 – naltrexone 498, 513, 526, 528 – non-CM 499, 528 – opioid dependence 498ff, 513, 526, 528 – placebo 526 – retention 498, 513 – side effect 498 Antidepressant 466, 506ff, 513, 533, 537, 554f – adjunctive treatment 466, 506, 513 – control 506 – meta-analysis 506, 537 – opioid dependence 506ff, 513 – placebo 537 – retention 506ff, 513 – selective serotonin reuptake inhibitor 506 – tricyclic antidepressant 506 Antidepressive treatment 533 – cocaine abuse 555 Antiepileptica 189, 204, 533, 537, 539f, 554f – meta-analysis 540 – placebo 537, 539f Anti-kindling effect 533 Antipsychotic drug 189, 190, 229, 249 – Alcohol dependence 260 – flupenthixol decanoate 260 – randomized placebo-controlled study 260 – schizophrenia 260 – tiapride 260 Antisocial personality disorder (ASP) 535, 542 Anxiety 300 Aprotinin 235 APS – see: Antisocial Personality Disorder ARR 26 ASAT 38 ASI – see: Addiction Severity Index 575 ASQ (Abstinence Symptoms Questionnaire) 202, 218ff, 222ff, 226ff Assessment in Health Care – see: SBU Associative learning 330 AST 3
Atenolol 220, 289 Attention deficit 577 AUDIT 16 AUDIT 8–21 12 Australia 18, 23f Aversive agent 249 – Alcohol dependence – Antabuse 252, 260 – non-manual-based study 254ff – supervision 254ff – Calcium carbamide 252, 260 – depot medication 253 – dipsam 252 – disulfiram 252f, 260 – no supervision 253 – supervision 253 – drug 253 – heroin addict 253 – manual-based study 258f – meta-anlysis 253 – no supervision 253 – oral administration 252 – placebo 252ff – supervision 253, 260 – vitamin tablet 252 AWAS (Alcohol Withdrawal Assessment Scale) 202, 218ff, 222ff, 226ff AWS (Alcohol Withdrawal Scale) 202, 218ff, 222ff, 226ff Axis-I disorder 362 Axis-II 376 Axis-II disorder 362
b b-blocker – see: beta-blocker Baclofen 458 Barbital 229 Barbiturate 228ff Barbituric acid derivative 192 BDI – see: Beck’s Depression Inventory Beck’s Depression Inventory (BDI) 394ff, 476, 508ff, 568 Behavior theory 329 Behavioral self control treatment (BSCT) 83 Behavioral therapy 350 – aversion therapy 330 – conditioning 330 – contingency management 330 – coping strategy 331 – drug addiction 330f – extensive psychotherapy 331 – modeling 331
Index – human relations training 57 – operant conditioning 331 – marital therapy 58 Benactyzine 229 – MATCH 57 Benzodiazepine 189, 192ff, 229 – relapse prevention 57f – Compared to – therapist-management 59 – antipsychotic drug 195 Bromocriptine 538, 541, 554 – barbiturate 195 BSI (Brief Symptoms Inventory) 500ff – chlormethiazole 195 Buprenorphine 417ff, 420, 449, 452, 462, 465, – haloperidol 195 467ff,470ff, 512ff, 554, 563 – hydroxyzine 195 – side effect 468 – placebo 191 Bupropion 536 – promazine 195 Buspirone 249, 541, 558 – vitamin B 195 – long-acting 194 – meta-analysis 235 c – short-acting 194 Carboxamide derivative 192 Beta-blocker 562ff Calcium antagonist 189, 192, 228 Beta-carbolin 192 California Civil Addict Program 320 Beta-receptor antagonist 189, 221, 238ff California 319 – benzodiazepine 220 Camprosate 249 – placebo 220 Canada 21 Beta-receptor blocker 192, 238 Canadian Medical Association 229 Bibliotherapy 4954ff Cannabis 513 – see also: Cannabis abuse – self-help manual – data 354 – self-treatment – see also: cannabis dependence Blood alcohol level 3 Cannabis dependence 317 Blood pressure 27, 31 – behavior therapy 354 Boston 317 – family therapy 354 Brief Psychiatric Rating Scale 202, 218ff, – meta-analysis 354 222ff, 226ff, 542 – Psychosocial intervention 354 BPRS – randomized controlled trial 356 – see: Brief psychiatric rating scale – randomized controlled trial 354 Brief advice 30ff, 34 – see also: cannabis abuse Brief counseling 7, 30 – teenager 354 Brief intervention 1ff, 14, 16ff, 23ff, 26ff, 30, Canterbury Alcoholism Screening Test 47, 575ff, 579 (CAST) 6, 16, 21 – analysis of special group 36ff Carbamazepine 215, 289, 533, 539, 554 – effectiveness 4ff – Compared to – elderly 19 – benzodiazepine 205 – general health survey 24 – chlormethiazole 205 – hypertension 20, 24 – phenobarbital 205 – important aspect 36ff – placebo 204 – literature review 4 – tiapride 205 – meta-analysis 4 – valproic acid 205 – primary care 18f – syrup 205 – problem with implementation 37ff – tablets 205 – pseudo-randomized 22 Carboxamide derivative 192 – staff education 37ff Cardiovascular effect 554 – woman 36ff Caroverine 228 Broad spectrum treatment Case management 326, 362 – CBT focus CAST – bibliotherapy 59 – see: Canterbury Alcoholism Screening Test – coping skills training 57 CB – Interactional therapy – see: cognitive-behavioral
615
616
Index CBT 47, 56, 564, 570 – see: Cognitive Behavior Therapy CBT focus – marital therapy 58 – MATCH 57 CBT study – Alcohol dependence – anxiety treatment 57, 63 – broad spectrum treatment 57 – community reinforcement approach (CRA) 57f – cue exposure 57, 62 – self-confrontation 57, 63 – self-control training 57, 61ff CCR – see: Cocaine craving scale CES – see: Cumulative Evidence Score CGI (Clinical Global Impressions Scale) 508ff Chlordiazepoxide 214f, 220, 229, 234f Chlormethiazole 220, 228, 238 – Compared to – other 204 – placebo 204 Chlorpromazine 234 Chlorprothixene 214 CIWA (Clinical Institute Withdrawal Assessment-Alcohol) 202, 218ff, 222ff, 225ff, 228, 234 Cleveland 578 Clinical Institute Withdrawal AssessmentAlcohol-revised (CIWA-Ar) 190 Clonidine 214, 234, 238, 418ff, 448f, 452, 458, 462 – Compared to – benzodiazepine 215 – carbamazepine 215 – chlormethiazole 215 – chlorprothixene 215 – placebo 214 Clorazepate 234 Cluster-randomization 327 CM – see: contingency management Cocaine – self-imposed abstinence 579 Cocaine abuse 363 – reduction 345 – see also: cocaine dependece Cocaine blocking agent 554 Cocaine craving scale 542 Cocaine dependence – amantadine 546
– – – – – – – – – –
antidepressant 351 antiepileptica 548 bromocriptine 552 buspirone 552 carbamazepine 548 cognitive therapy 351 combination therapy 351 desipramine 351, 542 dopamine agonist 546 Effect size 348 – retention 352 – Fluoxetine 546 – imipramine 351, 544 – institutional treatment 358 – long-term pharamcotherapy 542ff, 546, 548, 550, 563 – meta-analysis 344f, 358 – partial serotonin agonist 552 – pharmacological principle 533 – pharmacotherapy 533ff – phenytoine 550 – placebo 542ff, 552 – primary outcome measure 543ff – psychosocial intervention 348, 350 – publication bias 338 – Randomized controlled trial 348, 350, 358, 533 – institutional intervention 360 – institutional treatment 360 – psychosocial intervention 345, 352 – residental treatment 360 – retention 350 – secondary outcome measure 543ff – see also: cocaine abuse – SSRI 546 – tricyclic antidepressant 542 – withdrawal treatment 541, 552 Cocaine Selected Severity Assessment (CSSA) 568 Cocaine study – retention 350 Cocaine vaccine 554 Cocaine withdrawal 533 Cochrane Controlled Trials Register 190, 336 Cochrane database of systematic reviews 190 Cochrane Library 336, 462, 465, 533, 574 Cognitive-Behavioral Psychotherapy (CB) 334 Cognitive Behavior Therapy (CBT) 7, 16ff, 46f, 87, 329, 564, 568ff Cognitive therapy 16, 331ff – meta-analysis 332 – randomized study 332 Cognitive treatment 329 College sample 317ff
Index Community Reinforcement Approach (CRA) 60, 331 – homeless person 60 – partner 60 – 12-step treatment 60 – study 60 Community reinforcement 350 Comorbid depression 535 Company-based physician 24 Comparability 44ff Comparing intensity of treatment – aftercare 74ff Completer 251 Compliance – homeless abuser 362 – mentally ill abuser 362 Conclusion – SSRI 302 – total abstinence 302 Contract 17 Controlled drinking 318 Coping skill 56 Contingency management 472 Core city sample 317ff Core conflict 333 Cost saving 17 Counseling 34, 326 CPRS (Comphrehensive Psychiatric Rating Scale) 202, 218ff, 222ff, 226ff CRA 57 – see: Community Reinforcement Approach Crack 577 Craving 533, 567ff Cross-sectional study – alcohol dependence 316 Cross-tolerance 467 CSS (Craving scale scores) 500ff CSSA 563, 569 – see: Cocaine Selected Severity Assessment Cue exposure 330 – study 63 Cumulative Evidence Score (CES) 44
d Daytop 327 Deep sedation 448 Delirium tremens 189 – barbiturate 229ff – benzodiazepine 232ff – chlormethiazole 234, 236 – imidazoline agonist 234 – meta-analysis 230, 235 – other study 236 – other treatment 235
– randomized controlled trials – selected retrospective study 230 – treatment 232ff Delirium 214, 228f Depression 296 Desipramine 351, 535, 555 Detoxification 370 – drug 368 Dextroamphetamine 562, 566, 570 Diabetes 8 Diacetylmorphine – see: heroin 465 Diary 17, 19,21, 25 – drinking 17 Diastolic blood pressure 16 Diazepam 220, 229, 234 Diphenyl methylpiperazine derivative 192 Diphenylhydantoin 214 Discussion – antipsychotic drug 238ff – barbiturate 238ff – beta-receptor blocker 238 – Chlordiazepoxide 235 – chlormethiazole 238 – clonidine 238ff – disulfiram 295 – valproic acid 238ff Disulfiram 46, 562ff, 564 Dixyrazine 214 Dopamine 533 Dopamine agonist 249, 533, 538, 541, 554f, 562ff – Alcohol dependence – bromocriptine 260 – craving 260 – D2 dopamine receptor 260 – genetic variable 260 – randomized study 260 Dopamine antagonist 228 DRAMS – see: drinking reasonably and moderately with self-control scheme Drinking diary 30 Dropout 37 Drug abstinence 339 Drug abuse – chronic condition 321 – crack 398 – detoxification 398f – homeless 399 – homeless mother 398 – mental illness 362 – opiate 398 – relapse prevention 398
617
618
Index – Satori 396ff – standard treatment 398 – 12-step 397 Drug counseling 329 Drug craving 330 Drug dependence – categorization 326 – chronic condition 313 – comorbidity 313 – cross-sectional study 313 – epidemiological study 313 – gender 322 – homeless abuser 362 – long-term course 313 – long-term effect 322 – long-term followup 322 – long-term treatment strategy 322 – mental illness 362 – psychosocial treatment 325ff – randomized controlled study 327 – supportive treatment method 326 – treatment goal 313 Drunken driving 52 DSM 190, 466 DSM-III 314ff, 317, 319 DSM-III-R 394ff DSM-IV 221, 317, 534 DT (Delirium Tremens) 218ff, 222ff, 226ff Dynamic therapy – see: reconstructive therapy Dynamic treatment – Alcohol dependence 65 – behavior therapy 65 – cognitive behavior therapy 66 – comparison with other specific treatment 65 – comparison with standard treatment 65 – environmental therapy 65 – group therapy 65 – interactional therapy 66 – other dynamic therapy 66 – relapse prevention 66 – transaction analysis (TA) 65
e Early detection 1 – screening 37ff Early intervention 2 Early retirement 318 ECA – see: Epidemiologic Catchment Area Eclectic treatment 87 Economic analysis 17 Edinburgh 20
Educational program 18 Effect Size (ES) 53, 55, 80ff, 337ff, 341, 344ff, 350, 354 Elderly 19 Electroconvulsive treatment (ECT) 235 Enalapril 289 England 18 Enhancement treatment 58 Environmental therapy 328 Epidemiologic Catchment Area 315 Epidemiological paradox 85 Epidemiological study – alcohol dependence 315, 321 – cross-sectional-study 315 – opiate dependence 321 Epileptic seizure 214, 228 ES – see: effect size Ethanol 228 Ethyl alcohol 228 Europe 575 European study 471
f Family 69 Family intervention 88 Family practitioner 17, 24 Family therapy – comparison with individual therapy 69 – meta-analysis 333 – number of sessions 69 – randomized study 333 – relapse prevention 69 – strategic 332 – structural 332 – systematic 332 – transferential-existential 332 FAS – see: fetal alcohol syndrome Fatty acid derivative 192 FDA 417 – see: U. S. Food and Drug Administration Fetal alcohol effect 574 Fetal Alcohol Syndrome (FAS) 573ff – Fetal injury – alcohol-induced 573 Financial compensation 19 Finland 22, 24 Fixed model 467, 469, 473, 498 Fluoxetine 506, 536, 554 FRAMES 1 France 24, 269„ 575 Functional unit 18 Funnel plot 337
Index
g
Heroin 465, 471ff Heroin abuse – reduction 341 Heroin addiction 465 Heroin dependence – abstinence 319 – longitudinal study 320 Heroin withdrawal 415 – pregnancy 578 Homeless 6, 8, 88 – behavioral therapy 76 – case management 76 – contingency management 76 – CRA treatment 76 – dropout 76 – effect size 76 – holistic approach 76 – inpatient 76 – outpatient 76 – quality score 76 Homeless abuser 190, – compliance 362 Homeless alcohol-dependent – randomized treatment study 76 – treatment strategy 76 Homeless patient 52 Homeless substance-abusing mothers 368 Homeless treatment study 76ff – dropout 78 – inpatient 76, 78 – outpatient 78 h Hospital 6ff, 31, 26ff, 319ff Hallucinogen 5-HT agent 249 – pregnancy 578 5-HT system HARS (Hamilton Anxiety Rating Scale) 202, – Alcohol dependence 268 218ff, 222ff, 225ff – acamprosate 268 Harvard University 317 – buspirone 268 HAS (Hamilton Anxiety Scale) 202, 218ff, – ondasetron 268 222ff, 225ff – psychosocial treatment 268 Hazardous alcohol consumption – reduction of alcohol consumption 268 – early phase 20 – intervention 1ff – ritanserin 268 – primary prevention 1ff – study 268 – screening 38 – tianeptine 268 – secondary prevention 1ff Hydantoin derivative 192 Hazelden model 328, 331 Hyperactivity 577 HDRS (Hamilton Depression Rating Hyperlipidemia 8 Scale) 500ff, 508ff Hypertension 8, 452, 458 Head injury 8 Hypotension 449 Health examination 20 Health survey 23f i Hedges 339 ICD 190, 466 Hedges’ d 337ff, 341, 344ff, 350, 354 ICD-8 314ff Helsinki 22 ICD-10 19, 534, Gamma-hydroxybutyric acid 289 Gastrointestinal disease 5 Gender 5, 17ff, 36, 79ff – alcohol problem 79 – epidemiological study 79 – homeless 79 – matching effect 79 – randomized study 79 – sexual abuse 80 General health examination 30 General health survey 24 General practitioner 2, 18, 23 Germany 269 Gestalt therapy 326 GGT 3, 8, 16ff, 38, 20ff, 23 Global severity index 542 GP – see: general practitioner 4-grade scale 43 Great Britain 17, 19, 23, 221, Gross rating scale for alcohol withdrawal 202, 218ff, 222ff, 225ff Group pressure 327 GRSAW – see: Gross Rating Scale for Alcohol Withdrawal GSI – see: global severity index Guanfacine 418ff
619
620
Index Imidazoline agonist 214ff Imidazoline receptor agonist 192 Imipramine 535, 555ff Impulsiveness 577 Incentive – material 359 In-patient days 3 Institutional milieu therapy 325ff Institutional treatment – abstinence 395 – cocaine abuse 394 – court order 400 – crack 398 – depression 397 – detoxification 394, 397, 399 – detoxified abuser 396ff – drug abuse 394ff, 397ff, 400 – drug-abusing woman 396 – drug dependence 327 – homeless abuser 396 – homeless man 398 – homeless mother 398 – Meta-analysis – cocaine abuse 355 – opiate abuse 355 – reduced opiate 355 – methadone 394 – milieu therapy 327 – opiate abuse 394 – opiate detoxification 398 – organizational structure 327 – personality disorder 396 – quadrant 396ff – randomized controlled study 327 – randomized controlled trial 355 – relapse prevention 398 – retention 358, 399 – Satori 396f – selection 327 – standard treatment 398 – 12-step 397 Intensity of treatment 73, 88 – Aftercare – daycare 73 – Duration 74 – extent of treatment 73ff – Inpatient care – duration 73 – intensity 73 – outpatient care 73f – types of care 73ff Intention-to-treat (ITT) 251, 466 Interaction study 534 Interactional therapy 46f
Interpersonal psychotherapy (IPT) 334 Interpretation 44ff Intervention 1 IPT – see: Interpersonal Psychotherapy 334 Israel 359 ITT – see: Intention-to-treat
k Kenya 18 Kindling 533 Korsakoff’s psychosis 221 k-receptor 465, 468
l LAAM (Levo Alpha Acetyl Methadol) – see: L-alpha-acetylmethadol Laboratory test 25, 34 L-alpha-acetylmethadol (LAAM) 465, 469, 476, 512 Learning theory 329ff Lefetamine 418ff Lexington Hospital 319 Lifestyle 579 Lifestyle change 5 Light sedation 448 Literature search 4 Literature search strategy 574 Lithium 228, 249, 289, 536 – chlordiazepoxide 294 Liver disease 8, 10 Locus ceruleus 467 Lofexidine 418ff, 449, 452 – compared to placebo 215 Longitudinal study – alcohol dependence 317f – heroin dependence 319f – Long-term course in 317 – alcohol dependence 317, 319 – heroin dependence 319 Long-term course – alcohol dependence 313 – career abuse 313 – drug dependence 313 Long-term pharmacotherapy – amantadine 546 – antidepressant 542 – antiepileptica 548 – carbamezipine 548 – cocaine dependence 542ff – desipramine 542 – dopamine agonist 546 – fluoxetine 546
Index – imipramine 544 – phenytoine 550 – placebo 542 – primary outcome measure 543ff – secondary outcome measures 543ff – tricyclic antidepressant 542ff Low dependence 88 LSEQ (Leeds Sleep Evaluation Questionnaire) 202, 218ff, 222ff, 225ff
m Magnesium 189 Maintenance treatment 469 – methadone 359 Man – alcohol consumption 36 Manual-based counseling 326 Manual-based treatment 250 Marijuana – see: cannabis Marital therapy 88 – comparison with individual therapy 69ff – number of session 69 – relapse prevention 69 Massachusetts 18 MAST 6, 16, 23, 35 MATCH 47 Matched patient 70 Matching 88 – Alcohol dependence – CBT 71 – marital therapy 71 – MET 71 – patient characteristics 72 – psychiatric disorder 71 – relapse prevention 71 – result 72 – 12-step treatment 71 Maternal health service 579 Matrix treatment 331 MAWS (Mainz Alcohol Withdrawal Scale) 202, 218ff, 222ff, 225ff Mazindol 538, 554 MCV 12, 16, 38 MEDLINE 2, 43, 190, 314, 336, 465, 533, 562, 574 Mental illnes 8, 362ff – compliance 362 – drug abuse 362 Meprobamate 228 Meso-limbic area 467 MET – see: motivational enhancing tretment
Meta-analysis 3ff, 44, 51, 53, 80, 331, 466, 470ff, 534 – alcohol dependence 53f, 55, 59f – antidepressant 537 – antiepileptica 540 – bibliotherapy 55 – buprenorphine 468, 471, 475 – cannabis dependence 354 – cocaine abuse 577 – cocaine dependence 344 – cocaine dependence in Institutional treatment 358 – cocaine treatment 351 – control 468, 471, 499 – CRA-treatment 60 – dopamine agonist 539 – dose study 474f – Heroin abuse – pregnancy 578 – heroin treatment 351 – institutional treatment 355, 358 – interpreting the results 351 – LAAM 470 – methadone 468, 470f, 474 – naltrexone 499 – no treatment 52ff – opiate dependence 340 – placebo 507, 537, 539f – pregnancy 578 – primary care 5 – Psychosocial treatment 53f, 55, 59f – treatment 52ff Methadone 319ff, 334, 369f, 415, 418ff, 449, 452, 462, 465, 467ff, 470ff, 512ff, 538, 563, 578 – advantage 467 – heroin 467 Methadone clinic 359 Methadone Maintenance Treatment (MMT) 325, 334 Methamphetamine dependence 554ff – antidepressant 556 – antidepressive treatment 555 – control 556 – imipramine 556 – long-term pharmacotherapy 556, 558 – tricyclic antidepressant 556 Methamphetamine 534 Method 56 Mexico 18 Miami 577 Milieu therapy – category 327 Mismatched patient 70
621
622
Index MMPI (Minnesota Multifactorial Personality) 500ff MMT – see: methadone maintenance treatment Moderate dependence 88 Moderation oriented cue exposure (MOCE) 83 Morphine 498 Mortality – alcohol dependence 315, 317 Motivational interview 359, 576 Motivational methodology 54ff – bibliotherapy 55 – brief counseling 55 – CBT-counseling 55ff – enhancing treatment 54ff – ES 55 – interviewing 54ff – MET 56 – meta-analysis 54 – pregnant woman 54 – therapist-managed treatment 55 Motivational 57 Motivation-enhancing treatment 54, 56f Multicenter – United States 373 Multicenter study – Australia 23f – Canada 21 – MATCH 70ff – Spain 21 – Veterans 16 Multifactorial study – cannabis 577
n Nalmefene 269, 280ff, 288ff – acamprosate 281 – aversive agent 281 – BRENDA 280 – CBT 280 – cognitive coping skill 280 – cue-exposure 280 – meta-analysis 280f – naltrexone 281 – ondansetrone 281 – randomized study 288 – study 269 – supportive therapy 280 Naloxone 448 Naltrexone 47, 249, 269, 417, 448f, 452, 462, 465, 506, 562, 566, 570 – acamprosate 281, 288 – aversive agent 281
– BRENDA 280 – cognitive coping skill 280 – cue-exposure 280 – meta-analysis 280f – Nalmefene 269ff, 280ff, 288ff – ondansetrone 281 – randomized study 288 – study 269 – supportive therapy 288 Narcotics Anonymous 327ff National Comorbidity Survey 315 National Longitudinal Alcohol Epidemiologic Survey 315ff NCS – see: National Comorbidity Survey Neonatal period – see: pregnancy Neurobehavioral treatment 331 Neuroleptica 562, 564, 570 Neuronal change – locus ceruleus 467 – meso-limbic area 467 New Jersey 334 New Mexico 319, 576 New Zealand 21 NIH 449, 512ff Nimodipine 228 Nitrous oxide 221 NLAES – see: National Longitudinal Alcohol Epidemiologic Survey NNT – see: number needed to treat Nodelink 342, 346, 348 Node-link map 328, 352, 372ff Non-manual based counseling 326 Non-rapid detoxification study 419f, 422ff, 428ff, 434ff, 456ff – adrenergic agent 419f, 422ff – adrenergic agonist 422ff, 456 – amantadine 457f – ARCI (Addiction Research Center Inventory) 422ff – ASRS (Abstinence Symptoms Rating Scale) 422ff – baclofen 456, 458 – buprenorphine 419f, 428ff, 434f, 456ff – chlordiazepoxide 420, 436f – clonidine 419, 422, 456, 458 – dopamine agonist 457 – doxepin 419, 430ff – HDRS (Hamilton depression rating scale) 422ff – methadone 419f, 422ff, 434f, 456f
Index Opioid dependence – NARS (Nurse abstinence rating – adjunctive treatment 513 scale) 422ff – buprenorphine 475 – OOWS (Objective opiate withdrawal – dose study LAAM 475 scale) 422ff – heroin 472 – opioid agonist 420, 434, 457 – methadone 472 – opioid withdrawal scale 457 – pharmacotherapy 465ff – other adrenergic agonist 419, 430ff – OWC (Opiate Withdrawal Checklist) 422ff – randomized controlled trial 465 – retention 468, 513 – partial agonist 420 – search strategy 465 – placebo 419f, 422, 434f, 457f – withdrawal treatment 415 – propoxyphene 420, 436 Opioid receptor 468 – short opiate withdrawal scale 457 Opioid withdrawal – VAS (Visual analoge scale) 423 – adrenergic agonist 421 – WOW (Weak Opiate Withdrawal – anesthesia 417, 448 scale) 423ff – antiadrenergic agent 416 Nonspecific treatment 85ff – buprenorphine 421 Noradrenalin 533 – clonidine 416 Norway 18, 20 – Lofexidine 421 Number Needed to Treat (NNT) 3, 26 – MEDLINE 415 Nurse 24, 37ff – methadone 421 – naloxone 448 o – opioid agonist treatment 417 Opiate abuse 363 – pharmacotherapy 415ff, 465ff – see: opiate dependence – sedation 417, 448 Opiate dependence – systematic literature review 415 – effect 342 – treatment principle 416 – meta-analysis 341 Oregon Kaiser Permanente 19 – methadone maintenance 342 Orthostatic hypotension 418, 458 – psychosocial treatment 342 Outcome measure 534ff – publication bias 337ff – Randomized controlled trials of 342, 358 – summary 31, 33, 35 Overdose 359 – institutional intervention 360 OWRS (Opiate Withdrawal Rating – institutional treatment 358 Scale) 476ff – psychosocial intevention 341 Oxazepam 220 – residential treatment 356 Oxford 19 – retention in psychosocial Oxford movement 327 intervention 344ff Opiate study – conclusions 344 p – retention 344 Paraldehyde 229, 234 Opioid agonist 466 Parentrovite 221 – buprenorphine 420, 458 Parkinson’s syndrome 533 – chlordiazepoxide 420 Paroxetine 294 – methadone 420 Partial opioid agonist – placebo 420, 458 – buprenorphine 439 – propoxyphene 420 – clonidine 439 Opioid antagonist 438f, 460, 466, 562ff, – naltrexone 439 566, 570 Partial serotonin agonist 541, 558 – buprenorphine 438f Partner 69 – clonidine 439 Pediatric department 575 – methadone 438 Peptidase inhibitor 235 – naloxone 438 Pergolide 562ff – naltrexone 438f Perphenazine 234 – placebo 438 Personality disorder 313, 327
623
624
Index Pharmacotherapy research – Alcohol dependence – Abstinence 295 – total 302 – Acamprosate 274ff, 288, 295, 302 – odds ratio 280 – adjunctive therapy 508f – adrenergic agonist 421 – agonist 476ff, 520f, 525 – anesthesia 417, 448 – antagonist 486f, 504f, 527f – antiadrenergic agent 416 – antidepressant 508ff, 535, 554 – antidepressive treatment 294, 296ff, 536 – antiepileptica 554 – antiepileptic treatment 540 – aversive agent 252, 295 – bromocriptine 262f – buprenorphine 421, 473, 475, 478ff, 494ff, 520, 522ff, 525f – buspirone 294, 300ff – Categorization – agent 249 – CBT – randomized 288 – chlordiazepoxide 294 – client satisfaction questionnaire 524 – clonidine 416, 421, 455 – CM – see: contingency management – cocaine dependence 533, 535, 538, 540f, 558, 562, 564f – cognitive behavior therapy 302 – comorbidity 294 – complimentary search 248 – conclusion 452, 462, 512, 529 – contingency management 486f, 504f, 524, 527f – control 476f, 500ff, 508ff, 520, 525ff, 564f – CSQ – see: client satisfaction questionnaire – depression 294 – dextroamphetamine 566f – diagnostic criteria 415, 466, 534 – distribution principle 486f – distribution study 473, 499, 504f, 521, 525, 527f – disulfiram 295, 302, 564f – dopamine agonist 538, 541, 554, 564f – dose 295 – dose study 475, 490ff, 522, 525f – excluded study 416, 466, 534 – heroin 472, 484f, 520, 525
– – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – –
5-HT 270f included study 416, 466, 534 interaction study 554, 558 LAAM 476ff, 494ff lithium 290ff lofexidine 421 long-term pharmacotherapy 535, 562 manual-based treatment 266f, 272ff, 284ff, 300f MEDLINE 248, 415, 455 meta-analysis 280f, 416, 466, 506, 528, 534 methadone 417, 455, 472f, 476ff, 490ff, 508f, 520f, 525 methadone maintenance treatment 524 MMT – see: methadone maintenance treatment nalmefene 282f, 288, 302 naloxone 448, 526 naltrexone 282f, 288, 295, 302, 486f, 499ff, 504f, 510f, 527f, 566f narcotic treatment program 524 neuroleptica 564f non-contigent management 486f, 504f, 524, 527f non-manual-based treatment 264f, 270f, 274ff, 282f, 296ff non-opioid treatment 416, 421 non-rapid 416f, 449, 452, 455 NTP – see: narcotic treatment program opioid agonist treatment 417, 476f opioid antagonist 500ff, 566f opioid dependence 465ff, 475, 500ff, 512, 520ff opioid withdrawal 415ff other agents 289 outcome measures 416, 466, 534 outpatient care 488f, 521, 525 overview 250, 252 partial agonist 520, 525, 541, 554 patient 508ff pharmacological principle 533 placebo 288, 290ff, 520, 527, 564ff principle 416 psychiatric comorbidity 294, 296ff psychosocial intervention 566f psychosocial treatment 262ff, 270f quality rating 249 randomized controlled study 562 rapid 417, 438f, 452, 458 RCT 415, 465, 533 review 449, 462, 512 Risperidon 564f
Index – – – – – – – – – – – – – – – – – – – –
Ritanserin 566f search strategy 248, 415, 465, 533 sedation 417, 448 serotonin 541 serotonin agonist 566f social phobia 294 specialist clinic 488f, 521, 525 SSRI 264f, 294, 302, 510f 12-step therapy 288 stimulant 566f study 252 supportive therapy 288 systematic literature review 415 tables 250, 416 target group 240 treatment duration 295 treatment goal 249 tricyclic antidepressant 508f ultra-rapid 417, 448f, 452, 460 VAS – see: visual analog scale – visual analog scale 524 – withdrawal treatment 558 – Alcohol withdrawal syndrome – antiepileptica 206ff, 238ff – antipsychotic drug 238ff – barbiturate 238 – benzodiazepine 196ff, 235, 238ff – beta-receptor antagonist 222ff, 238ff – beta-receptor blocker 238f – calcium antagonist 239 – carbamazepine 238ff – chlordiazepoxide 235 – chlormethiazole 206ff, 238 – clonidine 238ff – delirium tremens 192, 229 – diagnostic criteria 190ff – drug test 192ff – imidazoline agonist 216ff – included study 191 – meta-analysis 191, 229 – other treatment 226ff – outcome measure 190ff – phenytoin 238 – placebo 238 – problem 239 – psychological treatment 226ff – RCT 191 – review 229 – search strategy 190ff – selection criteria 190ff – thiamine 226f – valproic acid 238 – withdrawal seizure 192
Pharmacotherapy – acamprosate 295 – Alcohol dependence 188, 247, 250, 252, 280, 294, 289 – conclusion 302 – discussion 295ff – alcohol withdrawal – discussion 235, 238f – summary 235, 238f – alcohol withdrawal syndrome 189, 228f – antidepressant 535ff, 554 – anti-depressive treatment294 – antiepileptica 554 – aversive agent 252 – barbiturate 229 – buspirone 294 – carbamazepine 238ff – clonidine 421 – cocaine dependence 533ff, 538, 541, 554, 558 – cognitive behavioral therapy 302 – comorbidity 294 – conclusion 452, 462, 529 – diagnostic criteria 415 – disulfiram 302 – dopamine agonist 538ff, 541, 554 – interaction 558 – interaction study 554 – long-term pharmacotherapy 534 – MEDLINE 455 – meta-analysis 229, 528 – Methadone 417 – naltrexone 295 – non-opioid treatment 416 – non-rapid 416f, 421, 449, 452, 455 – opioid dependence 465ff, 519, 528f – opioid withdrawal 415ff, 421, 438f, 448f, 452, 455, 458, 460, 462 – other agent 289 – other treatment 228 – partial opioid agonist 554 – partial serotonin agonist 541 – placebo 238 – problem 239 – psychiatric comorbidity 294 – psychological treatment 228 – randomized controlled trial 455 – rapid 417, 438f, 449, 452, 458 – review 229, 449, 462 – search strategy 415 – social phobia 294 – SSRI 294 – systematic literature review 415 – Tables
625
626
Index – overview 250 – treatment of delirium tremens 229 – ultra-rapid 417, 448f, 452, 460 – withdrawal treatment 541, 558 Phenobarbital 229 Phenytoin 214, 539 Philadelphia 334 Phoenix House 327 Physician 37ff Pindolol 220 Piracetam 234 Placebo 417 Poland 269 POMS (Profile Of Mood States) 508ff Post-treatment effect – cocaine abuse 363 – institutional treatment 368 – meta-analysis 363 – opiate abuse 363 – RCT of psychosocial intervention 363 – RCT of psychosocial treatment – opiate dependence 364 Pregnancy 10, 574 – alcohol 575 – Amphetamine 577 – Benzodiazepine 578 – cannabis 577 – central stimulant 577 – cocaine 577 – Detection – substance abuse 573 – hazardous drinking 576 – heroin withdrawal 578 – incidence of alcohol and drug use 573 – literature search strategy 574 – narcotica 576ff – opiate 578 – prevalence of alcohol and drug use 573 – search strategy 574 – staff training 579 – substance abuse 573ff – teenager 575 – treatment effect 574ff – treatment of drug abuse 573, 578 – treatment research 573, 578 Pre-treatment effect 363ff – cocaine abuse 363 – institutional treatment 368 – meta-analysis 363 – opiate abuse 363 – Randomized controlled trials of – psychosocial intervention 363 – psychosocial treatment for cocaine dependence 364
– psychosocial treatment for opiate dependence 366ff – residential treatment for cocaine dependence 370 – residential treatment for opiate dependence 370 Primary care 1, 6ff, 17, 19, 20ff, – brief intervention 18 – France 24 – meta-analysis 5 Primary health care 26 Primary outcome measure 466 Prison 319ff Propofol 235 Propranolol 220, 562, 568, 570 Proteinase inhibitor 193 Psychiatric comorbidity 88 Psychiatric condition 313 Psychiatric disorder 75 Psychiatric milieu therapy 328 PsychInfo 190 Psychopharmacological drug – active agent 247 – anticraving agent 247 – aversive agent 247 – older agent 247 – primary agent 247 – recent agent 247 Psychopharmacological treatment 75 Psychosocial intervention 566 Psychosocial method – clinical management 563 – cognitive behavioral treatment 563 – drug dependence 326, 329, 333 – reconstructive therapy 333 – re-educative method 329 – 12-step facilitation 563 Psychosocial treamtent research 48 – Alcohol dependence 50 – aftercare 49, 73, 158ff – assessment of effects 43 – booster session 49 – CBT-based study – broad spectrum therapy 106ff – CRA-treatment 110ff – cue exposure 116 – other methods 116f – self-control training 112ff – CBT treatment 58 – CES 44 – changing problem behavior 45 – comorbidity 49 – comparison 44, 48ff, 73, 84 – conclusion 87
Index – – – – – – – – – – – – – – – – – –
– – – – – – – – – –
– –
– – – –
contingency management (CM) 84 CRA treatment 60 cue exposure 63 discussion 85 dynamically oriented therapy 120f early review 43 effect size (ES) 86 evidence 43 family involvement 136f family therapy 69ff factores behind drinking problem 45, 66 findings 85 gender 49 – related effect 79, 176f homeless 49, 77 homeless abuser 170ff hours in treatment 158ff initial treatment 86 inpatient care 150ff – aftercare 154f – intensity 154f – treatment duration 154f intensity 49, 73, 158ff interactional therapy 122f interpretation 44 intervention partner 138f literature review 43 literature search 82 marital therapy 69ff, 132ff matching effect 72 matching result 70, 148f matching study 47, 140ff – partner 144f – specific treatment 140ff – supportive measurement 146f mentally disturbed abuser 166ff meta-analysis 44, 80ff – bibliotherapy 55 – cognitive beahvior therapy 59 – CRA treatment 60 – effect size (ES) 53 – motivational interviewing 54 – single interview 53 – treatment 53 – waiting list 53 method 46 methodological deficiency 45 motivation 46 motivation-enhancing treatment (MET) 96ff, 104 – bibliotherapy 102ff – CBT-oriented 98 – primary care 100ff – self-help manual 102ff
–
–
–
–
– nonspecific treatment 85 – outcome 86 – outpatient care 150ff – treatment duration 156f – psychotherapy 124f – self-control training 62 – specific treatment 85, 140ff – standard treatment 67, 126ff – 12-step program 64 – 12-step treatment 118f – study on – cognitive behavior treatment 83 – co-morbid patient 84 – length and intensitiy of treatment 83 – matching 83 – significant treatment 83 – supportive counseling 45 – supportive network 86 – supportive treatment 67 – therapeutic approach 174f – therapist factor 78 – treatment effect 47, 85 – treatment goal 86 – working alliance 78 Cocaine dependence – effect size 348, 352 – psychosocial intervention 348, 352 – RCT 348, 352 – retention 352 Drug dependence 325ff – categorization 326 – homeless 362 – mental illness 362 – axis-I-diagnosis 402 – behavioral skills 402 – case management 402 – homeless drug abuser 402 – schizophrenia 402 – sheltered housing 402 – 12-step treatment 402 – therapeutic community 402 – methadone treatment 334 – RCT 326 – supportive treatment 326 Opiate dependence – methadone maintenance 346 – psychosocial intervention 346 – RCT – retention 346 Research consideration – classifying 338 – data analysis 339 – meta-analysis 336, 339 – observational study 335
627
628
Index – psychosocial treatment for cocaine dependence 372ff – psychosocial treatment for opiate dependence 379ff Randomized Controlled Trial (RCT) 2, 43 – drug abuse 402ff – institutional treatment for drug abuse 394ff – mental illness 402ff – Meta-analysis – cannabis abuse 390ff – secondary prevention 5ff, 8 Randomized Treatment Study – limitation 369 Rapid detoxification study 439ff, 442ff, 446ff, 459ff – adrenergic agonist 440, 446 – buprenorphine 439, 442, 446 – Clonidine 439f, 446, 459f – HDRS (Hamilton depression rating scale) 440 – lofexidine 459 – methadone 439, 444 – Naloxone 439, 460 – naltrexone 439f, 446, 460 – opioid antagonist 440, 446, 459 – partial opioid 446 – placebo 439f – visual analog scale (VAG) 441 RCT – see: Randomized Controlled Trial Re-educative therapy 374ff, 381ff – abstinence 382 – abstinence reinforcement 390 – aversion therapy 374 – behavioral skills 374ff, 381 – behavioral skills training 382, 390 – behavioral therapy 374 – clinical management 383 – clonidine 374 – cocaine 390 – cocaine abuser 385 – cognitive behavioral therapy 383, 386 – cognitive relapse prevention 383ff – combined model 385 – community reinforcement 385 – contingency enhancement 374ff, 381 – contingency managment 385 – counseling 373ff q – crack abuser 385 Quality 16ff, 21ff, 26 – cue exposure 374 – depression 386 r – desipramine 383 Random model 467, 469 Randomized controlled study in meta-analysis – detoxification 384
– outcome measures 339 – publication bias 337 – quality rating 338 – randomized controlled study 336 – randomized study 339 – representativity 336 – search strategy 336 – synthesizing 338 – theoretical approach 335 – Versus no treatment 48, 90ff – drunken driver 51 – meta-analysis 52 – results of intervention 52 – waiting list 51, 94ff Psychotherapeutic intervention 329 – psychodynamic oriented method 326 – reconstructive oriented method 326 – re-educative method 326 – see: psychosocial method – supportive method 326 Psychotherapeutic treatment 325 Psychotherapy 65ff, 350, 369, 376ff, 379, 391ff – adolescents 377, 391ff – cognitive 377ff, 388 – counseling 387 – couples therapy 377, 387ff – cue exposure 388 – dynamic 377ff, 388 – family therapy 376ff, 387, 391 – group counseling 388 – inidividual therapy 377 – manual based treatment 388 – marijuana 387 – methadone 377ff – methadone maintenance 377ff – methadone maintenance treatment 388 – narcotica 377 – Purdue Brief Famuly Therapy (PBFT) 391 – supportive-expressive therapy 388 – teenage drug abuser 387, 391ff – therapeutic community 377, 392 Publication bias – cocaine dependence 338 – opiate dependence 337ff Pyridoxine 229
Index – – – – – – – – – – – – –
disulfiram 383 drug abstinence 386 drug education 381 environmental therapy 376 hallucinogen 390 homeless abuser 384 manual-based counseling 373ff, 380 manual-based therapy 383 manual-based treatment 385 mapping 373ff marijuana 382, 390 matrix-model 385 methadone maintenance treatment 373ff, 380, 384 – methadone treatment 375ff, 381ff – milieu therapy 376 – modeling 382, 390 – node-link mapping 373 – obsessive-compulsive 384 – obsessive-compulsory disorder 376 – outpatient care 385 – outpatient counseling 381 – pregnant cocaine abuser 381 – relapse prevention 376, 383ff – relaxation treatment 376, 384 – 12-step treatment 383 – stimulant dependence 385 – stimulus control 374 – therapeutic community (TC) 376, 382, 384 – voucher 382 – voucher reinforcement 390 Re-educative treatment 329 Relapse prevention 351, 359 – marijuana 391ff – outpatient treatment 391 Relative Risk Reduction (RRR) 3, 26 Relaxation 326 Relaxation training 59 Research consideration – observational study 335 – theoretical approach 335 Residential treatment 325ff Retention 339, 344, 469, 472ff, 534ff, 540 – cocaine study 350 – effect 351 – meta-analysis 350 – multimodal intervention 351 Reward effect 533 Reward mechanism 533 Risperidon 562, 564, 570 Ritanserin 562, 566, 570 Rosenberger’s Self-Esteem Scale 394ff RRR 26 Russia 18
s SBU 5, 229, 248ff, 251, 260, 337ff – see also: – Assessment in Health Care – Swedish Council on Technology Scandinavia 325ff Schizophrenia 84, 362 Scotland 20, 25 Screening 37f SE – see: supportive-expressive psychotherapy Search term 2, 313 Seattle 18 Secondary outcome measure 466 Secondary prevention 18 – Alcohol problem 1 – ARR 28 – brief intervention 1ff – early detection 1 – meta-analysis 26 – NNT 28 – quality of study 26 – randomized controlled trial (RCT) 6ff – risk reduction 28 – RRR 28 – study showing positive effect 26ff, 30ff, 34, 36 – summary 38 – treatment 1 Secondary prevention study – alcohol problem 28, 30, 34 – ARR 28 – NNT 28 – risk reduction 28 – RRR 28 – showing positive effect 30ff Seizure 214 Selective Serotonin Reuptake Inhibitor (SSRI) 506, 536, 542 Self-confidence training 59 Self-control training – aversion treatment 62 – bibliotherapy 62 – brief intervention 61 – controlled drinking 61 – study 62 Self-help manual 55, 84, 575 Self-help movement 327 self-help program 575 Self-motivation 575 Serotonin antagonist 562ff, 566, 570 Severity – alcohol problem 84ff
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Index Sheltered living 362 Sick days 3 Sick leave 11, 33 Signal transmission 533 Skills training 362 SMAST 8, 16 Social drinking 318 Solvent – pregnancy 578 South Africa 221 Spain 21 Specific treatment 85ff SSAS (Selected Severity Assessment Scale) 202, 218ff, 222ff, 227 SSRI – see: Selective serotonin reuptake inhibitor SSRI agent 249, 294 – citalopram 261 – familial alcoholism 261 – fluoxetine 261 – psychosocial treatment 261 – reduction of alcohol consumption 261 – sertraline 261 – study 261 – viqualine 261 – zimelidine 261 Standard treatment – Alcohol dependence – aversion technique 68 – comparison with – no treatment 68 – other nonspecific treatment 68 – specific treatment 68 – counseling – supportive contact 68 – twelve-step treatment 68 Stepped care 321 12-step treatment 46, 87, 362 – alcohol dependence 64 – approach 328ff – cocaine dependence 64 – cognitive behavioral therapy (CBT) 64 – MATCH 64 – motivation-enhancing therapy (MET) 64 – see: Twelve-step treatment Stimulant 562ff, 570 Stockholm 23, 25 Structured outpatient care 359 Structure-enhancing intervention 328, 359 Subgroups of alcohol dependent-patients 75ff, 78f Suggestion therapy 326
Suicide 359, 471 Summary – changes in alcohol consumption 31ff, 35 – changes in GGT 31ff, 35 – other changes 31ff, 35 Supportive intervention 328, 379ff – attention deficit disorder 379 – case management 372, 379 – counseling 372, 379 – crack 380 – detoxification 372 – homeless 372, 379ff – methadone 379 – methadone maintenance treatment 373, 379 – Node-link mapping 372ff, 379 – sheltered housing 379ff – social aftercare 379 Supportive therapy 350 Supportive treatment – case management 328 – drug dependence 327f – institutional 327 – nodelink mapping 328 – structure-enhancing intervention 328 Supportive-Expressive Psychotherapy (SE) 334 Sweden 22, 269, 328, 369, 574ff Swedish Council on Technology 337 SweMed 190 Sydney 23f Synanon 327 Systemic review – analyzing results 3 – dropout 37 – exclusion criteria 2 – gender distribution 50 – 3-grade scale 50 – inclusion criteria 2 – literature search 4, 50 – Long-term course – clinical study 314ff – cross-sectional study 314ff – epidemiological study 314 – inclusion criteria 313 – search result 314 – search strategy 314 – search term 313 – MEDLINE 2, 50 – meta-analysis 3ff, 51 – other searches 50 – outcome measure 3 – previous review 4 – Q score 50
Index – – – – – – – – –
randomized controlled trial (RCT) 5, 50 rating scientific quality 3 result 50 result protocol 50 search strategy 2, 50 search term 3 study population 37 study with positive outcome 16 study without significant effects 23
t Test of heterogeneity 467ff Tetrabamate 228 Therapeutic alliance 333 Therapeutic community 325ff, 362ff, 394ff Therapist factor – interpersonal skill 78ff – randomized study 78ff – therapeutic alliance 78ff Thiamine 189, 221 Tiapride 228 Timeline Followback Interview 575 Transference 333 Trasylol 235 Trauma 6, 8 – alcohol consumption questionnaire 21 – patient 18 Trauma patient 18 Treatment focus – drug abuse 369 Treatment for opiate dependence – meta-analysis 340 Tricyclic antidepressant 294, 535, 555 Tromsö 20 TSAS (Total Severity Assessment Scale) 202, 218ff, 222ff, 226ff Twelve-step treatment 63ff – alcohol dependence 64 – Alcoholics Anonymous (AA) 63ff – case management 64 – cocaine dependence 64 – comparison with other specific therapy 64 – comparison with standard treatment 64 – CBT 64 – CRA 64 – MATCH 64 – MET 64 – see also: 12-step treatment – study 64
u Ultra-rapid detoxification study 460ff – adrenergic agonist 450 – anesthesia 448, 450, 461 – Clonidine 450 – deep sedation 448, 450 – light sedation 450 – methohexital 460f – mild sedation 448 – Naloxone 448, 450 – naltrexone 450 – non-rapid 460f – opioid antagonist 450, 461 – placebo 448, 450 – propofol 460f – ultra-rapid 460f United States 17f, 37, 87, 315, 319, 325, 328f, 368, 465, 574ff, 579 Urinalysis 534ff Urine test 555 U. S. Food and Drug Administration (FDA) 417, 465
v Valproic acid 205 – phenobarbital Veterans 386 – administration 87 – multicenter study 16 – United States 16 Veterans Administration 87 Vitamin B 193
w Waiting list 52 Wernicke’s encephalopathy 221 WHO – see: World Health Organization Wisconsin 17 Withdrawal seizure 229 Withdrawal treatment 534 – Amantadine 552 – bromocriptine 552 – buspirone 552 – cocaine dependence 541 – dopamine agonist 552 – partial serotonin agonist 552 – placebo 552 Woman – alcohol consumption 18, 36 Working alliance 47 World Health Organization 5, 14, 18f, 36 WSR (Withdrawal Symptom Rating) 218ff, 222ff, 225ff, 228
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