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MEDICAL CO-PRESCRIPTION OF HEROIN

TWO RANDOMIZED CONTROLLED TRIALS

CENTRAL COMMITTEE ON THE TREATMENT OF HEROIN ADDICTS

This report was prepared by:

Wim van den Brink
Vincent M. Hendriks
Peter Blanken
Ineke A. Huijsman
Jan M. van Ree

© 2002 by Central Committee on the Treatment of Heroin Addicts (CCBH)
Stratenum (fifth floor)
Universiteitsweg 100
3584 CG Utrecht
The Netherlands

ISBN 90-806932-2-7
NUGI 746

All rights reserved. Any part of this report may be reproduced, provided that the reproduction serves a non-commercial purpose, and the source of the report is cited.

Contents:

Letter of submission
Note to the reader

PART I INTRODUCTION

Chapter 1 Background, rationale and objectives of the study
1.1 Introduction
1.2 Good medical practice
1.3 Illicit heroin use in the Netherlands
1.4 Methadone treatment in the Netherlands
1.5 Prescription of opiates other than oral methadone in the Netherlands
1.6 Effectiveness of medically prescribed heroin
1.7 Rationale for the study
1.8 Objectives of the study

PART II STUDY DESIGN AND METHODS

Chapter 2 Methods
2.1 Study population
2.1.1 Target population
2.1.2 Selection criteria
2.1.3 Recruitment and selection procedure
2.2 Study design
2.2.1 Randomized controlled trial
2.2.2 Separate trials for injectable and inhalable heroin
2.2.3 Blinding
2.2.4 Randomization
2.3 Multicenter study
2.4 Stages of the study
2.5 Ethics, informed consent, and remuneration
2.6 Non-adherence to the protocol
2.7 Organization and responsibilities
2.8 Medication and treatment in the study
2.8.1 Objective of the treatment
2.8.2 Prescribed medications
2.8.3 Study supplies and drug accountability
2.8.4 Termination of the co-prescription of heroin
2.8.5 Concurrent treatments
2.8.6 Treatment units and dispensing procedures
2.9 Assessments
2.9.1 Instruments and outcome measures
2.9.2 Timing of the assessments
2.9.3 Primary outcome measure
2.10 Documentation of safety and public order aspects
2.10.1 Adverse events, and serious/unexpected adverse events
2.10.2 Public order and controllability
2.11 Data quality assurance

Chapter 3 Data analysis
3.1 Calculation of sample size
3.2 Statistical analysis of the primary study question
3.2.1 Null hypothesis
3.2.2 Primary assessment-points
3.2.3 Study population in the primary analysis
3.2.4 Missing endpoint-assessments
3.2.5 Robustness of the findings
3.2.6 Exploratory analyses of the validity of the findings
3.2.7 Analysis model and statistical program
3.2.8 Verification of self-report data
3.3 Statistical analyses of the secondary study questions
3.4 Supplementary analyses

Chapter 4 Protocol amendments

PART IIIA STUDY FINDINGS INJECTABLE HEROIN TRIAL

Chapter 5A Selection and disposition of patients
5A.1 Selection procedure
5A.2 Treatment participation and treatment completion
5A.3 Adherence at two-monthly assessments

Chapter 6A Characteristics of the study population at baseline
6A.1 Intention-to-treat population
6A.1.1 Baseline characteristics
6A.1.2 Inclusion profiles
6A.1.3 Comparability of the treatment groups
6A.1.4 Baseline characteristics across the six study sites
6A.1.5 Comparison of the study populations in the injectable and inhalable heroin trials
6A.2 Treatment completers

Chapter 7A Effectiveness of co-prescribed injectable heroin versus methadone alone treatment
7A.1 Treatment response after 12 months
7A.1.1 Treatment response after 12 months in the intention-to-treat population
7A.1.2 Treatment response after 12 months among the treatment completers
7A.2 Treatment response after six months
7A.3 Exploratory analyses of effectiveness
7A.3.1 Improvement and deterioration as components of treatment outcome
7A.3.2 Response at subsequent assessments
7A.3.3 Relative contribution of the outcome domains to response
7A.3.4 Sustained response
7A.3.5 Patients no longer meeting inclusion thresholds of the trial
7A.4 Consequences of discontinuing the co-prescribed heroin treatment

Chapter 8A Safety of co-prescribed injectable heroin treatment
8A.1 Focus of the evaluation
8A.2 Serious adverse events in the experimental treatment phase of the trial
8A.3 Drug overdoses, psychoses and seizures during the experimental phase
8A.4 SAEs, drug overdoses, psychoses and seizures following the
discontinuation of co-prescribed heroin treatment

PART IIIB STUDY FINDINGS INHALABLE HEROIN TRIAL

Chapter 5B Selection and disposition of patients
5B.1 Selection procedure
5B.2 Treatment participation and treatment completion
5B.3 Adherence at two-monthly assessments

Chapter 6B Characteristics of the study population at baseline
6B.1 Intention-to-treat population
6B.1.1 Baseline characteristics
6B.1.2 Inclusion profiles
6B.1.3 Comparability of the treatment groups
6B.1.4 Baseline characteristics across the six study sites
6B.1.5 Comparison of the study populations in the injectable and inhalable heroin trials
6B.2 Treatment completers

Chapter 7B Effectiveness of co-prescribed inhalable heroin versus methadone alone treatment
7B.1 Treatment response after 12 months
7B.1.1 Treatment response after 12 months in the intention-to-treat population
7B.1.2 Treatment response after 12 months among the treatment completers
7B.2 Treatment response after six months
7B.3 Exploratory analyses of effectiveness
7B.3.1 Improvement and deterioration as components of treatment outcome
7B.3.2 Response at subsequent assessments
7B.3.3 Relative contribution of the outcome domains to response
7B.3.4 Sustained response
7B.3.5 Patients no longer meeting inclusion thresholds of the trial
7B.3.6 Underreporting of illegal drug use and treatment effect
7B.4 Consequences of discontinuing the co-prescribed heroin treatment

Chapter 8B Safety of co-prescribed inhalable heroin treatment
8B.1 Focus of the evaluation
8B.2 Serious adverse events in the experimental treatment phase of the trial
8B.3 Drug overdoses, psychoses and seizures during the experimental phase
8B.4 SAEs, drug overdoses, psychoses and seizures following the discontinuation of co-prescribed heroin treatment

PART IV FEASIBILITY OF HEROIN ON MEDICAL PRESCRIPTION

Chapter 9 Public order and controllability
9.1 Focus of the evaluation
9.2 Events not attributed to individual patients
9.3 Events in the trial on injectable heroin
9.4 Events in the trial on inhalable heroin

Chapter 10 Contact dermatitis

Chapter 11 The costs of medical co-prescription of heroin

PART V CONCLUSIONS AND RECOMMENDATIONS

Chapter 12 Conclusions

Chapter 13 Recommendations

PART VI REFERENCES

PART VII APPENDICES

1. Decision on the installation of the Central Committee on the Treatment
   of Heroin Addicts
2. Decision on the re-installation of the Central Committee on the Treatment
   of Heroin Addicts
3. Members of the Central Committee on the Treatment of Heroin Addicts, and
   Observers and advisors of the Central Committee on the Treatment of
   Heroin Addicts
4. Members of the National Research Board of the Central Committee on the
   Treatment of Heroin Addicts
5. Members of the National Safety Committee, and
   Members of the National Committee on Public Order and Controllability
6. International advisors
7. Statement of the National Safety Committee
8. Statement of the National Committee on Public Order and Controllability
9. Research projects related to the main study
10. Publications