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Opium tincture for opioid substitution treatment Nikoo, Mohammadali 2021

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  OPIUM TINCTURE FOR OPIOID SUBSTITUTION TREATMENT  by  Mohammadali Nikoo  MD, Tehran University of Medical Sciences, 2011  A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF  DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Experimental Medicine)  THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver)  April 2021  © Mohammadali Nikoo, 2021   ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the dissertation entitled: Opium tincture for opioid substitution treatment  submitted by Mohammadali Nikoo in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Experimental Medicine  Examining Committee: Reinhard Michael Krausz, Professor, Department of Psychiatry, University of British Columbia  Supervisor  Kerry Jang, Professor, Department of Psychiatry, University of British Columbia Supervisory Committee Member  Christian Schütz, Professor, Department of Psychiatry, University of British Columbia  Supervisory Committee Member Wofram Tetzlaff, Professor, Neuroscience Program, University of British Columbia  University Examiner Stephan Schwarz, Professor, Pharmacology Program, University of British Columbia  University Examiner  Additional Supervisory Committee Members: Wolfgang Linden, Professor, Department of Psychology, University of British Columbia Supervisory Committee Member     iii Abstract Opioids have served as a dual-purpose substance throughout the human history. While they are listed as an essential medicine by the World Health Organization, on account of their effectiveness at treating pain, their harmful use also leaves a significant burden on societies. Among treatments developed to address the latter, opioid substitution treatment (OST) is a very well-documented and evidence-based treatment, which has shown to improve a multitude of treatment outcomes for patients with opioid dependence. Besides well-established medicines for OST, such as methadone and buprenorphine, opium tincture (OT), a hydro alcoholic preparation of opium, is used for this purpose on a large scale in Iran. The first step of this thesis, which was a systematic review, (2014 - 2016) did not find adequate evidence to make a conclusive recommendation about the safety and efficacy of OT for OST. Following this review, a non-inferiority randomized clinical trial (opium trial) with 204 participants and a 12-week follow-up period, compared the safety and efficacy of OT with methadone in treatment of opioid dependence.  A comparison of international samples with participants of opium trial at baseline revealed that patterns of substance use and related risk behaviors differed significantly between Iran and other regions of the world, a factor which needs to be considered when generalizing the findings of the opium trial.  Next, the comparison of outcomes between the two arms showed that OT was a clinically effective medication and that OT was more effective than methadone at reducing participants’ opioid use outside of treatment; however, the study could not conclude whether or not OT was non-inferior to methadone at retaining participants in treatment. The number of people with AEs (adverse events) were not significantly different between the two groups. There was no serious adverse event in the OT arm and one in the methadone arm. Substitution treatment with OT has expanded in Iran since its introduction and the results of this   iv trial show potential for its further use. OT can serve as a culturally acceptable and widely available medication for OST, diversifying the treatment options for this condition.    v Lay Summary Opioid substitution treatment - the provision of opioid substances under medical supervision - improves the health of patients with opioid dependence and reduces their mortality. Opium tincture is used for substitution treatment in Iran. This thesis first reviewed previous studies and concluded that there was not enough research to show whether or not opium tincture was an effective and safe treatment for opioid dependence. Then, it compared opium tincture with methadone and concluded that it was an effective medication for retaining patients in treatment but was unable to determine whether or not it was as effective as methadone. However, opium tincture was better than methadone at reducing opioid use outside treatment with no major adverse events. This thesis adds to the existing evidence for substitution treatment with opium tincture, a culturally acceptable and widely available medication in certain regions of the world, which can diversify the treatments for opioid dependence.      vi Preface Professor Krausz introduced me to the idea of evaluating the use of opium for opioid substitution treatment in Iran given the fact that it is an established treatment in parts of Asia. After some field research, I moved to Canada and conducted the systematic review in parallel, also designing the opium trial (with support from Dr. Nooshin Nikoo) under the supervision of Professor Krausz. With support from Dr. Akhondzadeh, Dr. Kazemi, and Dr. Javid, I liaised with the clinical trial centres and arranged the implementation of the opium trial in these centres. In the next step, I prepared the training protocols, and also ran in-person training for the clinical trial staff with support from Dr. Moazen-Zadeh. I also ran one round of in-person interim visits of trial centres in Mazandaran and Fars provinces. Dr. Gholami (the medical director of two centres in Mazandaran), Dr. Tavakoli (the medical director of Shiraz Centre), Dr. Givaki (the medical director of Isfahan Centre), and their teams had a key role in conducting the clinical phase of the study and data collection. After collecting the data, I organized the data entry (by Ms. Tutian and her team), as well as their secure transfer and storage with support from Dr. Kazemi. I was responsible for the data analysis and interpretation under the supervision of Professor Krausz. Results of this research have been published in the following: Chapter 2 is a slightly revised version of the manuscript published in the journal Addiction by Wiley:  Nikoo M, Nikoo N, Anbardan SJ, Amiri A, Vogel M, Choi F, et al. Tincture of opium for treating opioid dependence: a systematic review of safety and efficacy. Addiction. 2017;112(3).  I was the first author of this publication and was responsible for conducting the review and the manuscript write-up under the supervision of Professor Krausz. Below is a detailed list concerning contribution of each author to the manuscript:   vii Mohammadali Nikoo: developing the protocol, electronic search, and appraisal and drafting the manuscript Nooshin Nikoo: developing the protocol, appraisal and revising the manuscript Sanam Javid: developing the protocol, selecting the articles and revising the manuscript Afshar Amiri: developing the protocol, selecting the articles and revising the manuscript Marc Vogel: developing the protocol, selecting the articles, appraisal and revising the manuscript Amir Hooshang Bagheri Valoojerdi: developing the protocol, manuscript write-up and revision Kerry Jang: developing the protocol, manuscript write-up and revision Christian Schütz: developing the protocol, manuscript write-up and revision Shahin Akhondzadeh: developing the protocol, manuscript write-up and revision Michael Krausz: developing the protocol, manuscript write-up and revision Chapter 3 describes the characteristics of opium trial participants at baseline and is currently under review for publication. I will be the first author and will be responsible for the conceptualization, data analysis, and manuscript write-up with support from Kiana Kainpoor under the supervision of Professor Krausz. Below is a detailed list concerning contribution of each author to the manuscript: Mohammadali Nikoo: developing the concept, statistical analysis, write up, edit, and review of the manuscript. Kiana Kianpoor: statistical analysis, edit and review of the manuscript. Nooshin Nikoo: developing the concept, edit and review of the manuscript. Sanam Javidanbardan: developing the concept, edit and review of the manuscript. Alireza Kazemi: edit and review of the manuscript. Fiona Choi: developing the concept, edit and review of the manuscript.   viii Marc Vogel: developing the concept, edit and review of the manuscript. Ali Gholami: developing the concept, edit and review of the manuscript.  Saeed Tavakoli: developing the concept, edit and review of the manuscript.  Ehsan Moazen‐Zadeh: developing the concept, edit and review of the manuscript. Reza Givaki: developing the concept, edit and review of the manuscript. Majid Jazani: conducting the the clinical study and and review of the manuscript. Fatemeh Mohammadian: conducting the the clinical study and and review of the manuscript. Nader Markazi Moghaddam: conducting the the clinical study and and review of the manuscript. Christian Schütz: developing the concept, edit and review of the manuscript. Kerry Jang: developing the concept, edit and review of the manuscript. Shahin Akhondzadeh: conducting the the clinical study, concept, edit and review of the manuscript. Michael Krausz: conducting the the clinical study, concept, edit and review of the manuscript. Chapter 4 is the primary analysis of the results from the opium trial and is currently under internal review and consideration for publication. I will be the first author and will be responsible for the conceptualization, data analysis, and manuscript write-up with support from Kiana Kianpoor under the supervision of Professor Krausz. Below is a detailed list concerning contribution of each author to the manuscript: Mohammadali Nikoo: developing the concept, trial design, conduct of clinical the study, statistical analysis, write up, edit, and review of the manuscript. Kiana Kianpoor: statistical analysis, edit and review of the manuscript. Nooshin Nikoo: developing the concept, trial design, edit and review of the manuscript.   ix Sanam Javidanbardan: developing the concept, conduct of the clinical study, edit and review of the manuscript. Alireza Kazemi: edit and review of the manuscript. Fiona Choi: developing the concept, edit and review of the manuscript. Marc Vogel: developing the concept, trial design, edit and review of the manuscript. Ali Gholami: developing the concept, conducting the clinical study, review of the manuscript.  Saeed Tavakoli: developing the concept, conducting the clinical the study, review of the manuscript.  Ehsan Moazen‐Zadeh: concept, edit and review of the manuscript. Reza Givaki: concept, conducting the clinical study, review of the manuscript. Majid Jazani: conducting the clinical study and review of the manuscript. Fatemeh Mohammadian: conducting the clinical study and review of the manuscript. Nader Markazi Moghaddam: conducting the clinical study and review of the manuscript. Christian Schütz: developing the concept, trial design, edit and review of the manuscript. Kerry Jang: developing the concept, edit and review of the manuscript. Shahin Akhondzadeh: developing the concept, trial design, conducting the clinical study, edit and review of the manuscript. Michael Krausz: developing the concept, trial design, conducting the clinical study, edit and review of the manuscript. Appendix B is a slightly revised version of the following manuscript describing the protocol of the opium trial and was published in the International Journal of Methods in Psychiatric Research by Wiley:    x Nikoo M, Moazen‐Zadeh E, Javidanbardan S, Nikoo N, Kazemi A, Choi F, et al. Comparing opium tincture and methadone for medication—assisted treatment of patients with opioid use disorder: protocol for a multicenter parallel group noninferiority double—blind randomized controlled trial. Int J Methods Psychiatric Res. 2019.  I was the first author of this manuscript and was responsible for the protocol write-up. Dr. Moazen-Zadeh drafted the manuscript based on the original protocol in consultation with me and under the supervision of Professor Krausz. Below is a detailed list concerning contribution of each author to the manuscript: Mohammadali Nikoo: developing the concept, trial design, write up, edit, and review of the manuscript. Ehsan Moazen‐Zadeh: write up, edit, and review of the manuscript. Nooshin Nikoo: developing the concept, trial design, edit, and review of the manuscript. Sanam Javidanbardan: developing the concept, edit and review of the manuscript. Alireza Kazemi: edit and review of the manuscript. Fiona Choi: developing the concept, edit and review of the manuscript. Marc Vogel: developing the concept, trial design, edit and review of the manuscript. Ali Gholami: developing the concept, review of the manuscript.  Saeed Tavakoli: developing the concept, review of the manuscript.  Reza Givaki: developing the concept, review of the manuscript. Majid Jazani: conduct, review of the manuscript. Fatemeh Mohammadian: conduct, review of the manuscript Nader Markazi Moghaddam: conduct, review of the manuscript Christian Schütz: developing the concept, trial design, edit and review of the manuscript.   xi Kerry Jang: developing the concept, edit and review of the manuscript. Shahin Akhondzadeh: developing the concept, trial design, conducting the clinical study, edit and review of the manuscript. Michael Krausz: developing the concept, trial design, conducting the clinical study, edit and review of the manuscript. Appendix C is an attempt to provide more context around the conceptualization, conduction, and interpretation of findings from this line of research, which will be published as a book chapter in Global Case Studies. I will be the first author and will be responsible for the chapter write-up under the supervision of Professor Krausz. Below is a detailed list concerning contribution of each author to the manuscript: Mohammadali Nikoo: developing the concept, write up, edit, and review of the manuscript. Kiana Kianpoor: edit and review of the manuscript. Ali Gholami: review of the manuscript.  Shahin Akhondzadeh: review of the manuscript. Michael Krausz: developing the concept, edit and review of the manuscript. The protocol of this study was reviewed and approved by both UBC Clinical Research Ethics Board (H15-00220) and Tehran University of Medical Sciences Institutional Review Board (28099).    xii Table of Contents Abstract ........................................................................................................................................ iii Lay Summary ................................................................................................................................. v Preface ........................................................................................................................................... vi Table of Contents ......................................................................................................................... xii List of Tables ............................................................................................................................... xix List of Figures ............................................................................................................................. xxi List of Abbreviations ................................................................................................................. xxii Glossary ..................................................................................................................................... xxvi Acknowledgements ................................................................................................................ xxviii Dedication ................................................................................................................................... xxx Chapter 1: Introduction ................................................................................................................ 1  Global history of opioid use with a particular focus on Iran/Persia ................................ 1 1.1.1 History of opioid use in Iran/Persia ......................................................................... 8  Prevalence and burden of opioid dependence with a particular focus on Iran .............. 12 1.2.1 Prevalence and burden of opioid dependence in Iran ............................................ 14  Current treatments for opioid dependence ..................................................................... 17 1.3.1 Current treatments for opioid dependence in Iran ................................................. 22  Substitution treatment: history, evidence and current options globally ........................ 27 1.4.1.1 Retention in treatment ....................................................................................... 28 1.4.1.2 Use of opioids and other substances outside of treatment ................................. 29 1.4.1.3 Viral infections and their related high-risk behaviours ..................................... 30 1.4.1.4 Mental health and quality of life ........................................................................ 31   xiii 1.4.1.5 Social outcomes: employment and criminal activity ......................................... 32 1.4.1.6 Mortality ............................................................................................................ 33 1.4.2 Substitution treatment in Iran ................................................................................ 34  Research question .......................................................................................................... 37  An Overview of the following chapters ........................................................................ 37 Chapter 2: Tincture of opium for treating opioid dependence: a systematic review of safety and efficacy. .................................................................................................................................. 40  Introduction ................................................................................................................... 40  Methods ......................................................................................................................... 41 2.2.1 Eligibility criteria, information sources & systematic search ................................ 41 2.2.2 Study selection & data collection process ............................................................. 42 2.2.3 Risk of bias ............................................................................................................ 43 2.2.4 Summary measures & planned methods of analysis ............................................. 43  Results ........................................................................................................................... 44 2.3.1 Study selection ....................................................................................................... 44 2.3.2 Study and intervention characteristics ................................................................... 44 2.3.3 Risk of bias within studies ..................................................................................... 45 2.3.4 Results of individual studies .................................................................................. 45 2.3.5 Reports on detoxification ....................................................................................... 46 2.3.6 Reports on long-term abstinence-based/maintenance treatment ........................... 48  Discussion ...................................................................................................................... 52 2.4.1 Summary of evidence ............................................................................................ 52 2.4.2 Limitations ............................................................................................................. 53   xiv  Conclusions ................................................................................................................... 54  Tables and figures .......................................................................................................... 55 Chapter 3: Patterns of substance use among patients with opioid dependence in Iran. ...... 68  Introduction ................................................................................................................... 68  Methods ......................................................................................................................... 70 3.2.1 Study setting .......................................................................................................... 70 3.2.2 Sample ................................................................................................................... 70 3.2.3 Assessments ........................................................................................................... 71 3.2.4 Statistical analysis .................................................................................................. 72  Results ........................................................................................................................... 73  Discussion ...................................................................................................................... 75 3.4.1 Strengths and limitations ....................................................................................... 78  Conclusion ..................................................................................................................... 80  Tables and figures .......................................................................................................... 81 Chapter 4: The opium trial: a randomized controlled clinical trial comparing tincture of opium with methadone for opioid substitution treatment. ...................................................... 91  Introduction ................................................................................................................... 91 4.1.1 Background ............................................................................................................ 91 4.1.2 Objective and hypotheses ...................................................................................... 91  Methods ......................................................................................................................... 92 4.2.1 Trial Design ........................................................................................................... 92 4.2.2 Changes to trial design .......................................................................................... 92 4.2.3 Participants ............................................................................................................ 93   xv 4.2.4 Study settings ......................................................................................................... 93 4.2.5 Interventions .......................................................................................................... 94 4.2.6 Outcomes ............................................................................................................... 95 4.2.7 Sample size ............................................................................................................ 95 4.2.8 Interim analyses and stopping guidelines .............................................................. 96 4.2.9 Randomisation: sequence generation and type ...................................................... 96 4.2.10 Randomisation: allocation concealment mechanism and implementation ............ 97 4.2.11 Blinding ................................................................................................................. 97 4.2.12 Similarity of interventions ..................................................................................... 97 4.2.13 Statistical methods ................................................................................................. 98 4.2.14 Additional analyses ................................................................................................ 98  Results ......................................................................................................................... 100 4.3.1 Participant flow .................................................................................................... 100 4.3.2 Baseline data ........................................................................................................ 100 4.3.3 Numbers analyzed ............................................................................................... 100 4.3.4 Outcomes and estimation ..................................................................................... 101 4.3.5 Ancillary analyses ................................................................................................ 101 4.3.6 Harm .................................................................................................................... 102  Discussion .................................................................................................................... 104 4.4.1 Interpretation ....................................................................................................... 104 4.4.2 Limitations ........................................................................................................... 109 4.4.3 Generalisability .................................................................................................... 110  Tables and figures ........................................................................................................ 112   xvi Chapter 5: Conclusion ............................................................................................................... 123  Summary of introduction ............................................................................................. 123 5.1.1 The case of Iran ................................................................................................... 125  Summary of chapter 2: systematic review (131) ......................................................... 127  Opium trial ................................................................................................................... 128  Summary of chapter 3: patterns of substance use among patients with opioid dependence in Iran. .................................................................................................................. 129  Summary of chapter 4: comparing opium tincture with methadone for opioid substitution treatment. ............................................................................................................. 130  Significance ................................................................................................................. 131  Limitations ................................................................................................................... 134  Future directions .......................................................................................................... 136  Concluding remarks ..................................................................................................... 137 Bibliography ............................................................................................................................... 140 Appendices ................................................................................................................................. 170 Appendix A. Appraisal of studies included in the systematic review ...................... 170 1. Tabasomi F et al. (138,139) ......................................................................................... 170 2. Seiri L., et al. 2014 (141) ............................................................................................. 175 3. Mehrjerdi ZA (2013) (142) .......................................................................................... 178 4. Tavakoli M., et al. 2012 (136,137) .............................................................................. 181 5. Somogyi AA, et al. 2008 (144) .................................................................................... 183 6. Mokri A, et al. 2007 (140) ........................................................................................... 188 7. Jittiwutikarn J, et al. 2004 (143) .................................................................................. 191   xvii 8. He M, et al. 1996 (145) ................................................................................................ 195 9. Auriacombe M, et al. 1994 (146) ................................................................................ 200 Appendix B. Comparing tincture of opium and methadone for opioid substitution treatment: protocol for a multi-center parallel group non-inferiority double-blind randomized controlled trial .......................................................................................... 205 Introduction ............................................................................................................................. 205 Background .............................................................................................................................. 205 Aims  ..................................................................................................................................... 206 Methods ................................................................................................................................... 206 Hypothesis and objectives ....................................................................................................... 206 Research design ....................................................................................................................... 207 Sampling, eligibility, and recruitment ..................................................................................... 207 Randomization, allocation concealment, and blinding ............................................................ 208 Treatment interventions ........................................................................................................... 209 Outcomes, instruments, and timeline ...................................................................................... 210 Primary outcome ...................................................................................................................... 210 Secondary outcomes ................................................................................................................ 210 Setting and personnel ............................................................................................................... 212 Quality assurance, data collection, monitoring, and confidentiality ....................................... 213 Consent, safety, and adverse events ........................................................................................ 214 Feasibility ................................................................................................................................ 215 Sample size .............................................................................................................................. 216 Statistical analysis .................................................................................................................... 217   xviii Dissemination of results .......................................................................................................... 217 10. Results ......................................................................................................................... 218 11. Discussion .................................................................................................................... 218 12. Tables and figures ........................................................................................................ 220 Appendix C. Substitution treatment with opium tincture in Iran: learnings for harm reduction on a global scale. ......................................................................................... 226 1. Context ......................................................................................................................... 226 City, region and/or country ...................................................................................................... 226 Core mental health issues and subpopulation .......................................................................... 227 2. Description of the intervention/program ..................................................................... 228 Defining the problem/situation leading up to the intervention/program ................................. 228 Implementation and delivery ................................................................................................... 229 3. Concluding the case, presentation and identification of follow-up issues to be examined .................................................................................................................................. 233 4. Tables and figures ........................................................................................................ 235   xix List of Tables Table 2.1 General characteristics of studies on using opium tincture for treating opioid dependence .................................................................................................................................... 56 Table 2.2 Characteristics of interventions used in studies on using opium tincture or the comparator medication for treating opioid dependence ................................................................ 59 Table 2.3 Selected studies retrieved through the electronic search but excluded from qualitative synthesis and the reasons for their exclusion. ................................................................................ 62 Table 2.4 Assessing risk of bias in studies on using opium tincture for treating opioid dependence based on the Effective Public Health Practice Project (EPHPP) Quality Assessment Tool for Quantitative Studies (130) ............................................................................................... 63 Table 2.5 Reported outcomes, measurement tools and effects of interventions among studies on using opium tincture for treating opioid dependence, a systematic search till February 31, 201565 Table 3.1 Characteristics of opium trial participants (N=204) at baseline .................................... 81 Table 3.2 Pattern of substance use and related risky behaviours among participants of the opium trial (N = 204) ................................................................................................................................ 82 Table 3.3 Comparison of sociodemographic characteristics, pattern of substance use, and its related risky behaviours between participants in urban (N=152) and rural centres (N = 52) ....... 85 Table 4.1 Frequency and contents of visits during the 12-week follow-up period in the opium trial. .............................................................................................................................................. 114 Table 4.2 Baseline characteristics of participants in the opium trial in both opium tincture (N=102) and methadone (N=102) arms. ..................................................................................... 115 Table 4.3Substance use outside treatment during the follow-up period of the opium trial at visits 22, 26, and 30. ............................................................................................................................. 118   xx Table 4.4 Self-reported use of opioids in the past 30 days in follow-up visits 22, 26, and 30 in the opium trial. ................................................................................................................................... 119 Table 4.5 Type and frequency of adverse events in the opium tincture and methadone arms of the opium trial. ................................................................................................................................... 122    xxi List of Figures Figure 2.1 PRISMA 2009 Flow Diagram ...................................................................................... 55 Figure 3.1 Patterns of substance use (Lifetime). ........................................................................... 89 Figure 3.2 Risk Profile of Participants. ......................................................................................... 89 Figure 3.3 The conceptual schematic of risk spectrum of patients with opioid dependence in Iran ....................................................................................................................................................... 90 Figure 4.1 Dosing strategy for treatment with opium tincture or methadone in patients with opioid dependence, where one unit of medication is equal to 1 ml of opium tincture or 0.5 ml of methadone. a) day 1, morning b) day 1, afternoon c) day 2-3 d) day 4-84 ................................. 112 Figure 4.2 Consort flow diagram ................................................................................................. 113 Figure 4.3 Relative retention rate of methadone arm compared to opium tincture. .................... 117 Figure 4.4 Comparison of self-reported opioid use in follow up visits 22, 26, and 30 in the opium trial. .............................................................................................................................................. 120 Figure 4.5 Survival analysis illustrating the trend of retention in treatment between methadone and opium tincture arms. ............................................................................................................. 121    xxii List of Abbreviations A.D. – Anno Domini AE – Adverse Event AIDS – Acquired immunodeficiency syndrome ALT – Alanine Transaminase ANCOVA – Analysis of Covariance ASI – Addiction Severity Index AST – Aspartate Transaminase ATS – Amphetamine-Type Stimulants BC – Before Christ BUN – Blood Urea Nitrogen CCMD – Chinese Classification of Mental Disorders CENTRAL – Cochrane Controlled Register of Trials CI – Confidence Interval CRF – Case Report Form CTQ – Childhood Trauma Questionnaire DALY – Disability-Adjusted Life Years  DCHQ – Drug Control Headquarters  DICs – Drop-In Centre Dr – Doctor DSM – Data and Safety Monitoring Board EBM – Evidence-Based Medicine ELISA – Enzyme-Linked Immunosorbent Assay   xxiii EPHPP – Effective Public Health Practice Project FDA – Food and Drug Administration GBD – Global Burden of Disease GDP – Gross Domestic Product HBV – Hepatitis B Virus HCV – Hepatitis C Virus HDL – High-Density Lipoproteins HIV – Human Immunodeficiency Virus HPLC – High Performance Liquid Chromatography IBM – International Business Machines ICMJE – International Committee of Medical Journal Editors INCB – International Narcotics Control Board  IRR – Iran Rials  ITT – Intention-To-Treat  IV – Intravenous LDL – Low-Density Lipoproteins LREST – Lifetime Retrospective Evaluation Score Table  MNSS – Mental disorders, Neurological disorders, Substance use disorders, and Self-harm MOCA – Montreal Cognitive Assessment NGO – Non-Governmental Organization NR – Not-Reported NSP – Needle and Syringe Programmes OOWS – Objective Opioid Withdrawal Scale    xxiv OST – Opioid Substitution Treatment OT – Opium Tincture OTI – Opiate Treatment Index PP – Per-Protocol PWID – People Who Inject Drugs  QALM – Quality-Adjusted Life Month QALY – Quality Adjusted Life Year RAR – Rapid Assessment Response RCT – Randomized Controlled Trials  RR – Relative Rate SALOME – Study to Assess Long-term Opioid Maintenance Effectiveness SASCAP – Substance Abuse Services Cost Analysis Program  SCL-90-R – Symptom Checklist-90-Revised  SD – Standard Deviation SOWS – Subjective Opiate Withdrawal Scale  SPSS – Statistical Package for the Social Sciences SROM – Slow-Release Oral Morphine STIs – Sexually Transmitted Infections THC – Tetrahydrocannabinol TPQ – Treatment Perception Questionnaire TUMS-EC – Tehran University of Medical Sciences Ethics Committee UBC-CREB – Clinical Research Ethics Board of University of British Columbia UDS – Urine Drug Screen   xxv UK – United Kingdom UN – United Nations UNGASS – UN General Assembly Special Session  UNOCD – United Nations Office on Drugs and Crime URICA – University of Rhode Island Change Assessment Scale  US – United States USD – United States Dollar VAS – Visual Analogue Scale WHO – World Health Organization WHOQOL-BREF – World Health Organization Quality of Life-BREF   xxvi Glossary Narcotic drug – In the context of international drug control, “narcotic drug” means any of the substances, natural or synthetic, in Schedules I and II of the Single Convention on Narcotic Drugs, 1961, and that Convention as amended by the 1972 Protocol Amending the Single Convention on Narcotic Drugs, 1961. In medicine, a chemical agent that induces stupor, coma or insensibility to pain (also called narcotic analgesic). The term usually refers to opiates or opioids, which are also named narcotic analgesics. In common parlance and legal usage, it is often used imprecisely to mean illicit drugs, irrespective of their pharmacology (1). Opiate – defined in the World Drug Report 2020 as a subset of opioids comprising the various products derived from the opium poppy plant, including opium, morphine and heroin. (2) Opioid – defined in the World Drug Report 2020 as a generic term that refers both to opiates and their synthetic analogues (mainly prescription or pharmaceutical opioids) and compounds synthesized in the body. (2) Opioid dependence – defined by the International Classification of Diseases (11th Revision), as a disorder of regulation of opioid use arising from repeated or continuous use of opioids. The characteristic feature is a strong internal drive to use opioids, which is manifested by impaired ability to control use, increasing priority given to use over other activities and persistence of use despite harm or negative consequences. These experiences are often accompanied by a subjective sensation of urge or craving to use opioids. Physiological features of dependence may also be present, including tolerance to the effects of opioids, withdrawal symptoms following cessation or reduction in use of opioids, or repeated use of opioids or pharmacologically similar substances to prevent or alleviate withdrawal symptoms (3). As per discretion of professor   xxvii Krausz, this term was also used in this dissertation to denote opioid use disorder as defined in the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (4). Opium tincture (OT) – Opium tincture, also called Laudanum, is a clear, reddish-brown hydroalcoholic preparation of opium with a characteristic odour and bitter taste. Morphine is the active ingredient of OT with the chemical formula of C17H19NO3 and each millilitre of OT contains 10 mg morphine equivalent  (5). Opioid substitution treatment (OST) – based on the definition in the joint position paper by World Health Organization, United Nations Office on Drugs and Crime, and the Joint United Nations Programme on HIV/AIDS in 2004, opioid substitution treatment is defined as the administration under medical supervision of a prescribed opioid, pharmacologically related to the one producing dependence (i.e., opioids), to people with opioid dependence, in order to achieve defined treatment aims. (6). There are alternative terms recommended for this concept including “maintenance treatment”, “opioid replacement therapy”, and “opioid agonist treatment”. As per the discretion of Professor Krausz, OST was chosen as the preferred term for this dissertation.    xxviii Acknowledgements Needless to say, I would not have been able to undertake a project of this size without the tremendous support that I have received from a lot of people over the past seven years; which I will do my best to acknowledge this support in this section.  I would like to start by paying my respects to all of the frontline workers who have lost their lives battling on the frontlines of the COVID-19 pandemic, including Dr. Amiri who was part of this research project before losing his life in this unprecedented situation. I thank the other clinical staff who conducted this research, in particular Dr. Gholami and his team, Ms. Yousefi and Ms. Bagherian, Dr. Tavakoli, and Dr. Givaki, and their team. Furthermore, I would like to thank Ms. Khunraz, Ms. Tutian, Ms. Hornby, and Ms. Shereen Leanne whose contributions were the building blocks of this research.  I would like to offer my enduring gratitude to my supervisor Dr. Krausz whose teachings have been instrumental to my growth far beyond my academic life. I would like to thank my supervisory committee members who provided insight and guidance along the way, particularly Dr. Jang who went out of his way to support me through this journey, mentoring me in both academic and non-academic aspects of life. The support and trust of my supervisor in Iran, Dr. Akhondzadeh, whose warm and welcoming attitude, one of the first sparks of this research, was vital for the progress of this project. I was also privileged to have a welcoming and supportive academic network at UBC that played an immense role in my training and in the conduct of this research. I would especially like to thank Dr. Kazemi who was a key player in setting up the opium trial, Dr. Choi whose welcoming presence in the lab was always an asset, Ms. Kianpoor whose help was instrumental   xxix in the final stages of this research, Dr. Vogel who generously shared his clinical experience and helped me to develop a better understanding of the clinical aspects of my research. I would also like to thank my family, and give special thanks to my parents for their unconditional support and to my older sister Nooshin who went above and beyond to support me and my wife throughout our challenging transition to the new academic and social environment in Canada.  Special thanks to my lovely beautiful wife Sanam, my dependable teammate and companion, who was has been right beside me throughout this journey; on top of her phenomenal emotional support, she also helped with the coordination of the trial when I was away.  Last but not the least, I would like to thank the participants of the trial who generously contributed to this research; their contributions have helped to develop a better understanding of opioid dependence and its care.  I would like to acknowledge Tehran University of Medical Sciences, Iranian National Science Foundation, AJA University of Medical Sciences, and DarouPakhsh Pharmaceutical Company for funding the opium trial. I would also like to acknowledge Canadian Institute of Health Research Frederick Banting and Charles Best Canada Graduate Scholarships (FRN = 157934), UBC Four Year Fellowship Award, Rix Family Leading Edge LEEF Award, Faculty of Medicine Graduate Award, Michael W. Stahl Memorial Graduate Scholarship, and Ibn Battuta Award for supporting me.    xxx Dedication To vulnerable patients suffering with addiction, those who are most in need, poorly understood, and often underserved.  1 Chapter 1: Introduction  Global history of opioid use with a particular focus on Iran/Persia Opioids have been used for thousands of years around the world. The opaque, milky-white sap has been obtained from the seedpods of the poppy plant (Papaver somniferum) since ancient times. This crude opium is composed of sugars, proteins, fats, water, meconic acid, latex, gums, ammonia, sulfuric and lactic acids, and, most importantly, numerous alkaloids including morphine, codeine, papaverine, thebaine, and noscapine (7). Archeological findings dated around 3000BC show that Bronze Age societies in Mesopotamia were familiar with opium; likewise, finding dated around 5000 BC show that Neolithic societies in Europe were familiar with it (8). In the Middle East, at the end of the third millennium BC, Sumerians who inhabited modern day Iraq likely first cultivated poppies and isolated opium (9). They described opium as joy, ‘gil’, and the poppy as plant of joy, ‘hul gil’. As early as the eight century AD, Arab traders were bringing opium to India and China, as well as to all areas of Europe in the tenth and thirteenth centuries.  By the sixteenth century, drug abuse and tolerance in Turkey, Egypt, Germany, and England has also been documented (9).  The earliest and most notable historical conflict related to opioids may be the Opium Wars against China. In the mid-seventeenth century, after tobacco smoking was banned in China, the use of opium as a replacement substance dramatically increased. Subsequently, in 1729, the importation and smoking of opium was made illegal in China. This prohibition riled the colonial British government as opium exports were a huge source of income for the empire. As such, the British, who were later joined by the French, tried to force China to continue permitting the trade and consumption of opium, leading to the Opium Wars (1839-1842 and 1856-1860) (7).    2  Although opioid use has been problematic, there are countless accounts of opium use for medicinal purposes in various cultures (8). In 1680, an English physician named Thomas Sydenham introduced the tincture of opium, also known as Laudanum, which was invented by Paracelsus, to the medical field in Europe (7). By the 17th century, many people in Europe were being treated for a variety of health problems with opium (7). For instance, opium was used to treat soldiers during the American Civil War (1861-1865), and during the 1800s, doctors prescribed “tonics” containing opiates for many conditions (7). By the 1870s, however, physicians also began to express concerns about the addictive effect of opioids, warning that “repeated indulgence” induced “bodily and mental prostration and mental perversion” (10). Nevertheless, the widespread known effects of opium led to a series of efforts to discover similar chemical compounds to opium. Having begun his work in 1803, the German pharmacist Friedrich Wilhelm Sertürner unequivocally reported the isolation of the active ingredient of opium in 1817, which he named after the Greek god of dreams Morpheus–morphine (11). Morphine and opium were widely sold over the counter in liquid, pill, and powder forms throughout the 19th century (12). In 1874, heroin was first synthesized from morphine by the British chemist Charles Adler Wright. Twenty three years later in 1897, Felix Hoffmann, as part of the synthesis of a number of compounds using the acetylation process in Friedrich Bayer & Co, synthesized heroin 2 weeks after he had synthesized acetylsalicylic acid. Initially, heroin was marketed as a cough suppressant with sligh stimulant action on the lungs with inferior analgesic action to morphine, with a popular reputation of being no more addictive than codeine, which was refuted with further clinical use (13). Then followed more inventions of synthetic opioids including oxycodone (developed in Germany) in 1917, meperidine in 1939, methadone in 1946,   3 as well as the first opiate antagonist, nalorphine, in 1942 (9,12). By the early 20th century, there was a concerning rate of opioid marketing and prescription to address many medical issues. Without any regulation, it was used for various ailments ranging from diarrhea to toothache. This unregulated use of opioids led to the widespread abuse of street heroin and to iatrogenic morphine dependence. Route of administration is another key consideration in the history of opioids. Opioids can be taken orally, sublingually or buccally, intranasally, via smoking, rectally, intravenously, transdermally, epidurally and intrathecally, and via subcutaneous injection. Smoking (inhaling) opium and later heroin (chasing the dragon) have been common methods for self-administration of opiates, historically. In this method, drugs bypass the venous system by directly reaching the alveoli of the lungs and subsequent rapid access to systemic circulation via the large alveolar capillary surface area. Hence, this method has the most rapid rate of drug delivery to the brain (14). Intranasal application (snorting) of heroin has a very close pharmacokinetic profile to the inhalation techinque (15). In contrast, oral route is a much less efficient and less unreliable method for the delivery of the opiates to the brain, which depends on a number of factors such as the properties of the oral dosage form, pH of gastric contents, gastric emptying time, intestinal transit time, integrity of intestinal epithelium, and the presence of blood flow. More importantly, first-pass metabolism in the liver has a significant impact on the bioavailability of the opiates. For instance, morphine undergoes extensive metabolism in the liver with a wide range of reported bioavailability between 35%–75% (14). Likewise, heroin has a very poor oral absorption and no heroin or 6-monoacetyl morphine could be detected in plasma after its oral ingestion, perhaps due to its conversion into morphine in the alkaline conditions of the duodenum. Moreover, heroin could be subject to the first pass metabolism by esterase in the   4 liver. Although the plasma concentration of morphine after oral ingestion of heroin is comparable to oral administration of morphine, the so called “flash”, the warm and intensive sensation after taking heroin via intranasal, intravenous, or inhalation, related to rapid absorption and rapid onset of action of heroin, is avoided in its oral administration. However, the euphoric, benumbed state, mostly related to the the effects of morphine and morphine-6-glucoronide is still preserved in this method (15). Invention of hypodermic syringes and hollow needles in the 1850s had a remarkable impact on the administration of opiates. Gradually thereafter, use of morphine became a standard practice for minor surgical procedures, postoperative and chronic pain, and as an adjunct to general anesthetics (9). In the case of heroin, parenteral route offered a very close peak onset of action to intranasal and inhalation route but two to three times higher bioavailability (15). Despite this pharmacological attraction, intravenous route gave rise to a number of harms related to opioids such as contraction of viral infections and higher risk of overdose, which will be discussed in details later. Opioids have undoubtedly demonstrated to be medically useful—especially for analgesia in both cancer and non-cancer pain—making it the World Health Organization’s (WHO) Model List of Essential Medicines. However, the co-existent addictive and pain-alleviating effects of opioids have led to never-ending fluctuations in the over- and de-regulation of opioids, meaning that policies regarding opioids need to achieve a fine balance between preventing diversion, overdose, dependence, and abuse while reaping the medical benefits of opioids (16). Failure to achieve that fine balance, either through poor regulation of opioid prescription or strict prohibition of opioids, can be detrimental. International efforts to control opioids and psychoactive drugs may have stemmed more from politics than from science. Since the 1912 Hague Opium Convention, the main approach to   5 opioids and psychoactive substance control has been achieved through policing, an approach that was further extended by the following three major international drug treaties (17,18): 1. Single Convention on Narcotic Drugs of 1961 amended by 1972 Protocol 2. Convention on Psychotropic Substances of 1971 3. UN Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances of 1988 These conventions have implemented measures for the illicit manufacture and distribution of narcotic drugs and psychotropic substances, becoming some of the most universally ratified instruments for countries around the world in the regulation of narcotics (18). The Single Convention on Narcotic Drugs of 1961 tried to unify older international drug policy agreements by applying similar policies to illicit drugs derived from cannabis, coca, and opium (19). It largely focused on prohibiting the use, manufacture, and distribution of these drugs while reserving a small quantity of narcotics for medical and scientific use (17). The Convention on Psychotropic Substances of 1971 expanded the scope of the existent policies to include synthetic psychoactive drugs such as opioids, amphetamine-type stimulants (ATS) and sedatives and hypnotics (19). The UN Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances of 1988 banned the trade in chemical substances used to manufacture scheduled substances, requiring UN member states to criminalize the possession, use, manufacture, and sale of prohibited drugs while allowing for their legitimate medical and scientific use under the supervision of the International Narcotics Control Board (INCB) (19). Finally, in 1998, the UN General Assembly Special Session (UNGASS) on drugs declared its commitment to a drug-free world in 10 years, endorsing drug-control policies that prohibit all the possession, production, and trafficking of illicit drugs (17).    6 Despite the global efforts to abolish drugs through these conventions, some countries have taken different routes. Some countries have already begun to relax their drug regulations especially those around cannabis but also those relating to heroin-assisted treatments and harm reduction strategies, suggesting that a change in direction from the widespread prohibitive approach to an evidence-based pragmatic drug policy must be sought (17). To give some examples, the Netherlands does not enforce criminal penalties for the use or sale of cannabis; Switzerland trialed a heroin-assisted treatment for opioid dependence in the 1990s and subsequently established supervised injection facilities in the 1990s and 2000s; meanwhile, Germany, Australia, and Bolivia have all legalized the traditional use of the coca leaf (19). The International Narcotics Control Board (INCB), an independent, quasi- judicial expert body that monitors and control over precursors of narcotics or psychotropic substances to prevent diversion and illicit manufacture, has not been able to discourage these governments from adopting such policies (18). Although it has been the main UN body charged with ensuring that all member states comply with the treaties, it has had limited resources to regulate countries. Therefore, its main approach has been only to publicize perceived breaches of noncompliant countries (19).  The effect of policies on health outcomes is difficult to quantify because it is very difficult if not impossible to pursue methodologies such as randomized controlled trials when it comes to evaluating the policies.  However, qualitative and quantitative studies, as well as natural experiments describing the enforcement of drug laws, can provide some clues. For instance, there is no explicit ban on opioid substitution treatment (OST), and, in fact, methadone and buprenorphine are included on the WHO’s Model List of Essential Medicines; however, drug-control laws in many countries can limit access to OST to various extents by enforcing arbitrary restrictions on the number of patients who can access OST, limiting dosages and the   7 duration of treatment, prohibiting take-home doses, confining OST to certain, often impoverished, geographical areas, and restricting access to OST in prison and pretrial detention (17). Needle and Syringe Programmes (NSP) are not banned either but they are undermined by various laws and policies. The “Global State of Harm Reduction”, a report on global analysis of harm reduction, reflects the influence of such restriction on the availability of harm reduction measures in different countries (20). An overview of availability of such harm reduction measures in different countries can be During a crackdown on drug use in Vancouver, BC, named Operation 24/7, there was a significant decline in access to sterile injection equipment as police actions drove people away from the only NSP open at night (21). Another qualitative study showed that routine policing near opioid prevention sites often deterred participants from accessing these sites and their particular NSPs (22).  A growing body of evidence reveals the harm and ineffectiveness of prohibition despite the international effort to control and prohibit illicit substances.  There has also been a steady increase in the global burden of substance use despite the “War on Drugs” strategy that has been in place for almost half a century (19). Over this period of time, illicit drug use has increased despite the UN’s goal of a “drug-free world” (23). It seems that a more realistic goal may not be to eliminate narcotics completely but to reduce the harm associated with illicit drug use. Some authors, however, argue that entirely legalizing illicit opioids would not reduce overdose fatalities and that some form of prohibition may work in reducing the availability of the drug (19,24). They argue that improved availability and access to supervised heroin-assisted treatment alongside the reduction of illegal polydrug use may be more helpful (24). This approach aligns with more robust evidence which has shown that access to heroin-assisted treatment in Switzerland has led to a significant reduction in the mortality rate from opioid overdose (25). In   8 other words, the focus should not simply be on the legalization of opioids but should include a holistic approach that seeks improved access to better health and social services for patients (26).   Currently, opioids are used both illicitly and medically on a global scale. Medical use of opioid analgesics is low in Africa, Asia, Central America, the Caribbean, South America, and east and southeast Europe. The United States of America consumes a significantly high amount of opioids: 68% of the world’s prescribed opioid analgesics between 2011 and 2013 (23). Elsewhere, illicit heroin has been the dominant form except in countries that produce opium (e.g. Afghanistan, Iran, and close neighbours) (23). Tramadol is used in relatively in high amounts  illicitly in South America, the Middle East, and Africa. For example, the Mediterranean School Survey Project on Alcohol and other Drugs (MEDSPAD) in Egypt showed that 2.5 per cent of male and 1.4 per cent of female students aged 15–17 had misused tramadol in the past year (2). Likewise, over-the-counter codeine use is reportedly common in Nigeria, Kenya, Zimbabwe, and Chad. In comparison, high-income countries attribute the priority prescription of opioids to the notable prevalence of iatrogenic dependence especially in Canada and USA. (23). 1.1.1 History of opioid use in Iran/Persia The region now known as Iran was among the first places in the world in which opium was used (8). There are plenty of references to opium use in Persian classic and medieval literature (27). It has been suggested that the habit of opium consumption was first introduced around 640 AD by Arab warriors who used opium to cope with the hardships of their military campaigns (28). Opium cultivated in the region has long been an item of trade, with reports of its exportation to China throughout the 14th century (8). During the Safavid dynasty (1501–1722), the cultivation and consumption of opium in Iran increased dramatically for both recreational   9 and medicinal purposes (8). The latter has been partly attributed to the lack of readily available, adequate healthcare options, which encouraged self-medication with opium and its derivatives (28,29). Traditionally opium was also used by peasants and villagers to bear their heavy seasonal workloads (29). There are also indications that opium has been used by certain religious groups such as “Dervishes” A, in order to reach a mystical state (29). In fact, Islam has significantly influenced the use of opium, as the Koran forbids alcohol, which it labels ritually unclean or “Najes”,  while opium escapes such judgement (8). Traditionally, the most common methods of consumption were smoking or orally consuming molded, raw and processed forms of opium (8).  The eighteenth century was an era of political instability and economic downturn in Iran after the overthrow of the Safavid dynasty by Afghan raiders. During this period, the production of opium looked set to decline, along with many other sectors of the economy; however, there is no consistent evidence of a decrease in opium consumption (8).  Although the crowning of Agha Mohammad Khan and the initiation of the Qajar dynasty (1796-1925) at the end of the 18th  A Britanica Encyclopedia: Dervish, Arabic darwīsh, is any member of a Ṣūfī (Muslim mystic) fraternity, or tariqa. Within the Ṣūfī fraternities, which were first organized in the 12th century, an established leadership and a pre-scribed discipline obliged the dervish postulant to serve his sheikh, or master, and to establish a rapport with him. The postulant was also expected to learn the silsilah, the spiritual line of descent of his fraternity. The main ritual practiced by the dervish is the dhikr, which involves the repeated recitation of a devotional formula in praise of Allah as a means of attaining an ecstatic experience. The rituals of the Ṣūfī brotherhoods stress the der-vishes’ attainment of hypnotic states and ecstatic trances through ritual recitation and through such physical exer-tions as whirling and dancing. Dervishes can be either resident in community or lay members, both of these groups being generally drawn from the lower classes. In the Middle Ages, dervish communities played a vital role in reli-gious, social, and political life in the central Islāmic lands, but their monasteries now are often under government control, and their theological standing is discounted by orthodox theologians. A wandering or mendicant dervish is called a fakir (faqir).     10 century was a period of economic recovery, Iran also became the battleground of two imperialist forces, Russia and Britain. As a result, there was a massive influx of foreign goods from these states to Iran (especially in the second half of the 19th century), while Iran, in turn, expanded its opium cultivation and exportation to offset the negative trade balance (8). The damage to Iran’s silk industry, as a result of Pebrine silkworm disease, and the attendant drop in silk exportation in 1864 was another contributing incentive for the Iranian government to increase its reliance upon opium as a cash crop in the second half of 19th century. Other economic hardships such as the growing burden of certain pensioners on the government, the Shah’s and his courtiers’ extravagant expenses, for which the government took out loans from European governments, and the abuse of land ownership systems were among the other economic struggles faced by the Iranian government during this period. For these reasons, the government started to become increasingly dependent upon its cash crops, including, in particular, opium (8). Between 1850–1880, in parallel with industrialization, Iran’s opium industry underwent a process of “modernization”  which resulted in a 20-fold increase in its opium production and a remarkable improvement in its quality (8). During this period, Iran’s opium industry was also better integrated into the global market (8). From 1880 till World War I, the production of opium in Iran stabilized and reached a plateau under the influence of a concerning increase in opium consumption in the country itself and the growing power of international anti-opium movements (8). Between 1921 and 1941, under Reza Shah, the opium industry was monopolized by the government and, despite growing international pressure, opium production continued at the same rate, with only a few superficial measures being taken to halt it (8). The beginning of the era of Reza Shah’s successor Mohammadreza Shah (1941–1975) was concurrent with the occupation of Iran by the Allied Forces during the early stages of World War II. Mohammadreza Shah   11 showed more determination to comply with the international opium treaties; however, this was initially hindered by ongoing economic pressure and instability due to the strong political opposition force led by Mohammad Mosaddegh who spearheaded the nationalization of Iran’s oil industry. After the coup against Mosadegh’s government in 1953, Iran renegotiated to gain 50% of its oil profits and there was an influx of American funding in particular, as Iran was a strategic US ally in Cold War. This strengthened Iran’s economy such that the government soon deemed the opium industry unnecessary to economic growth, quickly declaring a complete ban on the production, trade, and consumption of opium and its products in 1955 (8). At this time, addiction to opium had been recognized as a serious issue, with an estimated 1.5 million individuals being dependent on opium in a population of around 30 million in the country. Despite the initial reduction in numbers after the prohibition was declared, trafficked opium from neighbouring countries rapidly replaced the supplies (29). Later, Iran was a signatory of the 1961 Convention on Narcotic Drugs and its amendment in 1972, as well as the 1971 Convention on Psychotropic Substances (29). In 1978, after the Revolution, Iran’s new Islamic Republic government pursued an aggressively penal approach towards drug use. The death penalty was widely applied for drug trafficking, and prison terms ranging from 2 months to 15 years were handed out for the possession of drugs for personal use, alongside corporal punishment for some. People who were dependent were given 6 months to end their addictions, with or without treatment, before they were considered criminals (29). Additionally, opium cultivation was banned and completely eliminated across the country (29). This approach dominated untill 1994 when stakeholders began to appreciate the values of harm reduction measures after an alarming increase in HIV (Human Immunodeficiency Virus) infection among people who injected drugs (30).   12  Prevalence and burden of opioid dependence with a particular focus on Iran The United Nations Office on Drugs and Crimes (UNOCD), in 2018, estimated that 269 million people used drugs (excluding nicotine and alcohol) at least once in the past year corresponding to 5.4% (3.3–7.5) of the global population aged 15–64 (1 in every 19 people); the estimates for opioid and opiate use were 1.16% (57.8 million people) and 0.61% (30.4 million people) respectively (31). Among the 269 million  people who used drugs at least once in the past year, 35.6 million people (19.0–52.2) were estimated to suffer from drug use disorder corresponding to a prevalence of 0.7% (0.4–1.0) among the global population aged 15–64 (2). In comparison, the Global Burden of Disease (GBD) study, using a different methodology, estimated the age-adjusted prevalence of opioid dependence at 510 per 100,000 population (40.5 million cases) in 2017 (23). While opioids stand far behind cannabis in terms of their prevalence across the globe, they are of significant concern due to their egregious health consequences (2). For instance, in 2017, they accounted for 80% of the total lost disability–adjusted life years (DALYs) and 66% of the estimated 167,000 deaths attributed to drug use disorder (2). The prevalence of using opiates (opium and heroin) in the past year was significantly higher in the Near and Middle East and in South-West Asia and South Asia, regions which account for almost 60% of the estimated number of opiate users worldwide (2). Opioids are at the centre of several  drug-related crises across the world. Across West, Central, and North Africa, non-prescription use of tramadol is alarmingly high, with concerning numbers reported among students aged 15–17. In addition, there is an ongoing opioid overdose crisis, allegedly due to the adulteration of street substances with the potent opioid fentanyl across North America, particularly in the United States and Canada (2).    13 Well-known harms related to opioids include, among many others, the risks of overdose and of contracting viral infections such as HIV or Hepatitis C (HCV) and B (HBV), eventually leading to premature mortality. The injection of opioids, especially when accompanied by the sharing of contaminated needles, plays a significant role in creating these harms (2). The prevalence of injection varies among patients who use opioids by region (23). An estimated 11.3 million (8.9–15.3) people inject drugs corresponding to 0.23% of the global population aged 15–64. Injection accounts for 10% of HIV infections worldwide, and people who inject drugs (PWID) are 22 times more likely to be living with HIV, yielding a 12.6% prevalence of HIV among this population (2). Moreover, the prevalence of HCV and HBV infections among this population are 48.5% (5.5 million) and 8.3% (940,000), respectively (2). Fatal opioid overdose, among aforementioned harms, deserves particular attention because it has taken an unprecedented number of lives between 2015 and 2020, particularly in North America (23).  In the USA, around 450,000 people died from overdoses between 1999 and 2018. The most recent surge from 2013 onwards is associated with the combination of fentanyl and illicit drugs. In 2018, 67,367 drug overdose deaths occurred in the USA, corresponding to an age-adjusted death rate of 20.7 per 100,000, with opioids being the main driver of this crisis (nearly 47,000 of deaths in 2018) (32). Likewise, 15,393 apparent opioid-related deaths were recorded in Canada between January 2016 and December 2019, 3,823 of which occurred in 2019 alone, corresponding to a crude death rate of 10.2 per 100,000 population (33). British Columbia has been the epicentre of this crisis in Canada, with a crude death rate of 19.6 per 100,000 in 2019 (33).  Despite an observed trend of decline in the rate of opioid overdoses in 2019 and early 2020, it is worth noting that there have been signs of another surge in opioid overdoses during the COVID-19 pandemic (34,35).   14 Given all of the harms related to opioid dependence including, but not limited to, the above-mentioned ones, opioid dependence causes significant morbidity and mortality globally. Using a meta-analytic approach, the pooled all-cause mortality of people who used opioids for non-medical purposes was estimated at 1.7 per 100 person-years, 95% confidence interval (CI) [1.5, 1.9] almost corresponding to a ten-fold increase in the risk compared to the expected mortality for people of the same age (23). According to a GBD study, opioid dependence accounted for 0.86% of the total lost DALYs in 2017, the equivalent of almost 21.5 million DALYs out of a total of 27.2 million lost DALYs due to drug use disorder overall in 2017 (36). 1.2.1 Prevalence and burden of opioid dependence in Iran  The UNODC’s most robust estimates for the annual prevalence of opioid and opiate use B in Iran are 3.0% and 1.8% (2011), the latter being the highest reported prevalence of opiate use globally (2). Iran also has the highest rate of opioid seizures in the world (644 tons of opium, 21 tons of morphine, and 25 tons of heroin) (2). The first official statistics on substance use in Iran were published by the Opium and Alcohol Enforcement Society in 1943, which estimated the number of people who were dependent on opium at 1.5 million out of a population of 14 million, corresponding to a prevalence of 10.7%. This was followed by a second study in 1949 which estimated the prevalence at 11% (1.3 million) (27). Since then, a number of Rapid Assessment Response (RAR) studies, carried out between 1998 and 2007, have tried to estimate the  B Opiate here is defined as a subset of opioids comprising the various products derived from the opium poppy plant, including opium, morphine and heroin and opioid is defined as a generic term that refers both to opiates and their synthetic analogues (mainly prescription or pharmaceutical opioids) and compounds synthesized in the body. (2)    15 prevalence and characterize the populations who used drugs in Iran. All these RARs used snowball sampling, a methodological approach with its attendant shortcomings. The Iranian Welfare Organization, in collaboration with the UNODC, conducted the first RAR between 1998 and 1999 with 1,472 substance-using participants who were either homeless or recruited from treatment centres and prisons. Using indirect estimation, this study estimated the total number of patients with drug dependence (as per DSM IV criteria) at 1,200,000 to 2,000,000. In this study, the most common drugs of choice among participants (based on the month before the study began) were opium (73.3%), heroin (39.4%), and opium residues (21.9%); over 16% had injected drugs in the last month. Almost all of the participants reported lifelong opioid use (opium 94%, opium residues 50.1%, and heroin 43.5%) and 21.9% of the participants reported lifelong injection use (37). A second RAR by the same collaborators studied participants aged above 15 who were referred to emergency wards using urine samples and estimated the total number of people who used drugs at 3,761,000 among whom 2.5 million had problematic drug use (38). The third RAR in 2004, based on a sample of individuals who reported having been arrested (38.6%), imprisoned (29.5%) or enrolled in treatment (11.7%) at some point during the year before the study, estimated the total number of patients with drug dependence at 1,200,000 to 1,800,000, with opioids again being the most common substance of choice (39). The fourth RAR in 2007 was based on a sample of 7,769 participants (1264 from care centers, 580 from prisons, and 5943 homeless individuals) and the study estimated that 2,000,000 people used drugs and 1, 200,000 people were dependent on drugs in 2007 (40). In 2011, the Iranian household Mental Health Survey of 9,150 people aged 15-64 with available data for drug use among 85.7% of the sample, showed a prevalence of 3.02% for opioid use and a prevalence of 1.84% for opioid use disorder in the previous 12 months in Iran (41). This was compared to a 12-  16 month prevalence of 3.49% and 2.09% for any illicit drug use and use disorder respectively (41). Most recently, a 2015 cross-sectional household survey of 61,000 individuals aged 15-64 in urban areas and 623 participants aged 15-64 in rural areas found a prevalence of 8.5% and 4.3% for any past drug use and for recent (within a week) drug use respectively. Among the 4.3% of participants who reported using drugs in the past week, 3.2% reported using opioids, with opium being the most common opioid of choice (66.9% of all individuals who used drugs). Furthermore, 4.7% of those who used drugs reported lifelong injection use and, alarmingly, 63% of these individuals reported using non-sterile needles (42). Based on the results of these studies, the population of patients with opioid dependence in Iran can be characterized as predominantly male, married, and employed individuals whose most common opioid of choice is opium, taken orally or via inhalation with a 12-month prevalence of 5% for injection drug use (37–42).  Opioid use and dependence are a significant burden on the Iranian healthcare system. In a 2017 GBD study, opioid dependence contributed to a total number of 791,339 lost DALYs corresponding to 3.88% of total lost DALYs in Iran (20,376,961), which accounted of the majority of (93%) the total number of 849,715 lost DALYs due to drug use disorder overall (36). In comparison with neighbour countries, opioid use disorder accounted for 0.47%, 1.56%, 2.17%, 2.52% of total DALYs in Pakistan, Afghanistan, Iraq, and Turkey, respectively. It is estimated that there are a total of 260,000 people who inject drugs in Iran and that the prevalence of HIV is 13% among this population (43). This prevalence is indicative of a rising trend from 8.7% in studies prior to 2005 compared with 18.4% in studies after 2005 (43). Recent systematic reviews determined the prevalence of HCV and HBV among people who injected drugs in Iran to be 47% (44) and 4.9% respectively (45). It is worth noting here that one of the less commonly reported harms related to opium use in Iran is lead poisoning; there has been an increasing   17 number of reports describing outbreaks of lead poisoning among patients who use opium in Iran. This has been due to the adulteration of illicit opium to increase its weight and thus maximize the margin of profit for the drug manufacturers and distributers (46–48). In some cases, this has led to egregious consequences like unnecessary laparotomy (49).   Current treatments for opioid dependence  Proper understanding of and treatment planning for opioid dependence warrants atten-tion to patients’ complex and wide-ranging needs, including the concurrent use of other sub-stances, mental illnesses, physical illness, as well as patients’ social, residential, vocational, fi-nancial, and legal problems (50). Furthermore, the philosophy and the rationale behind design of a treatment system for opioid dependence is crucial to understanding the merits of various single interventions. An ideal treatment system for opioid dependence would be driven by patients’ goals such as abstinence, harm reduction, and controlled use, subject to change for an individual in different stages of the life. Such a system would provide a continuum of evidence-based phar-macological and psychosocial interventions, easily accessible to the patient to optimize the qual-ity and engagement with the treatment. Needless to say, such a system can only be in place with the help of all the relevant experts including but not limited to psychiatrists, addiction medicine experts, pain specialists, primary care providers, psychologists and counsellors, nurses, social workers, and occupational therapists, who work collegially in a multidisciplinary fashion posi-tioning the patient as the leader of the team (26,51).  There is a wide range of individual interventions for the treatment of opioid depend-ence, whose merits and risks are summarized in the following paragraphs and exhaustively dis-  18 cussed in recent reviews and practice guidelines (50,52–55); however, their role can only be un-derstood properly when considered as part of a continuum of care. This continuum addresses the aforementioned patients’ complex and wide-ranging needs, provided that patients are appropri-ately educated about the risks and benefits of each intervention, so that they can choose wisely among the treatment options, working their ways towards their goals. This notion is different from other approaches, which do not appreciate the complexity of treatment for opioid depend-ence such as a “paternalistic approach”, which takes away the opportunity of informed decision-making from patients and or a “golden bullet” approach in which, some interventions are con-sidered as a holy-grails and the other ones as completely futile. It is noteworthy that there is a huge treatment gap for drug users across the globe. For example, only one out of every eight people with drug use disorder has access to treatment globally (2). This proportion declines to a much lower number of 7.1% when looking at access to “minimally effective” treatment which is subject to further inequality across various jurisdictions, with only 1% access to minimally effec-tive treatment in low- and lower-income countries (56). The first intervention to be discussed here is withdrawal management, also known as detoxification. This type of treatment is the administration of medication to reduce the severity of withdrawal symptoms that occur when a patient with opioid dependence stops using opioids (57). Standalone withdrawal management has been associated with poor outcomes in the long run and also carries an increased immediate risk of overdose and mortality. As a result, standalone withdrawal management has been encouraged to be supplemented with additional long-term treatments (52,58). This intervention has its own merits for instance in the case of a patient’s preference, and also an inevitable part of the continuum of care in reality.    19 Naltrexone, which is a µ opioid receptor antagonist, is one of the medications used for long-term treatment of opioid dependence, in particular for patients who desire abstinence. Alt-hough the oral formulation has been no more effective than placebo in the long-term treatment of opioid dependence (59), extended-release forms have shown some promise. To elaborate, a 24-week follow-up multicentre clinical trial recruiting 570 patients in the US showed that extended-release naltrexone was not as effective as buprenorphine at retaining participants in treatment; however, it was found that patients who were inducted onto treatment had comparable outcomes to buprenorphine (60). Another clinical trial from Norway with a sample size of 159 and follow-up period of 12 weeks showed non-inferiority of extended-release naltrexone to oral buprenor-phine-naloxone with regards to retention in treatment and substance use outside treatment (61). However, there are two cohort studies which have failed to show any benefit for extended-re-lease naltrexone in preventing overdose (55, 56) and, in fact, there is evidence indicating an in-creased risk of overdose after discontinuation of naltrexone. Nevertheless, an appraisal of the ev-idence by the Canadian Agency for Drugs and Technologies in Health in 2017 concluded that extended-release naltrexone was favourable to usual treatment or buprenorphine in terms of re-tention in treatment and abstinence with comparable safety profiles (64). Psychological or behavioural interventions are one of the main treatments commonly offered as an adjunct to pharmacological interventions along the continuum of care for opioid de-pendence. Beyond their merits as a standalone intervention, they can also have synergistic effects with other interventions to improve retention in treatment, to improve quality of care and pa-tients’ satisfaction, to address concurrent disorders, and to assist with the behavioural manage-ment in relapse prevention. The self-medication hypothesis put forward by Drs. Khantzian and   20 Albanese provides a persuasive explanation for the close connection between addiction and psy-chological suffering and distress (65). Their role cannot be overemphasized, especially when one notices the high lifetime rate of psychiatric comorbidity among people with opioid dependence or drug use disorder in general (66,67).  Evidence supports the role of psychological interventions in the management of opioid dependence for OST, despite some controversial results. For instance, a Cochrane review indi-cated that psychosocial treatments combined with withdrawal management medications were ef-fective in improving treatment attendance, treatment completion, reducing opioid use, and long-term abstinence (68). Another Cochrane review did not demonstrate an additional benefit for specialized psychosocial interventions offered with OST (69); however, isolating the contribu-tion of psychological interventions and comparing it with a (presumably) placebo or no-treat-ment group in the setting of OST is extremely hard, if not impossible. This difference is due to the inevitably close therapeutic relationship, which is built between the patient and treatment team over the long-term course of OST requiring regular visits. Furthermore, this finding was not in line with an earlier review in 2007, which had found sufficient evidence to support the use of contingency management and cognitive behavioural therapy as an adjunct to substitution treat-ment (70). Moreover, another systematic review, conducted later in 2016, further supported the efficacy of psychosocial interventions in combination with medications for substitution treatment (71). There is a long and growing list of psychological interventions for opioid dependence cate-gorized under various taxonomies. Established interventions with a greater focus on individuals include, but are not limited to, both brief and more comprehensive interventions such as motiva-tional interviewing, standard cognitive behavioural therapy and relapse prevention, contingency management, and case management. Peer support programs including Narcotics Anonymous,   21 group therapy, and family therapy are other forms of psychological interventions for opioid de-pendence, which take place in a group setting. Trauma-informed care, which addresses the psy-chological pain rooted in early childhood traumatic experiences, is also increasingly recognized as an integral part of the continuum of psychological interventions for opioid use disorder (72), given the pervasiveness of such experiences among patients with opioid dependence (73,74). There are other types of interventions that diversify the treatment options along the con-tinuum of care for patients with opioid dependence. Psychological interventions are often con-ceptualized under the umbrella of psychosocial interventions, including interventions that target dysfunctional social relationships, unemployment, residential instability, and legal problems (69). Viewing the treatment in a broader sense, there are other key interventions for opioid de-pendence, which seek to minimize the burden of opioid dependence-related harms (tertiary pre-vention): 1) safe consumption facilities; 2) interventions aimed at the prevention and treatment of HBV, HCV, and HIV such as counselling, ancillary testing, and needle and syringe exchange programs offering sterile needles to people who inject drugs; 3) the prevention of sexually-trans-mitted infections through counselling and condom distribution; 4) the distribution of naloxone kits combined with the education of the patient and their social network to prevent fatal over-doses; 5) opioid prescription monitoring programs, guidelines, and abuse-deterrent opioid formu-lations; 6) suicide prevention strategies are among the most important treatments which can min-imize the harms related to opioid dependence globally (52). Other cited interventions for opioid dependence include faith-based interventions and alternative medicine such as acupuncture. The setting for treatment provision is a crucial factor for programs serving patients with opioid dependence. In addition to the office-based and inpatient forms of treatment, outreach programs serve a key function by connecting hard-to-reach populations of patients with opioid   22 dependence, particularly those with more severe forms of the disorder, to treatment. Residential abstinence-based treatments with various durations are another popular treatment method for pa-tients with opioid dependence across the globe. Some argue that this form may be beneficial be-cause patients are temporarily separated from dysfunctional environments which make relapses more likely. Although not only associated with this form of the treatment, the compulsory quar-antining of patients with opioid dependence in residential settings has given rise to considerable human rights controversy and backlash globally. A setting of particular interest in this regard is prisons as they often house a significant number of patients with opioid dependence, many of whom have been incarcerated for minor drug-related crimes. In addition, prisons can be associ-ated with a heightened risk of harms such as viral and sexually transmitted infections if adequate harm reduction measures are not in place. In fact, the provision of harm reduction interventions in prisons has been considered as an indicator of a government’s overall attitude and success with regards to treating substance use disorder. On the subject of treatment setting, technology has also started to offer new venues for the delivery of psychological interventions by standardiz-ing these interventions, making them accessible, and also decreasing the cost of their provision (75). A recent systematic review demonstrated a small but significant effect of internet interven-tions on illicit drug use (76). 1.3.1 Current treatments for opioid dependence in Iran  According to the 2011 Iranian Mental Health Survey, only 69% of patients with opioid dependence (based on the previous 12 months) reported a perceived need to use healthcare services. Among all of the patients with opioid dependence, 59% and 29% reported any ‘service use’ and any ‘healthcare service use’ respectively during the 12-month period. The former   23 consisted of self-help groups (35%, the most common type of utilized service); residential drug services, also known as “camps”, ; pharmaceutical services giving out medication without prescriptions (which is essentially illegal); and alternative medicine. The latter included outpatient treatment services (predominantly privately funded), prescription-renewal pharmaceutical services, hospital admission, and drop-in centres (DICs) (41). The outpatient OST centres were the most common form of treatment setting in the healthcare section (41).  The treatment of drug use in Iran after the 1979 Revolution only began in 1994 following a legislative change exempting patients with substance use disorder in treatment centres from prosecution. The first form of treatment introduced for opioid dependence in Iran was short-term detoxification using clonidine with adjunct psychological interventions during and after the 14-day pharmacological treatment, an approach that resulted in poor and undesirable outcomes in the initial studies, with 6-month dropout rates reaching 95% (77). This form of treatment is still offered in Iran, as evidenced by the recent published studies from Iran evaluating the outcomes of withdrawal management with various medication(s) (78,79). Another form of detoxification piloted and offered in Iran was ultra-rapid detoxification using heavy sedation with midazolam and the gradual IV administration of naloxone over a period of 6 hours (77). This method did not prove any better than more conventional methods of detoxification in terms of longterm retention in treatment. As a result (and also due to the mismanagement of the method in some centres), it has been limited to educational and research centres since 2007 by the Ministry of Health (80);  a 2016 study of patients who injected drugs in Tehran showed that a small proportion of patients (0.7%) had undergone this type of treatment in their lifetime, as opposed to other forms of detoxification such as compulsory detoxification in a residential setting (53%) (81).    24  Oral naltrexone was introduced in Iran in 1999 to combat the undesirable treatment outcomes associated with detoxification. Although better than detoxification, the outcomes were far from desirable, with more than a 50% 6-month dropout rate. This was followed by another multicentre trial in 2003, the preliminary results of which showed an abstinence rate of 30-45% at 6-month follow-ups (77). A more recent 2017 clinical trial in Iran concluded that sublingual buprenorphine/naloxone was superior to oral naltrexone in terms of opioid-negative urine tests and treatment retention, but significantly worse with regards to initial abstinence duration and proportions with sustained abstinence (82).  Psychological interventions such as individual counselling, supportive psychotherapy, structured relapse prevention group therapy, cognitive behavioral therapy, and motivational interviewing have always been a mandatory part of the treatments offered to patients with opioid dependence in Iran (77). This was evident in the first Iranian National Protocol for the treatment of opioid dependence, which requires the presence of a clinical psychologist in methadone maintenance treatment programs (30). In addition, Narcotics Anonymous was initiated in Iran in 1994 and is currently one of the most common behavioural intervention programs, with 5,500 groups, available to both men and women, currently meeting on a weekly basis in major cities and in rural areas (83). Moreover, the Matrix model was introduced in 2008 and has found its own place in the treatment of concurrent opioid and stimulant use disorder in Iran, particularly given the increasing prevalence of this condition in OST (up to 70% in some reports) (84).  Public health interventions with a harm reduction focus have also been an effective part of the evolution of opioid dependence treatment in Iran. Needle and syringe exchange programs were first implemented in Iran as part of the outreach programs in drop-in centres. These centres were opened in 2003 in order to access hard-to-reach at-risk populations, particularly patients   25 who injected drugs. Initially, they offered a range of provisions and services including clean needles and syringes, boilers, cotton pads, condoms, educational pamphlets about HIV and drug use, shelter, food, and clean clothes. Later, they were modified and granted permission to offer OST as part of their services, which gradually become one of their major roles (i.e., offering OSTs to high-risk populations) due to its positive reception by staff and patients (27).  In 2014, 580 centres in Iran distributed clean needles to about 10 million people over a one-year period, corresponding to between 44 and 60 needles per individual who injected drugs (85).  A range of interventions were provided in prisons by the Iranian government to address the twin epidemic of substance use and HIV in Iran. These interventions included educational interventions, needle exchange programs, condom distribution, and bleach distribution, in addition to low-threshold methadone OST (27). Triangular clinics, which were introduced in 2000, provided another innovative treatment program to address three issues simultaneously (hence the name triangular): injection drug use, sexually transmitted infections, and HIV/AIDS (Acquired Immunodeficiency Syndrome). These clinics often housed physicians, psychologists, nurses, and social workers who offered patients and family members education, counselling, and testing for HIV and sexually transmitted infections (STIs); condom and sterile syringe distribution; and diagnosis and treatment of STIs. Antiretroviral treatment and later, methadone maintenance treatment were also offered in some but not all triangular clinics (27). Another innovative treatment program included Women Only Drug Treatment and Harm Reduction Services, first initiated in Iran in 2001, which strived to serve the needs of a vulnerable subpopulation of patients with opioid dependence: female patients who were less likely to seek treatment for their substance use compared to their male counterparts (86–88).    26  Non-governmental organizations (NGOs) have also played a major role in serving patients with opioid dependence in Iran. One such organization is Rebirth Society, which was founded by people with lived experiences of opioid dependence in Iran and is one of the current largest NGOs in the country with more than 110 centres across 26 provinces; its initial focus is on residential treatment followed by a gradual incorporation of a therapeutic community concept (84). Another NGO worth mentioning in this section, and of particular interest to this research, is Congress 60. This organization was founded in 1998 by Mr. Dezhakam, a person with lived experience of opioid dependence, and has since expanded to encompass around 40 branches serving 20,000 patients with opioid dependence as of 2016. The pharmacological treatment offered by this NGO is exclusively OT with a gradual tapering plan made up of 14 steps over an 11-month period toward the goal of abstinence. The pharmacological treatment and associated psychosocial interventions are described in detail elsewhere (89).  Another controversial aspect of treatment programs in Iran is the temporary compulsory treatment in so-called camps (governmental, private, and illegal) for patients who are arrested or reluctant to seek treatment and referred by family members. The capacity of these camps significantly expanded after a 2010 law reform, and it has been argued that this form of treatment was introduced for multiple reasons such as offloading the burden of drug-related crimes from prisons and addressing the increasing prevalence of amphetamine-type stimulants without available treatments as effective as methadone. Regardless of the rationale behind their implementation, these camps have also been criticized for their substandard conditions and vicious treatment of patients (90).   27  Substitution treatment: history, evidence and current options globally  The joint position paper by the WHO, the United Nations Office on Drugs and Crime, and the Joint United Nations Programme on HIV/AIDS in 2004 defined “substitution therapy (“agonist pharmacotherapy”, “agonist replacement therapy”, “agonist-assisted therapy”) … as the administration under medical supervision of a prescribed psychoactive substance, pharmacologically related to the one producing dependence, to people with substance dependence, for achieving defined treatment aims. Substitution therapy is widely used in the management of nicotine (“nicotine replacement therapy”) and opioid dependence” (6).  Methadone was first developed in Germany between 1937 and 1938 and its patent was filed in 1941 (91). The idea of methadone maintenance treatment was first introduced by Ingeborg Paulus and Robert Halliday in Vancouver, BC, Canada as part of a program called “prolonged methadone withdrawal treatment” in 1959 (92). In the early 1960s in the USA, Drs. Marie Nyswander and Vincent Dole coined the term ‘methadone maintenance treatment’ for using this medication to treat individuals with opioid dependence who were not stabilized on morphine and required increasing doses of morphine (91). A seminal clinical trial between 1971 and 1976, which recommended a “greater change” toward methadone over heroin for patients with opioid dependence, had a role in the increased prescription of methadone for opioid dependence (91). Later, the prescription of methadone for opioid dependence expanded owing to two major public health challenges: the dramatic increase in the number of people who used heroin in Europe in 1980s and the HIV epidemic in 1980s and 1990s (91).  Currently, OST has expanded beyond the use of methadone racemate alone and includes a range of medications such as Polamidone (the active isomer of the racemate), buprenorphine and its combination with naloxone, slow-release oral morphine, opium tincture, and injectable   28 forms, heroin, hydromorphone, and codeine. A mounting body of evidence indicates that OST improves a multitude of treatment outcomes among patients with opioid dependence; as well as alleviating craving and withdrawals, research demonstrates its effectiveness with regards to retention in treatment, use of substances outside treatment, high-risk use (injection and needle-sharing), psychological health, physical health (particularly incidence of HIV and HCV infection), quality of life, overdose, suicide, and all-cause mortality (23). The following paragraphs will provide a concise reference to this body of evidence. This explains why methadone and buprenorphine are listed as essential medications by the WHO (93).  1.4.1.1 Retention in treatment  Retention in treatment is a key indicator and one of the most commonly measured outcomes for the treatment of opioid dependence. By definition, this outcome is a prerequisite if patients are to gain any benefit from the treatment and improve in other areas. A 2009 Cochrane systematic review showed a significant advantage for methadone over no pharmacotherapy, with a relative retention rate of 4.44 [3.26-6.04] (94). Likewise, a Cochrane systematic review found relative retention rates of 1.50, 95% CI [1.19, 1.88], 1.74, 95% CI [1.06, 2.87], 1.82, 95% CI  [1.15, 2.90] for low-dose, medium-dose, and high-dose buprenorphine compared to no pharmacotherapy (95). A systematic review of studies on OST in low- and middle-income countries indicated an overall 12-month retention rate of 54.3%, 95% CI  [46.2%, 63.7%] for buprenorphine and methadone; the corresponding rate for buprenorphine and methadone was 48.3%, 95% CI [22.1, 74.6%] and 56.6%, 95% CI [45.9%, 67.3%] respectively (96). A recent systematic review of clinical trials on slow-release oral morphine concluded that the rate of retention in treatment with this medication is no different from methadone (RR=0.98, 95% CI   29 [0.94 to 1.02]) (97). A systematic review by Strang et al., concluded a superior retention rate for injectable heroin over oral methadone (Relative Rate (RR) = 1.37, 95% CI [1.03–1.83]); however, it is important to bear in mind that the inclusion criteria for heroin-assisted trials are different from conventional trials, usually including people who have had poor outcomes with previous trials of oral treatment (98). The retention rate for hydromorphone, another injectable treatment, was also non-inferior to heroin in a SALOME (Study to Assess Long-term Opioid Maintenance Effectiveness) trial (99). Another systematic review, specifically looking into factors affecting retention in OST, showed an overall retention of 57% for OST after 12 months, which was inversely associated with younger age, substance use outside treatment (particularly cocaine and heroin use), a lower dose of methadone, criminal activity and/or incarceration, and negative attitudes towards treatment (100). In conclusion, despite the existing variance, all forms of OST seem to significantly outperform control conditions without pharmacological interventions when it comes to retaining patients in treatment. 1.4.1.2 Use of opioids and other substances outside of treatment   This outcome is another commonly measured indicator of the effectiveness of opioid use treatment. In the Cochrane systematic review comparing methadone with no treatment, methadone significantly decreased self-reported heroin use overall but the data from various studies were not pooled due to a significant heterogeneity. In addition, the pooled data from urine or hair analysis of morphine use showed a reduced morphine use with a relative retention rate of 0.66, 95% CI [0.56, 0.78] (94) (94). For buprenorphine, the Cochrane systematic review only showed a significant decrease in the mean number of positive urines for morphine with high doses of buprenorphine (16 mg or more) as compared to the placebo; this review did not show   30 any advantage of buprenorphine over the placebo in terms of reducing cocaine use (measured by urine tests) and only some advantage of medium dose buprenorphine (7mg–15mg) over the placebo in terms of reducing benzodiazepine use (95). In the systematic review of SROM, it was no different to methadone when it came to reducing opioid use outside the treatment with a RR of 0.96, 95% CI [0.61–1.52] (97). Among heroin trials, although the data regarding opiate use reduction was not pooled due to the heterogeneity, each individual study did show there was a positive effect of injectable heroin on heroin use outside of treatment (98). A SALOME trial also demonstrated the non-inferiority of hydromorphone to heroin in terms of reducing both self-reported heroin and opioid use, as well as reducing the proportion of heroin-positive urine tests during the follow-up period (99).  1.4.1.3 Viral infections and their related high-risk behaviours The incidence of viral infections (HIV and HCV) and their closely related risk behaviours (injection and syringe or needle sharing) have also been shown to reduce with OST. A Cochrane systematic review in 2011 showed a significant decrease in the number of patients who injected and in the frequency of injection prior to and after the initiation of OST (101). The reduction in the risk of injection among OST patients in follow-up compared to baseline ranged from 20% to 60% (101). OST significantly outperformed no treatment in terms of reducing the frequency of injection and the proportion of follow-up patients who reported injecting, with a reduction in the risk of injection ranging from 13% to 55% (101). Likewise, the reduction in the risk of sharing injection equipment with OST in this study ranged from 25% to 86%, depending on the duration of the follow-up. Additionally, among five studies which compared the effectiveness of OST with no treatment in terms of reducing the risk of sharing injection equipment, three showed a   31 statistically significant reduction in the risk with OST (101).  The same review, including these three studies, concluded that there was a decrease in seroconversion from HIV negative to positive among patients with OST when compared with other forms of treatment (101).  Another systematic review in 2012 pooled the data from nine of its twelve studies and concluded that there was a 54% reduction in the risk of HIV seroconversion among people who injected drugs with OST (102). Another systematic review looked at the effects of OST on HCV transmission and showed that there was a 50% reduction in the risk of HCV acquisition too (103). There are also single studies on injectable opioids which show a reduction in HIV and HCV infection, and the related risk behaviours, with this type of treatment. A two-year follow-up study of participants in a PESPA trial in Spain showed a decline in HIV risk behaviour among patients who had received, or were currently receiving, heroin-assisted treatment (104). A follow-up evaluation of participants in a PROVE study in the UK also found a decrease in the risk of HBV and HCV infection 6 months after the initiation of the treatment, alongside a parallel decline in self-reported needle-sharing behaviours among participants (105).  1.4.1.4 Mental health and quality of life  OST has also been associated with improvements in patients’ overall mental health and quality of life. A recent systematic review explored the effects of OST on various measures of mental health using a number of assessment tools: Symptom Checklist-90 (SCL-90) as well as shorter versions, Beck Depression Inventory (BDI), or Self Rating Depression Scale(106,107); total scores/global severity index from SCL-90, as well as shorter versions, Brief Symptom In-ventory (BSI), or Kessler psychological distress scale (K10) (108–110); composite scores of psy-chiatric status on Addiction Severity Index (ASI) or European ASI (111); and mental health   32 quality of life measured by Short Form Health Survey-36 (SF36) or Lancashire Quality of Life Profile (LQOLP) (112,113). This review showed the superiority of buprenorphine, methadone, and heroin over the placebo when it came to improvements in overall mental health outcomes for patients with opioid dependence (114). Further analysis in this review indicated the superiority of heroin over other medications, as well as an overall positive effect of OSTs on mental health, independent of psychosocial services (114). Likewise, a systematic review (made up of eight studies with a follow-up duration ranging from 6 to 24 months) of OST in low- and middle-income countries demonstrated a significant improvement in all four domains of health-related quality of life among patients with opioid dependence in OST (115). The same review assessed the improvement in relation to the seven domains of the Addiction Severity Index (ASI) and showed improvements in four domains, including legal and family relationships (115). 1.4.1.5 Social outcomes: employment and criminal activity  The effect of OST on functional outcomes such as criminal activity and employment has also been studied. A 2020 systematic review identified three RCTs and two observational studies which had evaluated employment outcomes in substitution or naltrexone treatment and found no difference between participants under control conditions and those who received pharmacotherapy in their employment outcomes (116). It must be noted that the authors acknowledged that a lack of evidence, and weaknesses in the body of evidence, prevented drawing any strong conclusions in their review. Likewise, most studies which explored employment outcomes for injectable opioid agonist treatment did not find any difference between oral and injectable forms of OST (117). A Cochrane systematic review in 2009 was not able to find a statistically significant improvement with regards to criminal activity when   33 comparing methadone to no treatment (94). A 2020 systematic review on functional outcomes found mixed results on the reduction of criminal activity with pharmacotherapy, with some studies showing improvements while others failed to show any difference between pharmacotherapy and control conditions (116). Decreases in criminal activity seem to have been more consistent with injectable opioid agonist treatments compared to oral methadone in the literature (117). However, the lack of consistent evidence supporting improvements in functional outcomes such as employment and criminal activity might be partly due to the complexity of these outcomes in the long term and the multiple interventions required for their improvement. 1.4.1.6 Mortality  Research has used mortality (and its closely related outcomes, overdose and suicide) as an indicator of treatment effectiveness. Although the 2009 Cochrane systematic review (in which only four studies were analyzed for mortality data) was not able to demonstrate a significant effect of methadone on mortality (RR=0.48, 95% CI [0.10, 2.39]) (94); later, a systematic review of cohort studies explored the risk of all-cause mortality and overdose during and after OST with methadone and buprenorphine (118).  This review showed an all-cause mortality per 1000 persons of 11.3 and 36.1 in and out of methadone treatment compared with 4.3 and 9.5 in and out of buprenorphine treatment (118). Similarly, overdose-related mortality per 1000 persons was 2.6 and 12.7 in and out of methadone treatment compared with 1.4 and 4.6 in and out of buprenorphine treatment (118). The first 4 weeks after the initiation of OST, and the first 2 weeks after leaving OST, were associated with the highest risk of all-cause mortality (118). Likewise, another systematic review of observational studies showed a relative rate of 2.56, 95% CI [1.72, 3.80] and 8.10, 95% CI [4.48, 14.66] for all-cause mortality and overdose outside OST,   34 compared with all-cause mortality and overdose rates when receiving the treatment (119). Furthermore, a large Australian study of more than 42,000 patients with a median of 9.2 years of follow-up in OST showed a decrease in death due to suicide and unintentional injury in OST, as well as a decrease in all-cause and overdose-related mortality (120). Similarly, observational studies with long-term follow-ups have demonstrated a decrease in mortality rate with heroin-assisted treatment; however, the results regarding the difference in mortality between oral and injectable forms of agonist treatment have been inconclusive, mostly due to the rarity of this outcome in either form of treatment (117).  1.4.2 Substitution treatment in Iran Traces of OST in Iran predate the 1979 Revolution. In the spring of 1968, the Iranian government embarked on a new program for the control and treatment of drug dependence (29,121,122). The basic objective of this program was to provide regulated opium to opium dependent individuals over the age of 60 who were, on account of their presumed frailty, unable to undergo detoxification and rehabilitation. Younger patients with opioid dependence were also included in the program if they had severe or chronic comorbidities preventing them from maintaining abstinence from the substance upon which they were dependent (122). Consequently, after nearly 14 years of total prohibition, limited poppy cultivation and legal opium distribution were reinstated to address the needs of these registered seniors who were opioid dependent (123).  The government would buy the raw opium, process it, and sell it to regulated agents who would then distribute it amongst the registered coupon holders. As such, by 1975 around 185,000 patients with opioid dependence were registered in the program (123). However, in 1978, the   35 Iranian Revolution and Islamic Republic government put an end to this treatment-based approach to drug use, gradually closing down all voluntary treatment programs for almost 15 years, such that compulsory treatment in correctional settings became the only available treatment option for patients with opioid dependence (124).  Opioid substitution treatment was only reinstated as part of the care for patients with opioid dependence in 2002. This was largely due to the fact that the Iranian government was faced with a growing number of people injecting heroin, among whom there was also a tragic rise in HIV prevalence in the 1990s and 2000s (124); the reinstatement of OST was also due to the failure of previous measures (1997–2002), such as detoxification and oral naltrexone (sometimes accompanied by psychosocial interventions), to control these two epidemics (27,77). As a result, the first substitution program with methadone was piloted in 2002 in Iran (77). Next, OST programs with buprenorphine, first studied in Iran in 2002 (125), were officially launched in 2006 (124). In July 2007, the Iranian Drug Control Headquarters (DCHQ) anticipated the introduction of OT to the national protocol for OST. Subsequently, in April 2008, the DCHQ declared that OT had been proven to be effective for OST based on a pilot phase-2 clinical trial (126). In early 2010, the Ministry of Health officially approved the integration of OT into the national protocol for OST. Finally, in May 2010, OT was officially made available to all opioid treatment centers across the country as part of a national protocol. However, this treatment option was not widely used in these centers by clients until the end of 2011, when the primary protocol revisions by the Ministry of Health facilitated the provision of OT to clients. The revisions included an increased number of take-home doses, especially evening and weekend doses, and an enhanced practice of confidentiality and respect for patients’ privacy, reflected in the reduced number of unnecessary   36 monitoring staff and surveillance cameras employed during the process of determining a patient’s eligibility for the use of OT in the centers (126). To date, OST programs have continued to expand in Iran despite facing challenges (124). As of March 2018, there were about one million patients in OST in more than 7,000 public and private centres (97.3% private centres) as well as in prisons across the country (124). OST centres offered  methadone (78%), buprenorphine (12%), and OT (10%) in the order of frequency (124). The latter pertains to both forms of treatment with OT: OST and the model used in Congress 60 with gradual tapering over an 11-month period (124). This thesis was interested in OT, a clear, reddish-brown hydroalcoholic preparation of opium with a characteristic odour and bitter taste. Although morphine is the main active ingredient of OT (each millilitre of OT contains 10 mg morphine equivalent) (5), cultural acceptability of OT given its close nature to opium and its other ingredients, codeine and thebaine, two other alkaloids under international control can set it apart from morphine in its clinical application.  Several reasons make OT an attractive option for pharmacotherapy of opioid dependence in certain parts of the world such as Middle East and countries close to “Golden Triangle”, where the borders of Thailand, Myanmar, and Laos meet. First reason is the cost of opium in the mentioned areas where retail level prices of opium (measured in United States dollar per gram) are 0.1 in Afghanistan, 1.0 in Iran, 0.3 in Pakistan, 1.8 in Myanmar and 2.1 in Thailand as opposed to retail level prices of 22.0 in Russian Federation, 184.0 in Sweden, 52.6 in Canada and 34.0 in United States of America (127).  Second reason is availability of opium in these areas where from 6,883 tons of opium production in the world in 2013, 5,500 tons were produced in Afghanistan and 893 tons in Myanmar (128). Afghanistan and Iran have also the highest rate of   37 opium seizure in the world (126,128). Third is the cultural acceptability and fewer stigmas towards opium in these regions due to longstanding use of the substance in the region, in many cases as a medicine (129), which can eventually increase the compliance of patients with the treatment. For instance, in a qualitative study among 52 patients receiving OT, reported reason for switching to OT were dependence on methadone, chemical nature of methadone and its long duration of methadone treatment, as opposed to herbal nature of OT, its ability to improve the general health as well as treatment of craving and withdrawal. Provided reasons in fact included some misconceptions or false beliefs about methadone but at the same shows positive attitude of patients towards OT compared to methadone (130). Last but not the least, we still do not have a satisfactory safe and effective treatment for detoxification and maintenance treatment of opioid dependence and OT could have added value as an alternative treatment option in other parts of the world, as well. Having said that, demonstration of adequate level of evidence supporting safety and effectiveness of OT for treating opioid dependence is the absolute prerequisite for its further use for this indication. The objective of this thesis was to address this gap in the literature and analyze the role of OT for the purpose of OST.   Research question Is OT an effective and safe medication for OST?   An Overview of the following chapters  The following chapters describe the consecutive steps undertaken for my PhD core research project. Chapters 2–4 and appendices B and C have been separately either published or are currently under review for publication.    38 Chapter 2 is a systematic review of studies about using OT for the treatment of opioid dependence as of 2016. This review aims to assess the evidence on the safety and efficacy of OT for OST and did not find adequate evidence to make a conclusive recommendation about the safety and efficacy of OT for OST. Essentially, the review exposes the knowledge gap resulting from the lack of relevant, adequate, published evidence on OST with OT, which justified the need for a trial to address this knowledge gap (131). Appendix A provides a detailed appraisal of studies included in the review. Chapter 3 describes the data using the baseline characteristics of the 204 participants in the opium trial recruited in three urban (N = 152) and one rural (N=52) OST clinics. Specifically, the study assesses the pattern of substance use in a sample of treatment-seeking patients with opioid dependence using the ASI–5, blood tests, urine toxicology, and sociodemographic questionnaire administered at baseline in the opium trial and then compares the patterns between urban and rural centres.  Chapter 4 describes opium trial, the first study to compare the safety and efficacy of OT with methadone for OST. The trial was a multicenter, double-blind, non-inferiority controlled trial, with a stratified sample of 204 participants with opioid dependence who were randomized to receive either OT or methadone, with an allocation ratio of 1:1 using a patient-centered flexible dosing strategy. Eligible participants were followed for a period of 12 weeks. The primary outcome was retention in treatment at the endo of the 85-day follow-up period. After describing the baseline characteristics of participants in the two arms, the study primarily aims to test if OT is equally as effective as methadone at retaining participants in OST. In addition, data on the self-reported use of opioids outside treatment and adverse events (AEs) are compared between the participants who were receiving OT and methadone. Appendix B provides further   39 details about the design of opium trial. Appendix C is a public health case study which elaborates on the development of this line of research by inquiring into the effectiveness and safety of opium, a widely used and culturally acceptable medication, for the treatment of opioid dependence in Iran. Specifically, it starts with a an overview of sociodemographic characteristics and the substance use profile of Iran, where opium is being widely used for OST. It then provides a historical perspective on the development of the OT program and its current status in Iran. Next, results of the opium trial are briefly presented (OT is a clinically effective and safe OST), highlighting their relevance to the work of improving treatment options for opioid-dependent patients. Some conclusions and suggestions for further research on this subject are then discussed. Finally, Chapter 5 summarizes chapters 1-4 and appendices A - C, including the results and conclusions from each step. Then the chapter explains the strengths and limitations of the research project and discusses the implications of the findings from this research. It concludes by making recommendations for possible directions that future studies in the field may take.    40 Chapter 2: Tincture of opium for treating opioid dependence: a systematic review of safety and efficacy.   Introduction In recent years, there has been a growing interest in using OT for detoxification and OST of opioid dependence in certain parts of the world, particularly Iran (132,133). OT has gained growing popularity since its introduction in national protocol of opioid dependence treatment in Iran in 2010 (30,85,134) and there have been two different models for long-term treatment with OT; maintenance treatment and gradual dose reduction combined with self-help programs including peer counseling and recreational activities in NGO (30). A report in 2014 provided a detailed profile of the treatment model used by an NGO in Iran (Congress 60) treating more than 20,000 patients with OT in 38 branches all over the country (89).  The present review sought to retrieve all available literature purporting to evaluating the safety (measured through 1. withdrawal symptoms 2. craving 3. retention in treatment 4. abstinence from illicit use of drugs) and efficacy of OT for detoxification or maintenance treatment of opioid dependence.       41  Methods 2.2.1 Eligibility criteria, information sources & systematic search Given the scarcity of evidence on the subject, the search strategy had no limitations for the language or publication date of the retrieved studies.  Electronic searches were conducted on the following databases: 1. CENTRAL: EBM Reviews: Cochrane Central Register of Controlled Trials-Ovid (Till February 31, 2016)  2. Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations and Ovid MEDLINE(R) (1946 to 2016) 3. EMBASE - Ovid platform (1974 to 2016) 4. Web of Science core collection (1900-2015) 5. PsychINFO (1938-2013) 6. ProQuest Dissertation & Theses Database (Until February 31, 2016) 7. Iran Medex (http://www.barakatkns.com) (Until February 31, 2016) 8. www.clinicaltrials.gov (Until February 31, 2016) 9. www.who.int/trialsearch (Until February 31, 2016) Below is the search strategy on the Ovid platform for Medline database: 1. tincture of opium.mp.   2. opium tincture.mp.  3. tinctura opii.mp. 4. laudanum.mp.   5. 1 or 2 or 3 or 4     42 After selecting articles from electronic search, which assessed safety and efficacy of OT for treating opioid dependence, reference lists of the selected articles, as well as studies citing them were also screened with the same selection criteria. 2.2.2 Study selection & data collection process Duplicate articles were removed and the remaining titles, abstracts and when necessary, full-texts were screened to determine whether the study was assessing the safety or efficacy of OT for treating opioid dependence. The first step employed two reviewers (MN and NN) who selected the studies for inclusion and any disagreements were resolved by consensus. A third reviewer was consulted to address the unresolved disagreements on inclusion and exclusion of the articles (MV). Titles and abstracts of articles in the reference lists of the selected studies, as well as studies citing them were also screened.   Articles reporting on randomized controlled trials, cohort studies, case-control studies, cross-sectional studies and case series with accessible report at the time of manuscript preparation were considered eligible for inclusion. The primary investigators of the study were contacted in cases of unpublished reports. At this stage, we also identified the selected articles that reported on the same study.  Two reviewers (MN and NN) independently retrieved the intended information as described below and disagreements were resolved by consensus. A third reviewer’s (MV) opinion was obtained on any disagreement. The primary investigators of the study were contacted in case of any missing information or unpublished data. For each included study, data was extracted on: 1) Type and country of study, 2) Detoxification vs. maintenance treatment, 3) Participants (number, age, gender, inclusion criteria, exclusion criteria), 4) Type of interventions (medication,   43 e.g. OT vs. comparator, dosing strategy, duration of treatment, duration of follow-up), 5) Measured outcomes and methods of assessments, 6) Results of assessments. 2.2.3 Risk of bias Two reviewers (MN and FC) assessed the included studies independently using Effective Public Health Practice Project (EPHPP) Quality Assessment Tool for Quantitative Studies (135). Disagreement on each assessed item was resolved by asking for the third reviewer’s opinion (MV).  2.2.4 Summary measures & planned methods of analysis Primary outcomes for the included studies were retention in treatment, abstinence, withdrawal symptoms and craving. Other reported outcomes were also summarized. Assessed outcome measures and methods of assessment/measurement were summarized in Table 2.5. Despite our primary intention for providing a quantitative report, we decided not to conduct a meta-analysis due to high risk of bias, heterogeneity in the interventions and assessment methods as well as inadequate reporting of the outcomes.       44  Results 2.3.1 Study selection After removing duplicates, 322 articles were reviewed for titles and abstracts and full-texts when necessary. Fourteen articles fulfilled the inclusion criteria of “assessing the safety or efficacy of OT for treating opioid dependence”, from which 3 studies were excluded after the full text review and contacting primary investigators or corresponding authors. These 3 studies and the reasons for their exclusion are summarized in Table 2.3. Among the remaining reports, 2 pairs of reports were on 1 study (136–139). Therefore, a total of 9 studies (6 full-text articles and 3 abstracts/conference proceedings (140–142)) were considered for the appraisal and qualitative synthesis procedure. (See Fig 2.1) 2.3.2 Study and intervention characteristics Among the 9 included studies, 5 were from Iran (136–142) (19-25), 2 from Thailand (143,144), 1 from China (145) and 1 from France (146). Three Randomized Controlled Trials (RCTs) (138,139,144,145) and 1 Cohort study (two groups pre + post) (143) assessed detoxification as opposed to 4 uncontrolled prospective case series (136,137,140,142) and 1 uncontrolled retrospective case series (146) that assessed long-term/maintenance treatment.  Of the 4 studies on detoxification, 110 patients were treated with OT for the duration of 5-10 days, using a dosing range of 15-140 mg morphine equivalents/day for detoxification (138,139,143–145). Each study had also used a range of doses based on factors such as patients’ prior use of illicit opioids (143,145) or ASI score (147). One of these studies compared different doses of OT (144) and one decided not to compare two groups due to significant baseline   45 differences between the two groups. The active comparator was methadone (138,139) and buprenorphine/naloxone in the other two studies (145).   Five studies on maintenance/long-term treatment consisted of 4 uncontrolled prospective case series (136,137,140–142) and 1 uncontrolled retrospective case series (146). These studies reported on maintenance treatment of 570 patients with OT for the duration of 6-12 months. While 2 studies (140,146) with smaller sample sizes had continued the maintenance dose, the other 3 studies (136,137,141,142) had allowed patients to taper their dose aiming for abstinence. Only 1 of the studies had a treatment control group with buprenorphine (146) which did not provide any comparison between two groups. The reported dosing range for long-term/maintenance treatment was higher, between 100 mg and 400 mg morphine equivalents/day (140,141,146) compared to detoxification treatment studies (15-140 mg morphine equivalents/day) (138,139,143–145). General characteristics of the selected studies and characteristics of interventions used in them are summarized in Tables 2.1 and 2.2, respectively.  2.3.3 Risk of bias within studies Overall potential risk of bias (Global rating) was assessed to be low in 1 study (138,139), medium in 2 studies (144,145) and high in the other 6 studies. Table 2.4 shows the results of the appraisal in different domains. Detailed appraisal of the studies and related quotes are provided in the supplementary section 1.  2.3.4 Results of individual studies A qualitative summary of the included studies is presented in Table 2.5. All 9 studies reported at least on one of the efficacy measures (treatment retention, abstinence, craving,   46 withdrawal symptoms) and 4 studies reported on safety of OT for this indication. The only outcome reported by a sufficient number of studies (4 studies) to be considered for a quantitative summary was withdrawal symptoms in detoxification studies. However, due to an overall high potential risk of bias, inadequate reporting, and heterogeneity of the design, interventions, and reported outcome measures; authors decided not to conduct a meta-analysis.  2.3.5 Reports on detoxification  Tabasomi et al., (138,139) conducted a randomized double-blind controlled clinical trial to compare OT and methadone for detoxification of patients with opium dependence. Study population, characteristics of patients and interventions in each group are summarized in Table 2.1 and 2.2 respectively. They compared withdrawal symptoms and side effects between two groups and observed significant decrease in withdrawal score in both groups [OT: baseline = 10.68 (SD = 0.78); Day 10 = 0.51 (SD = 0.26); p < .001; methadone group: baseline = 11.55 (SD = 0.52); Day 10 = 0.52 (SD = 0.18); p < .001), no statistically significant difference between two groups (pooled withdrawal score; OT: 4.69 (0.20); methadone: 5.00 (0.20; p = .32) and no statistically significant difference in two groups regarding incidence of side effects. Perspiration (67.5%) and sleepiness (65.7%) were the most common side effects in both groups (138,139). All patients remained in the treatment till the end of the study but they did not report on the abstinence and craving. Somogyi et al., (144) conducted a randomized open-label clinical trial to evaluate the clinical effectiveness, pharmacodynamics and pharmacokinetics of a range of OT doses in the management of opioid withdrawal in Thailand. Study population, characteristics of patients and interventions in each group are summarized in Tables 2.1 and 2.2 respectively. On the day 5,   47 they conducted an interdosing interval study to measure plasma concentration of morphine, heart rate, blood pressure, respiratory rate and withdrawal symptoms in all subjects. The time to maximum plasma concentration (Tmax) was 1 h for all three groups. Adjusting for prior daily opioid use and plasma morphine concentration, there were significant effects of dose for both diastolic (p =.021) and systolic blood pressure (p = .01), but not for time (p > .05). In contrast, there were no significant effects of either time (p = .08) or dose (p = .41) on heart rate. Effect of time on respiratory rate was significant (p = .001), with mean respiratory rates at 1 h and at 3 h post dosing significantly lower than those at 8 h (p = .04; p = .001), however the observed difference was not clinically significant (Range between 20 and 22). Controlling for prior opioid use and plasma morphine concentrations, there was a significant effect of time (p = .040), but not dose (p = .170) on withdrawal scores. All 32 patients remained in the treatment, but they could not show an effect of increasing OT dose on decrease of withdrawal scores. They also did not report on craving, abstinence and adverse effects among participants. Jittiwutikarn et al., (143) conducted a Cohort analytic (two groups pre + post) study allocating 15 inpatients, who used opium, to receive OT and 15 inpatients, who used heroin, to receive methadone for detoxification. After 4 days of receiving the treatment, they measured plasma morphine, drug effect score, withdrawal score and high/liking score in two groups. In OT group, withdrawal symptoms (p = .013), drug effect score (p < .001) and high/liking score (p = .002) showed significant change over time. In methadone group, only drug effect score (p < .001) showed significant change over time. Authors did not perform formal statistical analyses to compare outcomes between the two groups, since patients in one group were intravenous (IV) heroin users and the other group, opium smokers. With that in mind, withdrawal scores in the OT group (baseline = 8.97, 95% CI [8.24, 9.70]); hour 8 = 7.68, 95% CI [6.73, 8.63]) were overall   48 higher than methadone group (baseline = 4.61, 95% CI [3.37, 5.85]; hour 8 = 3.92, 95% CI [2.32, 4.97]. All patients remained in the treatment throughout the follow-up period in both groups and craving, AEs and abstinence were not reported.  He Ming et al., (145) conducted a randomized single-blinded controlled study to compare retention in treatment, withdrawal symptoms and craving in patients with heroin dependence admitted for detoxification, receiving either buprenorphine plus naloxone or OT for 15 days. Total withdrawal scores at the end of both agonist treatment periods at day 10 (OT = 15.60, 95% CI [14.07, 17.13]; buprenorphine/naloxone = 11.10, 95% CI [10.01, 12.19]) and end of study (OT = 12.20, 95% CI [11.00, 13.40]; buprenorphine/naloxone = 5.20, 95% CI [4.69, 5.71]), withdrawal scores were higher in the OT group. Total craving scores were significantly higher in OT group at day 10 (OT = 343.9, 95% CI [-149.04, 13.40]; buprenorphine/naloxone = 25.6, 95% CI [-65.54, 116.74]) and day 15 (OT = 303.0, 95% CI [-144.664, 750.664]; buprenorphine/naloxone = 0.0). The proportions of patients retained in treatment at the end of the study were not significantly different (p=.26). The study did not report on abstinence and safety outcomes. 2.3.6 Reports on long-term abstinence-based/maintenance treatment Seiri et al., (141) reported on a prospective case series of 226 male patients, diagnosed with opioid-dependence (72.6% used opium). Patients were initially stabilized on a dose of OT and in case of consent; their doses were tapered every 21 days. After a 12-month follow-up, 167 clients (74%) remained in the treatment and no important AE was observed among the population. In addition to OST, patients participated in a series self-help programs provided by a NGO. The study did not report on abstinence, craving or withdrawal symptoms.   49 Mehrjerdi Z. (142) reported on a prospective case series of 283 female patients diagnosed with simultaneous dependence on opium and benzodiazepines. Patients underwent 6 months of treatment with OT and assessed on a monthly basis using the ASI-5th edition (147) and urine toxicology. From 283 patients who started the treatment, 221 (78.90%) remained in the treatment at the end of 6 months and 71% remained abstinent from both opium and benzodiazepines. No important side effects were reported, and the study did not report on craving or withdrawal symptoms.  Tavakoli et al., (136,137) reported on a prospective case series of 33 male patients over 40 years old who were diagnosed with opiate dependence. OT was administered for them in an NGO-based treatment setting and it was tapered over 11 months. Quality of patients’ life was assessed using Short Form Health Survey–36 (SF-36) at baseline as well as 1 and 3 months after initiating the treatment. Investigators also measured the cost-effectiveness of the intervention at the end. Total score of SF-36 significantly improved at the end of the study compared to the baseline (P<0.001). Cost-effectiveness analysis showed that the monthly cost of OT per person was 1,598,490 Iran Rials (IRR). Also, the net cost benefit ratio was about 58% and the reported saved net sum was 167,744,740 IRR over the three-month study period. The study did not report on AEs, abstinence, craving or withdrawal symptoms. Mokri et al., (140) reported on an uncontrolled prospective case series of 22 male opium dependent patients with opium use disorder. Patients received 10-40 ml of OT based on their prior opium use in two divided doses each day for 6 months. The 6-month retention rate in treatment was 71% with an average daily dose of 31.6 ml. They observed a decrease in illicit opium use, money spent on drugs and improvement in familial and social scales but did not   50 report on the effect size. No major AEs were observed, while craving and withdrawal symptoms were not reported. Auriacombe et al., (146) reported on a retrospective case series of 18 treatment-resistant participants diagnosed with heroin-dependence from whom, 6 patients were receiving OT 15 ml/day as opposed to 12 patients receiving 2-4 mg/day of buprenorphine and retrospectively assessed their outcomes after on average 16 months of receiving treatment using Lifetime Retrospective Evaluation Score Table (LREST) (148) and ASI -French version (147). They did not provide head-to-head comparison of two medications and reported on outcomes of patients treated with two medications together. After initiation of treatment, patients showed significant improvement in physical (p < .001), psychological (p= .001), family (p= .009) and weight (p= .012) but not sociological domain of LREST (p= .239). Reported number of days of heroin use in the past 30 days was less than one and there was not shift to other drugs. Studies on maintenance treatment or long-term treatment were comparably less homogenous in terms of reported outcomes, however 3 out of 5 studies reported a retention rate of 71-78% within 6 to 12 months (140–142). Comparing before and after intervention, patients on maintenance or long-term treatment with OT showed improvement in other reported outcomes i.e., illicit use of drugs (140–142,146), different dimension of substance use disorder (based on ASI (147)), money spent on drugs (136,137,140), quality of life (136,137) and AEs (140,141).  For studies on detoxification treatment, apart from withdrawal symptoms being reported by all four studies, craving (145), pharmacodynamic measures (143,144), AEs (138,139), perception of drug effect (143,144) and retention in treatment (145) were measured in some but not all studies. In before and after comparisons, OT was associated with improvement in   51 measured outcomes in all studies on detoxification; however when compared to control group, in 1 study OT showed similar results to methadone (138,139) and in another one showed worse outcomes compared to buprenorphine and methadone (145).         52  Discussion 2.4.1 Summary of evidence  We found 9 completed studies with accessible published reports (6 full text articles and 3 abstracts/conference proceedings) about using OT for detoxification or maintenance treatment of opioid dependence. Most studies were performed in particular regions of the world such as Iran and Thailand, possibly due to lower operating costs, and greater availability and cultural acceptability of opium in these areas (129,134). All three RCTs were investigating detoxification treatment. There was no published RCT or controlled study on the use of OT for the maintenance treatment of opioid dependence. Altogether, these studies have included 680 patients with opioid dependence using OT in inpatient and/or outpatient treatment settings (110 participants for detoxification and 570 for maintenance treatment). Apart from one study, participants have largely been men. Although this is in line with the substance use profile of opioid dependent populations in countries where the studies were conducted, a purposive sampling to recruit a sufficient number of patients from both genders is suggested in future studies.  The dosing strategy used for OT is variable across studies with a wide range of 10-400 mg morphine equivalent/day. Studies on detoxification used a lower dose range (10-135 mg/day) compared to studies on maintenance treatment (100-400 mg morphine equivalent/day). Most studies used a twice-daily dosing strategy. Among studies on detoxification, while earlier studies tended to use comparably lower doses (less than 50 mg morphine equivalents/day); the most recent one used higher doses (45-135 mg morphine equivalents/day) (138,139). While the latter, using higher doses of OT, has shown similar results to methadone, earlier studies with lower   53 doses have shown worse outcomes compared to methadone or buprenorphine. This indicates that adequate doses of OT must be prescribed for achieving successful outcomes.  Published evidence supporting maintenance/long-term treatment of opioid dependence is lacking. Despite an acceptably high long-term retention rate with OT among current reports (71-78%), no RCT or controlled study has been conducted on long-term maintenance treatments to compared OT with other standard treatments such as methadone. Moreover, efficacy and safety of OT have not been uniformly assessed, methods of outcome measures were heterogeneous, the overall potential risk of bias was high and details of studies on this type of treatment have not been adequately reported. Thus, it is not possible to draw any conclusion on the safety and efficacy of OT for long-term maintenance treatment with OT at this point. In summary, although results of pre/post comparisons in current uncontrolled studies show promises for using OT in terms of retention in treatment, control of withdrawal and craving, improved quality of life and cost-effectiveness for treating opioid dependence, results are not conclusive due to lack of active control and further studies are required to assess the safety and efficacy of OT for opioid dependence before proposing this medication as an alternative treatment in the future.  2.4.2 Limitations The small number of available studies provides limited evidence to make any judgement at this point. High-potential risk of bias among included studies did not allow us to conduct a meta-analysis. Additionally, the heterogeneity of the interventions in both the OT and control groups and methods of outcome measurement limited the reliability of comparisons made between different studies. Moreover, incomplete reporting of measured outcomes in some   54 studies made the overall assessment of OT efficacy and safety impossible. We focused our search specifically on tincture of opium to achieve more homogenous results. Broader electronic search strategies with search terms such as “opium”, “substitution treatment”,  “opioid dependence” were not used since they yielded a large number of unrelated results; however, citation tracking was used to mitigate this limitation. A review of opium, as a substance itself, would be useful in shedding light on the physiological effects of opium, especially in terms of safety and AEs.  Conclusions Although a few studies exist assessing safety and efficacy of OT for treating opioid dependence with promising results, especially for detoxification, making conclusive recommendations is not possible at this point. Thus, future clinical trials are required to provide adequate evidence about the safety and efficacy of OT for treating opioid dependence, particularly for long-term maintenance treatment.     55  Tables and figures Figure 2.1 PRISMA 2009 Flow Diagram     56 Table 2.1 General characteristics of studies on using opium tincture for treating opioid dependence	Study Type  Intervention  Number of participants  Age (years)  Gender (M: F) Language Country  Inclusion/Exclusion criteria   Tabasomi F et al. (138,139) RCT ** Detoxification 74 Mean 40 Only Male  English Iran Inclusion criteria: -Meeting the DSM-IV-TR** criteria for opium dependence -First time detoxification  - 18 - 60 years of age Exclusion criteria:  -Physical illnesses that needed methadone treatment - Use of other medications or substances except nicotine -Major psychiatric disorders  - Major physical illnesses - Pregnancy - Lactation -	Unwilling to follow researcher instructions or maintenance therapy with other opioids Seiri L., et al. 2014 (141) Uncontrolled prospective case series Abstinence-based/maintenance treatment 3 226 Mean (SD **) 37.1 (11) Only   Male English Iran Not Reported (NR)  1 Mehrjerdi ZA (2013) (142) Uncontrolled prospective case series Abstinence-based/maintenance treatment 3 283 Mean (SD **) 36 (9.8) Only Female English Iran Simultaneous dependence on opiates and benzodiazepines Study Type  Intervention   Number of participants  Age (years)  Sex (M: F) Language Country  Inclusion/Exclusion criteria     57 Tavakoli M., et al. 2012 (136,137) Uncontrolled prospective case series Abstinence-based/maintenance treatment 3  33 Over 40 NR Persian Iran Inclusion criteria: - Treatment with opium tincture - Over 40 years of age Exclusion criteria:  - Severe mental or physical health condition Somogyi AA, et al. 2008 (144) RCT ** Detoxification 32 Mean 38.4 31:1 English Thailand Inclusion criteria: -Inpatients at the Drug Dependence Treatment Centre Exclusion criteria:  - Taking medications that alter the pharmacokinetics of morphine - Significant medical illness - Pregnancy - Breast-feeding Mokri A, et al. 2007 (140) Uncontrolled prospective case series Maintenance treatment 22  Mean 39.4 Male only English Iran Inclusion criteria: -	Opium dependent clients - Voluntary  - Written informed consent Jittiwutikarn J, et al. 2004 (143) Cohort analytic (two groups pre + post) Detoxification 30 Mean 34.5 29:1 English Thailand Inclusion criteria: -Inpatients at the Drug Dependence Treatment Centre  Exclusion criteria:  - Positive HIV test - Pregnancy - Breast-feeding He M, et al. 1996 (145) RCT ** Detoxification 42 Mean 28.8 36:6 Chines, with English abstract China Inclusion criteria: - Opiate dependence based on CCMD-2** and   DSM-IV** opioid substance diagnostic criteria  - Current substance use - Positive urine opiate screen - Previously received education for > 3 years Study Type  Intervention   Number of  participants Age  Gender (M: F) Language Country  Inclusion/Exclusion criteria     58 Auriacombe M, et al. 1994 (146) Uncontrolled retrospective case series Maintenance treatment 18 Mean 33 14:4 English France Inclusion criteria: Treatment-resistant participants diagnosed with heroin-dependence 1 Not Reported; 2  Unpublished data and made available according to communication with authors; 3 Patients could choose to taper their medication to attain abstinence; * Through communication with the corresponding author; **Abbreviations: CCMD= Chinese Classification of Mental Disorders, DSM= Diagnostic and Statistical Manual of Mental Disorders, RCT=Randomized controlled trial, TR= Text Revision, yrs.=years 			  59 Table 2.2 Characteristics of interventions used in studies on using opium tincture or the comparator medication for treating opioid dependence Study Number of participants Dosing strategy (Fixed vs. individualized)  Treatment duration** Follow-up duration**  Medication (compared with OT) Number of participants Dosing strategy  Treatment duration (days)  Follow-up duration**  Tabasomi F et al. (138,139) 35 Fixed: Based on Addiction severity Index-baseline score, 45, 90 and 135 mg were administered, respectively. Drug was continued in two divided doses for 5 days with a constant dose and then tapered 20% per day. At the end of 10th day drug was discontinued 10d 10d Methadone 39 Fixed: Based on Addiction severity Index-baseline score, 15, 30 and 45 mg were administered, respectively. Drug was continued in two divided doses for 5 days with a constant dose and then tapered 20% per day. At the end of 10th day drug was discontinued 10d 10d Seiri, L. et al. 2014 (141) 226 Individualized: The clients were initially stabilized on an equivalent dose of opium tincture and in case of consent, their doses were tapered by 10% every 21 days NA 12m NA NA NA NA NA Mehrjerdi ZA (2013) (142) 283 NR 6 m 12 m NA NA NA NA NA Tavakoli M, et a. 2012 (136,137)  33 NR NR 3m NR NA NA NA NA   60 Study Number of participants Dosing strategy (Fixed vs. individualized)  Treatment duration** Follow-up duration**  Medication (compared with OT) Number of participants Dosing strategy  Treatment duration (days)  Follow-up duration**  Study Number of  participants Dosing strategy (Fixed vs. individualized)  Treatment duration*  Follow-up duration*  Medication Number of  participants Dosing strategy  Treatment duration *  Follow-up duration*  Somogyi AA, et al. 2008 (144) 32 Individualized: Opium tincture mixture twice a day: - 13 patients 6.66 mg morphine equivalents - 8 patients: 13.3 mg morphine equivalents -11 patients: 20 mg morphine equivalents 5d 5d NA NA NA NA NA Mokri A, et al. 2007 (140) 22 Individualized: - According to prior illicit opium use initiated on 10-40 ml of tincture - Dose was gradually increased till clients reported no craving or withdrawal symptoms - Twice daily dosing NA 6 m NA NA NA NA NA   61 Study Number of participants Dosing strategy (Fixed vs. individualized)  Treatment duration** Follow-up duration**  Medication (compared with OT) Number of participants Dosing strategy  Treatment duration (days)  Follow-up duration**  Jittiwutikarn J, et al. 2004 (143) 15  Individualized: Based on prior dose:  every 12h morphine equivalents: - 4 patients 3.33 mg  - 10 patients 6.66  - 1 patient 10 mg  5d 5d Methadone 15 Individualized: Based on prior use every 12h: - 1 patients 5 mg - 5 patients 10 mg - 4 patients15 mg - 5 patients 20mg 5d 5d He M, et al. 1996 (145) 28 Individualized: Based on reported prior dose, 10-14 mg/d which decreased daily to reach zero in 10 days 10d 15d Buprenorphine + naloxone 14 Individualized: -Based on reported prior use started with buprenorphine 0.9 – 1.2 mg/d for 5d, and reduced daily.  - After the 5th day of hospitalization, naloxone hydrochloride 0.8 mg per day, increasing daily to 1.6 – 2.0 mg per day and maintained until discharge 10d 15d Auriacombe M, et al. 1994 (146) 6 Fixed: Laudanum,  15 g/d NA 1.4 ± 1.2 y Buprenorphine 12 2-4 mg/d NA 1.4 ± 1.2 y * Through communication with the corresponding author; ** d: days, m: months, y: years; NA: Not Applicable; NR: Not Reported     62 Table 2.3 Selected studies retrieved through the electronic search but excluded from qualitative synthesis and the reasons for their exclusion. Study Type  Intervention   Country  Reasons for exclusion Krausz, R. & Akhondzadeh S. (149) Randomized Controlled Trial Maintenance treatment Iran A registered randomized controlled trial at the WHO trial registry website and the study (www.who.int/trialsearch) was excluded because the study is not completed at the time of publication. Sohrevardi M. 2014 (150) Randomized Controlled Trial Detoxification Iran A registered and completed controlled trial at the WHO trial registry website and the study (www.who.int/trialsearch) was excluded due to unavailable results despite contact with the authors at the time of writing this review Natpratan C. 2000 (151) Prospective case series Maintenance treatment Thailand The study was excluded due to unavailable data on the methods and outcome measures despite contact with the authors at the time of writing this review.    63 Table 2.4 Assessing risk of bias in studies on using opium tincture for treating opioid dependence based on the Effective Public Health Practice Project (EPHPP) Quality Assessment Tool for Quantitative Studies (135)  Study (Date) Selection bias Allocation bias Confounders Blinding Data collection Withdrawals and drop-outs Global Rating Tabasomi F et al. (138,139) Moderate Strong Strong Strong Strong Strong Strong Somogyi AA, et al. 2008 (144) Strong Strong Moderate Weak Strong Moderate Moderate Jittiwutikarn J, et al. 2004 (144) Moderate Moderate Weak Weak Strong Strong Weak He M, et al. 1996 (145) Moderate Strong Strong Moderate Strong Weak Moderate Seiri, L. et al. 2014 (141) Moderate Weak Weak Weak Weak Strong Weak Mehrjerdi ZA (2013) (142) Moderate Weak Weak Weak Strong Moderate Weak Tavakoli M, et al. 2012 (136,137) Moderate Weak Weak Weak Strong Moderate Weak   64 Study (Date) Selection bias Allocation bias Confounders Blinding Data collection Withdrawals and drop-outs Global Rating Mokri A, et al. 2007 (140) Moderate Weak Weak Weak Strong Moderate Weak Auriacombe M, et al. 1994 (146) Moderate Moderate Weak Weak Strong Weak Weak      65 Table 2.5 Reported outcomes, measurement tools and effects of interventions among studies on using opium tincture for treating opioid dependence, a systematic search till February 31, 2015 Study Outcome (s) Tools Results Tabasomi F et al. (138,139) * Withdrawal signs and symptoms Objective Opioid Withdrawal Scale (OOWS) (152) -Significant decrease in withdrawal score in both groups (p < .0001)  2 - No statistically significant difference between two groups in withdrawal score 2 Side-effects Questionnaire -No statistically significant difference in two groups regarding incidence of side-effects -Perspiration (67.5%) and sleepiness (65.7%) were the most common side-effects in both groups  Mehrjerdi ZA (2013) (142) Retention in treatment Abstinence  Self-report Urine toxicology  Addiction Severity Index-5th - 6-month retention in treatment = 78.1% - 6-month abstinence from non-prescribed benzodiazepine use = 86% - 12-month abstinence from non-prescribed benzodiazepine use = 71% - Attending psychotherapeutic meetings and family support for treatment were associated with treatment success.  Older age, being divorced, current psychiatric diagnosis with depression and current conflicts with family were associated with failure in treatment. - Tincture of opium can prevent non-prescribed use of benzodiazepines among opium-dependent women in Iran but further studies are required to examine this issue. Seiri L, et al. 2014 (141) Retention in treatment  Patients who complete the follow-up sessions - 37 (16.4%) dropped off treatment  - 22 (9.8%) voluntarily tapered opium tincture and abstained illicit opiate use - 167 clients (74%) continued to receive opium tincture on a daily basis  Side-effects NR No important side effect was reported   66 Study Outcome (s) Tools Results Tavakoli M, et a. 2012 (136,137) Cost-effectiveness    Quality of life - Checklist of costs (136)   - SF-36 (153) - Net cost-benefit ratio was about 58%  - Saved net sum was $15677, (167,744,740 IRR) during the three-month study period for 33 participants - Opium tincture improves the indices of health-related quality of life except LQH11_2 و LQH11_1 (The changes are all statistically significant) Somogyi AA, et al. 2008 (144) Plasma concentration of morphine  Blood sampling and HPLC-electrochemical detection (154) - Peak concentration 1 h after administration - Wide range of inter-individual variation for all parameters Heart rate Radial pulse palpation No significant effects of either time or dose on heart rate Blood pressure Sphygmomanometer Few observable changes in either diastolic or systolic Blood pressure for each dose of OT Respiration rate Direct observation Few observable changes across the inter- dosing interval for respiration Withdrawal symptoms Methadone Symptoms Checklist (155) Repeated measures ANCOVA, controlling for prior opioid use and plasma morphine concentrations revealed significant effects of time but not dose Mokri A, et al. 2007 (140) Retention in treatment Patients who complete the follow-up sessions 6-month retention rate reached 71% (87% excluding first week drop outs) Abstinence  Addiction severity index (147) Decrease in illicit opium use Money spent on drugs Addiction severity index (147) Decrease money spent on drugs ($170 on average per month per client) Daily dose NR Average daily dose after stabilization was 31.6 ml of tincture Major adverse event NR No major adverse event He M, et al. 1996 (145)       Retention in treatment Patients who complete the follow-up sessions - 7 out of 14 (50%) patients in buprenorphine/naloxone group and 11 patients out of 28 (39%) patients in the opium tincture group withdrew before completing treatment (p > .05)   67 Study Outcome (s) Tools Results Jittiwutikarn J, et al. 2004 (143) Plasma concentration of morphine  Blood sampling and HPLC-electrochemical detection (154) Plasma morphine concentrations showed significant changes over time specifically between zero and 3h. Heart rate Radial pulse palpation No significant changes over time for any objective measure Blood pressure Sphygmomanometer Respiration rate Direct observation Body temperature NR Withdrawal symptoms Methadone Symptoms Checklist (155) For the tincture of opium patients, withdrawal scores showed significant changes over time For the methadone patients, there was no statistically significant change over time for withdrawal scores, but high/liking scores showed significant changes over time Withdrawal scores appeared higher amongst the tincture of opium treated patients at each time point compared to the methadone treated patients. Patients’ perception of drug effects Self-report of ‘high/liking’ on a scale from 0 to 4 (0 = no effect; 4 = maximal effect). Time courses of withdrawal and drug effect/high/liking scores were inversely associated Auriacombe M, et al. 1994  (146) Substance use history Lifetime Retrospective Evaluation Score Table (LREST) (148) There was a significant increase of all scores after initiation of maintenance except for socio-professional status. Impact of substance use in seven areas (general information, medical, employment/support, drug/alcohol use, legal, family/social, psychiatry) Addiction Severity Index (ASI)-French version (147)  Reported number of days of heroin use over the past 30 days was less than one There was no shift to other drugs as number of days of alcohol use reported was 7 (less than one for alcohol intoxication), 4 days for cannabis use and no cocaine use. HIV status Serology NR  * Through communication with the corresponding author NR: Not Reported; 2 According to communication with authors   68 Chapter 3: Patterns of substance use among patients with opioid dependence in Iran.  Introduction Iran has the highest reported prevalence of opiate use globally with an interestingly unique profile of opioid use. For instance, opioid dependence is more common than cannabis use disorder and the three most commonly used opioids are opium/opium dross (82.3%), the condensed extract of smoked opium ashes (‘shireh’) (27.8%), and methadone (not prescribed by a physician) (16.6%) (41) C. In contrast, cannabis is the most widely used drug worldwide and pharmaceutical opioids account for half of the opioid consumption globally and up to 81% and 94% of opioid consumption in North America and Oceania, respectively (156). Europe, where opiates account for the majority of opioid consumption (90%) (156) has also a different picture with 78% of treatment entrants having reported heroin rather than opium or its derivatives as their opioid of choice (157). Therefore, exploring the patterns of substance use and the related risk behaviors in Iran can reveal how certain unique contextual factors could affect the profile of substance use, its related risks, and as important, the overall treatment outcomes. The success of the Iranian system of opioid treatment may depend on its ability to respond to these factors.             In Iran 21% of the population lives in rural areas (158), with a different sociodemographic and cultural context compared to urban areas. Moreover, urban and rural areas are different in terms of opioid supply and access to treatment (159).  These factors are  C Comparison of alcohol is not feasible given that its forbidden status in Sharia and law, affect both its use and its self-reporting.   69 intertwined with substance use and related risk behaviors and impact the health of patients with substance use disorder. Previous studies have demonstrated such differences but their correlation with substance use disorder outcomes is complex and needs further research (160).  This separate chapter was dedicated to describing the baseline sample from a clinical trial comparing methadone and OT for treatment of opioid dependence (161) because they were recruited from a hard-to-reach population in an under-researched but interesting country from an opioid use perspective. Findings will contribute to an improved understanding of the profile of opioid use in Iran and its differences with those described in other regions such as North America, Australia, and Europe. It also explores the differences in substance use patterns and risk behaviors in urban and rural areas of Iran. Additionally, it will hypothesize how these differences could lead to different treatment needs, requiring tailored treatment approaches.       70  Methods 3.2.1 Study setting Data were obtained from opium trial (162), which further details about its design is provided in the following chapter and appendix B (161). 3.2.2 Sample Recruitment centres were primarily four outpatient OST clinics located in major cities in Iran: Sari and Tehran in the north, Isfahan in the centre, and Shiraz in the south. Tehran centre dropped out due to an inability to recruit participants. This may be attributed to a busy lifestyle in the capital city, which made the time required for completing the assessments a significant barrier for the potential participants in Tehran. A rural centre was added in Sari. Participants were recruited between July 2017 and January 2018 in four centres: Sari-urban, Sari-rural, Shiraz and Isfahan. Sari-urban centre was a drop-in centre located in the North of Iran. Drop-in centres provide services to the high-risk and socially disadvantaged groups in the community including precariously housed individuals. These services include OST, needle exchange, HIV counselling and testing, provision of food, and clothing. Shiraz and Isfahan centres were private substitution clinics located in two major urban centres of Iran in South and Centre, respectively. As opposed to other centres, Sari-rural centre was located in a rural district with a population of around 10,000 people approximately one-hour drive from Sari. Participants were individuals with opioid use disorder based on the diagnostic and statistical manual of mental disorders fifth edition (DSM-5) criteria. Female participants of childbearing age were included only if they agreed to use an acceptable method of contraception   71 approved by the research physician during the study follow-up period. Participants were excluded if they met any of the following criteria: severe hepatic impairment; hypersensitivity to methadone, opium, or their ingredients; pregnancy; severe chronic respiratory disease; head injuries and raised intracranial pressure; biliary tract disease; consumption of monoamine oxidase inhibitors within the last 14 days prior to the study. The initial design required a stratified randomization with a female/male ratio of 1: 9 and 1: 2: 1 age proportions for <30/30–49/>= 50. To facilitate the recruitment, age criteria was relaxed but it was ensured to purposely recruit adequate number of female participants, who are often underrepresented in previous studies. As a result, final f: m ratio was 23: 181 and final age ratio <30/30–49/>= 50 was 34: 142: 21. 3.2.3 Assessments  Data were obtained from the ASI–5 (147), blood tests, urine toxicology, and sociodemographic questionnaire at baseline visit. Variables to investigate were those commonly reported at baseline in previous OST clinical trials (95,99,163,164): patterns of substance use, risk behaviors (e.g. drug injection in the past 30 days, polysubstance use), age, gender, marital status, educational level, employment, HCV/HIV status, history of incarceration, history of overdose, and residential status (95). Polysubstance use was defined as using 3 substances or more. Satisfaction with family situation at baseline was also described given its contribution to better understanding of the sociocultural context.   72 3.2.4 Statistical analysis  Descriptive statistics (mean and standard deviation for scale variables, frequencies and percentages for categorical variables) were performed and participants in urban or rural centres compared on all variables using the effect size. Those who refused to answer or did not know the answer were considered missing.  Bivariate analysis was performed using pairwise deletion of the missing data. Categorical variables were compared using Chi-square test and the magnitude of the effect size was calculated using Cramer’s V test. Scale variables were compared using independent samples t-test and the magnitude of the effect size was measured using Cohen’s d effect size. All analyses were performed using IBM SPSS Statistics, version 25.0.      73  Results A total of 204 participants (152 in urban centres and 52 in rural centres) were recruited with a mean age of 37.42 ± 9.34 and a male to female ratio of 181: 23. From this population, 130 (65%) people were married, 122 (62%) were employed, and 107 (53%) had high school or higher education. Also, 98% of participants had a place to live, 76% owned their place of residence, and 26% had a lifetime history of incarceration. Further characteristics of participants are presented in Table 4.1. The three most commonly reported substances used in lifetime were opium 166 (82%), Shireh/Sukhteh 123 (72%) and methadone 140 (67%). A total of 71 (35%) and 143 (70%) participants used three or more substances in the past 30 days and lifetime, respectively (Figure 4.1). Lifetime history of overdose was positive in 18 (9%), and 14 (7%) participants reported injection in their lifetime. Table 4.2 and Figure 4.2 provides additional details on the patterns of substance use. Rural participants were characterized by lower frequency of lifetime incarceration (14% vs. 30%, p= .02, V Cramer = 0.166) and higher frequencies of employment (18% vs. 45%, p <0.01, V Cramer = - 0.249), residential property ownership (92% vs. 70%, p= .01, V Cramer =  - 0.230) and satisfaction with family situation (85% vs. 70%, p = .04, V Cramer = - 0.149). Regarding the pattern of drug use, participants in urban centres reported higher proportions of heroin use both in lifetime (30.9% vs. 11.5%, p = .01, V Cramer = 0.193) and in the past 30 days (19% vs. 0, p = .01, V Cramer = 0.238), and amphetamine use also both lifetime (44.1% vs. 23.1%, p = 0.01, V Cramer = 0.193) and in the past 30 days (35% vs. 19%, p = .04, V Cramer = 0.154). In contrast, participants in urban centres reported lower opium use in the past 30 days (30% vs. 58%, p= .01, V Cramer = - 0.256). The urine toxicology results showed that participants in urban centres had a   74 higher proportion of methamphetamine (47% vs. 22%, p < .01, V Cramer = 0.216) and methadone (77% vs. 59%, p = .01, V Cramer = 0.175) positive tests at baseline. Moreover, participants in urban centres demonstrated a more severe risk profile with a higher lifetime number of overdoses (12% vs. 0, p = .01, V Cramer = 0.189).  Table 4.3 presents the comparison between urban and rural participants.     75  Discussion Iran, with a reported prevalence of more than 2%, has the highest reported prevalence of opioid dependence globally (41). In line with previous literature, the present study showed that Opium and Shireh are the most commonly used opioids; and also a lifetime proportion of 9% for overdose and 7% for injection in the sample (40,41). The pattern of opioid use and dependence described for other regions such as Europe, Canada, Australia, and US is different from Iran in a number of ways: 1) the global prevalence of opioid dependence is lower than Iran (the prevalence of opioid dependence worldwide = 0.55, North America = 1.4, US = 1.45, Canada = 1.0, and Europe = 0.4) (165); 2) heroin (Europe) (157) and prescription opioids (Australia and North America) (156) are the most commonly used opioids, and 3) prevalence of overdose and injection is higher among patients with opioid dependence in those regions (annual prevalence of injection drug use [not only but mainly opioids]; Global = 0.33%, North America = 1.06%, Australasia = 0.59%, Eastern Europe = 1.3%, Western Europe = 0.34%, Middle East and North Africa = 0.33% (166); a systematic review which estimated the lifetime prevalence of non-fatal overdose based on 27 samples from North America, Australia, and Europe yielded  a range of 16.6% to 68.0% with a mean of 45.4%, and a standard deviation of 14.4% (167). A potential explanation is that individuals who are using opioids in Iran and countries with similar opioid use profile, although categorized under the umbrella of opioid dependence, are a heterogeneous group which could be conceptualized under two subpopulations: 1) patients mainly using heroin with an associated high level of stigma and severe risk profile including polysubstance use, injection, overdose, and viral infections, 2) a larger group who are mainly using opium (nasal and oral route) with relatively lower levels of stigma and risky behaviours. Although described here as two subpopulations to facilitate understanding the concept, they might be better described   76 as two ends of a spectrum (Figure 4.3). This suggests there are different needs at each end of the spectrum with a more resource-intensive and comprehensive care plan for the high-risk group. It is warranted to test if OT is a suitable option particularly for the low-risk end because it is close to their substance of choice.     Other notable patterns observed in the present study were high levels of amphetamine-type stimulants use (31.3% in past 30 days and 39.1% in lifetime) and lower level of cannabis use (11.9% in past 30 days and 24.5% in lifetime) compared to international numbers. A recent systematic review reported a wide range of 11.2%–78.6% for prevalence of any recent or current (i.e., not lifetime measurements) cannabis use among patients in methadone maintenance treatment without calculating the pooled prevalence due to heterogeneity of the data (168). Reported prevalence of recent amphetamine use in OST outside Iran ranges between 5.3%–24% (169–171). Amphetamine type stimulants use is an alarming emerging trend in the drug market in Iran (172) aligned with the global pattern (173). Of particular concern are the potential negative consequences on individuals’ psychological well-being, quality of life, social functioning compared to relatively few number of effective evidence-based interventions for this condition to date (172). This finding indicates the need for educational programs targeting ATS use in young population, early intervention, multidisciplinary treatment programs, and investment in research to expand on available treatments for this condition.  Unique types of substances in the Iranian drug market such as Crack heroin, Norjizak, and Deta are the other findings of note in this study. Crack heroin or “crack” as it is called in Iranian drug market is a heroin-based narcotic with a significant amount of acetyl codeine combined with heroin, codeine, caffeine, morphine, thebaine, and acetaminophen, different from cocaine-based crack which is known as crack in most other countries’ drug market. Iranian crack   77 is used both through sniffing and injection and is different from heroin since it is odorless and can be used by needle without the need for preheating (174). “Norjizak” is a combination of opioids with Dexamethasone or benzodiazepines. It is mainly injected and has been attributed to a wide range of side effects including extensive skin infections and abscesses, corticosteroid side effects, significant risk of bloodborne infections such as HCV, and increased mortality (175). A drug called “Deta” was reported to be used by two participants in this study. To our knowledge, this substance is not mentioned in the scientific literature to date. A review of the grey literature indicated it is an opioid based substance sold under the umbrella of brand of natural products, and has effects similar to opioids (176). These patterns observed among participants in the present study call for close monitoring of such patterns, familiarizing care providers with these substances and their effects, compound analysis of new emerging products such as “Deta” and similar products, and investment in effective treatments for harms related to these substances. This study also revealed a high level of social functioning based on education, employment, house ownership, and marital status among participants, which is comparable to previous studies in Iran (40,41). This finding could be a result of lower level of stigma towards opioid use, particularly those individuals who mainly use opium (29). As a result, these individuals are able to maintain a high level of social function despite their habits. In addition, the threshold for employment may be comparably low in Iran given relatively low minimum wage and less eligibility criteria for entering the job market. These factors could be responsible for the maintenance of a high level of social function that help minimize the harms related to substance use and improve overall health outcomes for people with opioid dependence (177,178). Also, the cultural, legal, and financial context discouraging divorce could contribute to high proportion of married relationship among participants.     78 Finally, comparison between participants in urban and rural areas indicated a higher level of risk indicators such as heroin use, amphetamine-type stimulant use, and overdose in the urban group. This could reflect the different nature of substance use in these two regions with low risk opium use being more common in rural areas. Also, another reason could be the immigration of individuals who are developing high risk substance use such as injection from rural to urban areas given the comparably tight-knit nature of rural communities, where social environment has a stronger influence on health behaviours, possibly increasing social pressure on individuals with undesired behaviours such as injection drug use (179).  This finding calls for an increased availability and provision of harm reduction interventions such as education about the risks of injection, needle exchange programs, HIV counselling particularly in urban regions. Also, higher levels of education, employment, and residential stability are great resources, which provide an opportunity for strength-based treatment approaches in general particularly in rural areas. An outstanding finding was the absence of any self-reported lifetime overdose in rural areas as compared to 18 (12%) patients in urban areas. This warrants further research on how much each of the differences between urban and rural centres in this study such as patterns of substance use, risky behaviours, and social functioning each contribute to this decreased risk. This line of research could be very relevant given the current overdose crisis mainly in North America, which may also affect other parts of the world to variable extents. 3.4.1 Strengths and limitations This study explores in detail the patterns of substance use among a hard-to-reach population with opioid dependence in Iran. It also provides an informative overview of patterns of substance use among patients with opioid dependence seeking treatment. The sampling   79 method is not a random sampling method, hence the sample is not representative sample of patients with opioid dependence seeking treatment in 3 provinces of Iran and the findings can only be generalized to the general population of patients with opioid dependence with extreme caution.      80  Conclusion The use of psychotropic substances in different regions and cultures is showing significant differences likely based on traditions, availability, and preferences. Also, the prevalence of use, level of social integration among users, and the routes of administration are significantly different indicating that the overall prevalence rate is only part of the picture. A global comparison between countries, regions and subpopulations can contribute to a better understanding of the needs. Specific examples inferenced from this study are a potential role for OT in OST in Iran given its close characteristics to the most commonly used opioid in Iran, i.e., opium; increased prevention, early intervention, and treatment for stimulant use given its increasing prevalence; close monitoring and education of providers about the nature of substances specific to Iranian drug market; increased provision of harm reduction interventions particularly in urban regions given their more severe risk profile, and the opportunity for strength-based approaches building on the observed high level of social function particularly in rural areas.     81  Tables and figures Table 3.1 Characteristics of opium trial participants (N=204) at baseline  Frequency (Mean) Percentage (CI) Age 37.42 [36.1, 38.7] Male Gender 181 88.7 Married 130 64.7 Education                Illiterate 10 5.0              Elementary School 23 11.4              Middle School 61 30.3              Secondary School 82 40.8              Post-Secondary School 25 12.4 Living Situation                Homeless 2 1 Employment                Employed 122 61.9 History of incarceration               Lifetime 51 25.9 Last 30 Days 6 3.1 Satisfied with Family Situation 147 73.5 Owns a house 150 75.8 * Participants who refused to answer or did not know the answer were considered missing.     82 Table 3.2 Pattern of substance use and related risky behaviours among participants of the opium trial (N = 204)  Frequency  Percentage  Lifetime polysubstance Use * 126 75.5 HIV ELISA (+) 1 0.5 HBS antigen (+) 1 0.5 HCV antibody (+) 12 5.9 Lifetime overdose 18 8.8 Lifetime injection 14 6.9 Alcohol - Any consumption               30 Days 21 10.3             Lifetime 79 38.7 Alcohol - Intoxication               30 Days 3 1.5             Lifetime 7 3.4 Heroin               30 days 29 14.2             Lifetime 53 26.0 Opium               30 days 75 37.7             Lifetime 166 81.8 Shireh/Sukhteh               30 days 79 47.0   83  Frequency  Percentage              Lifetime 123 72.4 Crack Heroin               30 Days 2 1             Lifetime 48 23.5 Tamjizak, Norjizak               30 Days 3 1.5             Lifetime 10 4.9 Methadone               30 days 123 60.3             Lifetime 140 68.6 Other opioids               30 days 5 2.5             Lifetime 6 2.9 Barbiturates               30 days 1 0.5             Lifetime 1 0.5 Benzodiazepines               30 days 39 19.1             Lifetime 40 19.7 Cocaine               30 days 1 0.5   84  Frequency  Percentage              Lifetime 1 0.5 Amphetamines               30 days 63 31.3             Lifetime 79 39.1 Hashish               30 days 24 11.9             Lifetime 50 24.5 Tramadol               30 days 1 0.5             Lifetime 3 1.5 Deta               30 days 2 1             Lifetime 2 1 * Defined as use of 3 substances or more.     85 Table 3.3 Comparison of sociodemographic characteristics, pattern of substance use, and its related risky behaviours between participants in urban (N=152) and rural centres (N = 52)  Urban (N = 152) Rural * (N = 52) Effect size ** Lifetime polysubstance Use *** 96 (76.8%) 30 (71.4%) 0.054 HCV (+) 11 (8.5%) 1 (2.1%) 0.113 Lifetime overdose 18 (12.3%) 0 (0%) 0.189 Lifetime injection 13 (8.6%) 1 (1.9%) 0.114 Alcohol–Any Consumption    30 days 19 (12.5%) 3 (5.9%) 0.092 Lifetime 61 (40.1%) 18 (34.6%) 0.049 Alcohol - Intoxication                30 Days 3 (2.0%) 0 (0%) 0.071             Lifetime 6 (3.9%) 1 (1.9%) 0.048 Heroin                30 Days 29 (19.1%) 0 (0%) 0.238             Lifetime 47 (30.9%) 6 (11.5%) 0.193 Opium                30 Days 45 (30.4%) 30 (58.8%) - 0.256             Lifetime 122 (80.8%) 44 (84.6%) - 0.049 Shireh                30 Days 59 (46.5%) 20 (48.8%) - 0.020             Lifetime 93 (72.7%) 30 (71.4%) 0.012   86  Urban (N = 152) Rural * (N = 52) Effect size ** Crack Heroin                30 Days 1 (0.7%) 1 (1.9%) - 0.056             Lifetime 40 (26.3%) 8 (15.4%) 0.112 Norjizak                30 Days 1 (0.7%) 2 (3.8%) - 0.115             Lifetime 8 (5.3%) 2 (3.8%) 0.029 Methadone                30 Days 97 (63.8%) 26 (50.0%) 0.123             Lifetime 109 (71.7%) 31 (59.6%) 0.114 Other Opioids                30 Days 3 (2.0%) 2 (3.8%) - 0.053             Lifetime 4 (2.6%) 2 (3.8%) - 0.031 Barbiturates                30 Days 1 (0.7%) 0 (0%) 0.041             Lifetime 1 (0.7%) 0 (0%) 0.041 Benzodiazepines                30 Days 32 (21.1%) 7 (13.5%) 0.084             Lifetime 33 (21.9%) 7 (13.5%) 0.092 Cocaine                30 Days 1 (0.7%) 0 (0%) 0.041             Lifetime 1 (0.7%) 0 (0%) 0.041   87  Urban (N = 152) Rural * (N = 52) Effect size ** Amphetamine                30 Days 53 (35.6%) 10 (19.2%) 0.154             Lifetime 67 (44.7%) 12 (23.1%) 0.193 Hashish                30 Days 19 (12.7%) 6 (11.8%) 0.012             Lifetime 38 (25.0%) 12 (23.1%) 0.019 Tramadol                30 Days 2 (1.3%) 1 (1.9%) - 0.022             Lifetime 2 (1.3%) 1 (1.9%) - 0.022 Urine Toxicology (+)                Morphine 106 (73.1%) 43 (84.3%) - 0.115             Tramadol 13 (9.2%) 2 (4.4%) 0.074       Methamphetamine 67 (46.5%) 10 (21.7%) 0.216             Cannabis 18 (12.7%) 5 (11.1%) 0.020             Methadone 112 (76.7%) 30 (58.8%) 0.175 Age  38.0 (9.2) 35.9 (9.6) 0.227 Gender                  Male 131 (86.2%) 50 (96.2%) - 0.137 Employed 80 (54.8%) 42 (82.4%) - 0.249 Homeless 2 (1.3%) 0 (0%) 0.059 Owns a house 102 (69.9%) 48 (92.3%) - 0.230   88  Urban (N = 152) Rural * (N = 52) Effect size ** Marital Status                  Married 94 (62.7%) 36 (70.6%) 0.137               Divorced 24 (16.0%) 3 (5.9%)                Widowed 1 (0.7%) 0 (0%)                Single 31 (20.7%) 12 (23.5%)  Education                 Illiterate 7 (4.7%) 3 (5.8%) 0.130              Elementary School 17 (11.4%) 6 (11.5%)               Middle School 46 (30.9%) 15 (28.8%)               Secondary School 64 (43.0%) 18 (34.6%)               Post-Secondary School 15 (10.1%) 10 (19.2%)  History of Incarceration                 Lifetime 44 (30.3%) 7 (13.7%) 0.166             Last 30 Days 5 (3.4%) 1 (2.0%) 0.037 Satisfied with Family Situation 103 (69.6%) 44 (84.6%) - 0.149 * Reference group. ** Categorical variables and scale (age) were compared between two groups using Cramér's V  and Cohen’s d effect size. *** Defined as use of 3 substances or more.     89 Figure 3.1 Patterns of substance use (Lifetime).  Figure 3.2 Risk Profile of Participants.     90 Figure 3.3 The conceptual schematic of risk spectrum of patients with opioid dependence in Iran     91 Chapter 4: The opium trial: a randomized controlled clinical trial comparing tincture of opium with methadone for opioid substitution treatment.  Introduction 4.1.1 Background As described in Chapter 2, a number of countries use OT for OST among which, Iran is the only country that has reported its (131) widespread use for the treatment of more than 90,000 patients (124). Nevertheless, the systematic review in 2016 indicated a lack of adequate published evidence supporting its effectiveness and safety for this indication (131). Hence, opium trial was conducted to address this knowledge gap by comparing OT with methadone, the first and most widely used medication for OST across the globe. 4.1.2 Objective and hypotheses This chapter used opium trial data to test if OT was non-inferior to methadone in retaining participants in OST. In addition, self-reported use of opioids outside the treatment and AEs were comparted between the participants who were receiving OT and methadone.     92  Methods The protocol of opium trial has been described in details in Appendix B (161). As such, this chapter will provide a more concise description of the procedures and core features of the design, which can assist with the interpretation of non-inferiority comparison.  4.2.1 Trial Design Opium trial was a phase III multicentre stratified parallel group double-blind, non-inferiority randomized clinical trial with an allocation ratio of 1:1, which was conducted in Iran (ClinicalTrials.gov: NCT02502175; IRCT.ir: IRCT201506261556N78).  4.2.2 Changes to trial design The trial faced some challenges for the recruitment of participants, resulting in a total sample size of 204 instead of the targeted 240 participants. This sample size still yielded a lower yet acceptable power of more than 80% instead of the planned 90% (n=174 yielded a power of 80% to conclude non-inferiority of OT to methadone if it is in fact non-inferior to methadone with the predefined non-inferiority margin). To elaborate, the recruitment was challenging, because the busy lifestyle in the city made the time required for completing the assessments a significant barrier for the potential participants. Also, the initial design required a stratified randomization with a female/male ratio of 1: 9 and 1: 2: 1 age proportions for <30/30–49/>= 50. To facilitate the recruitment, age criteria was relaxed but it was ensured to purposely recruit adequate number of female participants, who are underrepresented in previous studies in the field of addiction (180). As a result, final F: M ratio was 23: 181 and final age ratio <30/30–49/>= 50 was 34: 142: 21. Also, active participation in another treatment program for opioid dependence   93 within the last 14 days was one of the exclusion criteria which was later removed to facilitate the recruitment from the collaborating centres. Moreover, one of the initial recruitment centres in Tehran dropped out due to aforementioned recruitment challenges and was later replaced by a rural center in Mazandaran to improve the representativeness of the sample, having participants from both urban and rural areas.  4.2.3 Participants Participants provided informed consent before any study‐related procedure. Eligible participants were individuals who met the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM‐5) criteria (American Psychiatric Association, 2013) for opioid use disorder. Study included the participants if they were willing and able to adhere to the treatment protocol as per the study physician’s discretion. Female participants of childbearing age were included only if they were not pregnant and agreed to use a method of contraception approved by the physician during the follow‐up period. Participants were excluded if they met any of the following criteria: severe hepatic impairment; hypersensitivity to methadone, opium, or their ingredients; pregnancy; severe chronic respiratory disease; head injuries and raised intracranial pressure; biliary tract disease; and consumption of monoamine oxidase inhibitors within the last 14 days prior to the study. 4.2.4 Study settings The trial took place in four private outpatient OST clinics located in Sari- Urban (n=128), Isfahan (n=9), Shiraz (n=15), and Sari-rural (n=52). The recruitment period was July 2017–January 2018, and the data collection was completed in April 2018.   94 4.2.5 Interventions The study assigned patients to either opium tincture (10mg/ml) or methadone syrup (5mg/ml) both manufactured by DaruPakhsh.co, Tehran, Iran using a patient-centred flexible dosing strategy, described in Fig 4.1 (161). In summary, the initial maximum induction dose for participants who entered the treatment were 50 mg and 200 mg for methadone and opium tincture, respectively. Higher doses were allowed as per judgement of the clinician only for patients who were already in methadone treatment in other centres. Medications were prescribed twice daily throughout the study and Subjective Opiate Withdrawal Scale (SOWS) (181), intoxication symptoms and signs, craving, missed doses, and clinician’s judgement of patients’ condition and needs were used to adjust the total daily dose. In the first day, incremental doses were administered under supervision in the morning with a smaller additional dose in the afternoon to determine an initial total daily dose no more than the above-mentioned limits. This dose was then divided equally to two doses which were administered in later days. Afterwards, twenty five percent increments to the total daily dose during the first three days and 10% increments from day four onwards were allowed between the two visits. Participants visited the treatment center twice daily for the first three days, once daily until day 14 except weekends, three times each week for the next 14 days, and once weekly until the end of the follow-up period and one last follow-up visit on day 85 (Table 4.1). They received take-home doses until the next scheduled visit. The study used twice daily dosing for methadone as opposed to the usual once daily dosing for blinding purposes, because opium tincture needs to be ingested twice daily given its shorter half-life. Take-home doses started in both arms on day four for the afternoon dose, day six for the weekend, and day 15 for weekdays. This could influence the   95 retention in methadone arm compared to previous studies arguably in both directions. All medications and assessments were provided free of charge.  4.2.6 Outcomes The primary outcome was retention in treatment defined as a minimum attendance of 70% of the follow-up visits in each phase of the follow-up period (99). Participants were considered “retained in treatment” only if the attended minimum of four out of six visits in the first three days, six out of nine visits in days four to fourteen, four out of six visits in days 15 to 28, and six out of nine visits in days 29 to 85. This method was chosen because in Iran, OST medications are dispensed in the clinic and assessments of this study took place on the days when the medication was dispensed.  The secondary outcome, illicit substance use was assessed using the self-report section of the Addiction Severity Index (147), which was modified to include the substances in the Iranian drug market and urinalysis at the end of weeks 4, 8, and 12 in the follow-up period. During the same visits, point-of-care urine dipsticks, which tested for tramadol, morphine, amphetamine, cannabis, and methadone were also obtained. For AE, the following measures were described for each arm: type and frequency of each AE, number of people who had an AE, total count of AE, number of people who had a serious adverse event (SAE), and total count of SAE. Also, the average dose of opium tincture and methadone was calculated and reported.  4.2.7 Sample size The sample size was calculated following FDA guidelines for non-inferiority trials using the 95%-95% fixed margin approach (182). The study selected a confidence interval procedure   96 using the relative rate of retention in methadone to opium tincture for comparing the primary outcome in two arms. Using the pooled data from a Cochrane systematic review (94), M1 was set at 3.26 with a conservative M2 of 1.25 which corresponded to a 15% reduction in the absolute treatment retention given the 3-month retention rate of 77.7% in the methadone group, based on a systematic review of retention in methadone treatment in low and middle-income countries (96). To clarify, M1 is equal to the entire effect of the active control (methadone in this case) compared to the placebo. M1 is not directly measured in non-inferiority studies and is estimated based on the performance of the active control in previous studies. M2, often a smaller margin with a set equal to a certain proportion of the M1, is then defined as the largest clinically-acceptable difference of the test drug (OT) compared to the active control (182). 4.2.8 Interim analyses and stopping guidelines One interim analysis was conducted and reviewed by the Data Safety and Monitoring Board. Three independent experts reviewed the results in terms of safety and efficacy and recommended to continue the trial without any amendments to the study protocol. 4.2.9 Randomisation: sequence generation and type Participants were randomized with a 1:1 allocation ratio to methadone or OT treatment arms using a stratified randomization block technique with block sizes of two stratified by sex (female/male ratio = 1/9). This was based on the reported gender distribution of the population with opioid dependence in Iran in 2011 (183). Initially, randomization was also stratified based on age distribution, which was later removed to facilitate the recruitment. The randomization list was created using Sealed Envelope Ltd., 2015   97 (https://www.sealedenvelope.com/simple!randomiser/v1/lists [Accessed 17 June 2017]; seed number: 276524980879508). None of the individuals involved with conducting the trial were aware of randomization details. 4.2.10 Randomisation: allocation concealment mechanism and implementation To conceal the allocation, the randomization list was uploaded on the trial website (metopitrial.ir), which was then used for both allocation and dispensing of medication. Study pharmacists oversaw obtaining of the randomization codes and dispensation of the medications, and were not involved in the study assessments.   4.2.11 Blinding The patients, investigators, treatment team (except pharmacist), and assessors were only aware of the randomization code for each participant, but not the allocation label or randomization tables. An essence was added to methadone syrups to make them similar to opium tincture in terms of smell, color, and taste. Randomization and allocation concealment could be broken in the emergency situations at the discretion of the responsible physician.  4.2.12 Similarity of interventions Given the differences in the potency and the allowed maximum dose for methadone and opium tincture at the beginning, doses were reported in units (0.5 ml of methadone 5 mg/ml and 1 cc of opium tincture 10 mg/ml) to avoid unblinding of assessors based on the patients’ reported or received dose at each visit, particularly the initial visits, when the maximum allowed doses were different for the two arms.    98 4.2.13 Statistical methods For primary outcome analysis, confidence interval procedure was used to compare relative retention rates using one-sided 90% confidence intervals. The null hypothesis was rejected if the upper bound of the CI ruled out the non-inferiority margin (M2 = 1.25). Retention in treatment was illustrated using Kaplan-Meier survival curves, compared with the log-rank test. Days in treatment until drop-out or completion of the 12-week follow-up period were taken to calculate the cumulative retention in treatment.  4.2.14 Additional analyses   Baseline characteristics of participants in both groups were described as mean (SD) for scale and frequency (percentage) for categorical variables. The following ad hoc analyses were performed: 1) the total number of patients in the per-protocol sample who experienced AEs was compared between the two arms using Fisher’s exact test, 2) percentages of follow up visits in which participants in the per-protocol sample reported any illicit opioid use were calculated for each arm and the rate difference was compared between the two arms using a confidence interval procedure assuming non-inferiority of the opium tincture to methadone. The Cochrane systematic review which compared methadone with no treatment showed 127 self-reported heroin use out of 344 participants (36.9%) in methadone as compared to 256 out of 338 participants (75.7%) in no treatment group. Although the pooled risk difference was not calculated formally due to heterogeneity of data, this yields a risk difference of 38.8%, 95% CI [32.0%, 45.7%]. The M1 was therefore considered 32% for the comparison of the self-reported substance use in this study and M2 was set at 10%. Although this was planned post hoc, previous studies have used a similar procedure with an M2 non-inferiority margin of 10-15% (163,184),   99 yet results must be interpreted with caution. Self-reported illicit substance use was only reported for the duration before dropping out of the treatment and the percentage of missing values was reported for the attended visits.      100  Results 4.3.1 Participant flow The study randomized a total of 102 participants to each arm. In each arm, one participant dropped out of treatment before receiving any study medication. Intention-To-Treat (ITT) and Per-Protocol (PP) analyses of the primary outcome were performed for 204 and 202 participants, respectively. See the Consort Flow Diagram (Fig 4.2).  4.3.2 Baseline data Baseline characteristics of participants are summarized in Table 4.2. A more detailed description of the sample is provided in Chapter 4.  4.3.3 Numbers analyzed The follow-up period was 12 weeks. Participants were followed for a mean duration of 57.9 (35.6) days (mean follow-up period was 53.6 (37.7) in opium tincture and 62.2 (33.0) days in methadone arms). For the primary outcome (retention in treatment), all 102 participants who were randomized to each arm, were included in the intention-to-treat analysis. Per-protocol analysis was performed for 101 participants who at least received one dose of the assigned medication. No participant switched treatment arms in the trial.  Out of 204 randomized participants, 131 (70 in methadone arm and 61 in opium tincture arm), 127 (69 in methadone arm and 58 in opium tincture arm), and 126 (67 in methadone arm and 59 in opium tincture arm) were present at the follow-up visits 22, 26, and 30, when the   101 Addiction Severity Index and urinalysis were administered. Data of the case report forms and collateral information from follow-up phone calls for those who dropped out of treatment were used to document all AEs. For the average dose calculation, all 101 participants who received a minimum of one dose were included in the analysis. Data on the dispensed medication dose were available for all the 4594 possible observation points (2445 in methadone arm and 2149 in opium tincture arm). 4.3.4 Outcomes and estimation A total of 70 participants (68.6% in ITT and 69.3% in PP analyses) in the methadone group and 61 participants (59.8% in ITT and 60.4% in PP analyses) in the opium tincture arm remained in treatment until the end of the 12-week follow-up period. This is compared to 74 (72.5%) and 63 (61.8%) participants who only attended the last follow-up visit. The relative retention rate of methadone to opium tincture at the end of this 12-week study was 1.15, 90% CI [0.97, 1.36] in both ITT and PP analysis. Hence the upper bound ruled out M1 (3.26) but not M2 (1.25). The former translates to opium tincture being a clinically effective medication presumably if compared to placebo, but the latter indicates that study was not able to make any conclusions if it was non-inferior to methadone in retaining participants in the treatment using the predefined clinical not-inferiority margin (M2) (See Fig 4.3).  4.3.5 Ancillary analyses Table 4.3 summarizes the results of illicit substance use at follow up visits V22, V26, and V30. These results were the same for intention-to-treat and per-protocol samples. Table 4.4 shows the self-reported opioid use at visits 22, 26, and 30. In this analysis, 46 out of 152 (30.3%)   102 responses were positive in the opium tincture arm and 83 out of 168 (49.4%) responses were positive in the methadone arm. The difference in these two proportions (opium tincture - methadone) was -19.0%, 90% CI [-28%, -10%], negative sign meaning in favor of opium tincture, which not only ruled out the non-inferiority margin of +10% but also indicated superiority of opium tincture to methadone (See Fig 4.4).  Survival curves were drawn to illustrate the trend of drop-out in both arms (See Fig 4.5). The comparison of ITT and PP curves using log-rank test yielded p values of 0.12 and 0.11, respectively. The calculated average daily dose for opium tincture and methadone in this study were 273.42 mg, 95% CI [245.14 mg, 301.71mg] and 79.53 mg, 95% CI [69.64 mg, 89.42 mg], respectively. Also, the average starting dose was 206.67 mg, 95% CI [194.44 mg, 218.89 mg] for opium tincture and 57.02 mg, 95% CI [52.70 mg, 61.36 mg] for methadone. Maximum average daily doses for opium tincture and methadone were 1078.40 and 341.0 mg daily.  4.3.6 Harm There were 22 AEs (Adverse Events) in the opium tincture arm and three AEs in the methadone arm. The proportion of patients experiencing AEs were nine (8.8%) and two (2.0 %), respectively. There were no SAEs (Serious Adverse Events) in the opium tincture and one SAE in methadone arm. There were no fatality or respiratory arrest in either of the two arms. One allergic reaction to opium tincture required intervention (betamethasone and chlorpheniramine injection) and was managed on an outpatient basis. In the methadone arm, there was one case of hospital admission due to a seizure related to the patient’s underlying epileptic disorder. However, it was discerned that the patient had used the provided weekly take-home dose of methadone over 1–2 days, which raised the question of an overdose. In addition, use of illicit   103 tramadol is also a common reason for seizure among patients in OST in Iran. In this case, the exact underlying reason for the patient’s admission to hospital could not be ascertained. There was a non-significant difference in the proportions of patients who experienced AEs between the two arms (Fisher’s exact test p = .06). Table 4.5 illustrates type and frequency of adverse events.    104  Discussion 4.4.1 Interpretation This is the first randomized clinical trial to study opium tincture for OST of opioid dependence. The results remained inconclusive as to whether opium tincture was non-inferior to methadone for OST because the calculated confidence interval for relative retention rate of methadone to OT (0.97, 1.36) did not rule out the non-inferiority margin M2 (1.25). It is still unclear whether the somewhat lower retention of opium could be clinically acceptable due to other potential advantages such as cultural acceptability. The results showed that opium tincture was an effective medication for retaining patients in OST because the calculated confidence interval for relative retention rate of methadone to OT (0.97, 1.36) ruled out M1 (3.26). This means that opium tincture would have done better than placebo or no treatment if there was a placebo/no treatment arm in this study. To elaborate, the treatment retention for opium tincture was 60% in this study. This is comparable to the far lower retention rates of the control arms, which did not involve OST (e.g. detoxification, placebo), in previous randomized controlled trials. For example, among the seven studies included in a Cochrane systematic review of methadone compared to no treatment, the overall retention rate with no OST ranged between 7%–34% with a pooled retention of 20% across all studies (94).  Retention in the methadone arm, the active comparator, was 67%. In a Cochrane systematic review of methadone compared to no treatment, the retention rate for methadone ranged between 52–86% with an overall pooled retention rate of 72% (94). There is another systematic review that focussed on the retention in OST in low and middle-income countries with the results broken down over the follow up durations. In this review, the three–month   105 retention rates for methadone and buprenorphine were 77.7%,  95% CI  [70.7%, 84.7%] and 74.5%, 95% CI [67.2%, 81.9%], respectively. The 12-week retention rate of methadone arm in our study, 69%, was lower than the assumed 78% rate reported in this review (96).A possible reason for a lower retention rate of methadone in our study could be the bitter taste of methadone resulting from the addition of the added essence for the blinding purpose. Another reason is the stricter definition of treatment retention in this study; however, the retention rate in methadone only increased slightly (n = 74 [72.5%] vs. n = 70 [68.6%]) if last visit was considered the last day of treatment retention. Long list of assessments in the study was an obstacle for participants and they might have dropped out to avoid such long assessments. Also, free medications in the study could serve as an incentive for participants to remain in the study; however, methadone is currently widely available in the grey market of Iran at a decreasing price, which could reduce the strength of this financial incentive.  Daily witnessed ingestion of the medication observed by the clinical staff or pharmacist or self-reported ingestion of the medication are alternative methods for determining retention which could yield slightly different results. The former probably resulted in a lower retention and the latter in a higher retention rate. Also, a stricter definition of the attendance rather the last attended visit to determine retention in treatment may have decreased the reported retention rate. Nonetheless, the reported retention rate in methadone arm in this study was lower (69%) compared to previous studies (78%) (96).  Given its effectiveness, compared to placebo in retaining participants in OST, opium tincture will remain a clinically viable OST in the future. However, further studies are required to provide further evidence about the comparison of opium tincture with standard agonist treatments such as methadone or buprenorphine.    106 OT was more effective than methadone concerning the reduction of use of illicit opioids.  In the three major follow up visits and among participants who self-reported their drug use outside treatment, 21–36% in the OT group (9%–22% missing) and 41–61% in the methadone group (12%–21% missing) endorsed opioid use outside treatment. Pooled together, participants endorsed illicit opioid use in 30% of encounters in the OT arm compared to 49% in the methadone arm. Methadone and opium and its derivatives were the most commonly reported used illicit opioids during the follow up period. To put this in context, in the Cochrane systematic review comparing methadone with no OST, the rate of self-reported heroin use ranged between 17%–73% in the methadone arms and 61%–100% in the control arms. OT may have been more effective in reducing illicit opioid use because of the similarity of OT to the primary opioid of choice in Iran, opium. Similar to heroin assisted treatment, the shorter time to peak plasma level of morphine compared to methadone may be related to stronger subjective euphoria, diminishing craving for short-acting opioids on top of methadone.  There are several limitations to this finding: 1) a significant number of patients in opium tincture arm were using methadone outside of treatment (45–53% positive UDS in different visits) and about 6–9% of patients in the methadone arm had a negative urine drug screen for methadone. This may dilute the comparison of OT and methadone. However, using illicit methadone ‘on top’ and diversion of methadone by patients in treatment are inevitable and recognized realities of opioid dependence and OST (91), 2) self-report of substance use is different from the actual use of substances outside treatment, best captured by a combination of subjective (self-report) and objective measures like urine drug screen. The validity of the latter was compromised in this study due to due to the cross-reactivity of opiate urinalysis with opium tincture. For instance in this trial, in visit 26 (week 8), only 10 out of 48 (20.8%) participants in   107 OT arm who self-reported their use, endorsed the use of opioids outside treatment in the opium tincture arm and at the same visit, 24 participants (45.3%) had a urine drug screen positive for methadone. This may indicate a an under-reported opiate use outside the treatment; however, it is noteworthy that opiate urinalysis is also subject to both false-positive and false-negative results. In summary, the decrease in illicit opioid use in the opium tincture arm is a very interesting finding that can be attributable to its different pharmacological profile or its similarity to the opioid of choice in Iran. The investigators of this study are currently examining the possible associations between the patients’ opioids of choice and their treatment success.  We therefore recommend caution with interpreting this finding until it will be replicated in future studies ideally in more controlled settings such as inpatient or in the setting of daily-witnessed OST in a jurisdiction where opium and its derivatives are not the opioid of choice. A total of 22 AEs was observed in the OT arm compared to three in the methadone arm and there was a non-significant difference in the proportions of participants who reported AEs between the two arms (P = 0.06). Nausea, headache, and restlessness were the most commonly reported adverse events with OT. Most of the AEs occurred in the initial visits and collateral information from the study nurse indicated that some were due to the use of both morning and afternoon doses of OT together. This behaviour was not continued throughout the follow-up period as patients were informed to avoid taking AM and PM doses altogether. Also, when compared to previous studies of OST and the prevalence of side effects for methadone (163), a higher number of AEs were expected. As there were a higher number of AEs observed in the OT arm, this calls for a close monitoring and documentation of AEs with OT OST. It was reassuring though that no major AE was observed with opium tincture.    108 The average daily dose for methadone in this study was 79.53 mg, 95% CI [69.64 mg, 89.42 mg], which is in line with practice guidelines endorsing a starting dose of 30–40 mg with a subsequent maintenance dose of 60–120 mg for OST with methadone (185). The average OT dose in this study was 273.42 mg, 95% CI [245.14 mg, 301.71mg], which was guided by patients’ needs and symptoms based on clinician’s judgement. However, on a closer look, about 50% of patients in the OT arm were using illicit methadone. In addition, a 60–120 mg daily dose of methadone is interpreted to a minimum dose of 405–450 mg morphine equivalent using the conversion ratios in OST for (slow-release) morphine to methadone (186). Average OST dose for slow-release oral morphine with the same active ingredient is 506.8 mg/day (97). Therefore, a higher dose may be required to achieve a better control of symptoms and improve the outcomes with OT. In addition, twice daily dosing was selected in this trial based on the previous studies (131) and the current practice guideline for opium tincture in Iran (187). The active ingredient in OT, morphine, has a relatively short half-life. However, the active metabolite morphine–6–glucoronide has a longer half-life and may contribute to the long-term effects of OT along along with other alkaloids contained in the tincture. However, this additional effect may not be significant because only about 10% of morphine is converted to this active metabolite and its half-life is approximately about 6-8 hours (188).  It is noteworthy that, through personal communication with physicians prescribing opium tincture, a number of patients who were taking OT appeared to divide their take-home doses themselves and take them every 3–4 hours, which may indicate suboptimal treatment with twice daily dosing. Therefore, individualized and more frequent dosing of OT up to four or five times daily may improve the outcomes of OST with OT. Furthermore, given the fact that about half of participants in the OT arm used illicit methadone, the provision of a baseline dose of methadone supplemented with additional doses of   109 OT may be a successful treatment strategy for hard-to-treat patients. Such a pattern would be similar to the provision of baseline methadone with additional injectable opioids in injectable OST (99). In summary, more frequent dosing in the day and higher doses than in the current study may improve the treatment outcomes of OST with OT.    4.4.2 Limitations Our study has a number of limitations. First, the majority of participants did not attend the follow-up assessments after discontinuing the treatment. As a result, data for these participants were not available after dropping out of the treatment. In addition, despite all the efforts (follow up phone calls and reaching out to next of kin only with patient’s consent) to follow participants till the end of the 12 weeks, this study was not able to discern the reason for the treatment drop-out in all patients and also was not able to collect follow up data on the majority of participants after they dropped out of the treatment. Second, after trial initiation, sample size had to be reduced to 204 from 240 due to the limitation in the resources. However, the calculated power of the study was kept above 80%, which is still acceptable. Third, the non-inferiority margin for self-reported opioid use as a secondary outcome was not set a priori. However, given the superiority of OT over methadone in this outcome, this did not impact the findings. Fourth, a significant number of participants in the OT arm were using illicit methadone. Also, fewer than 10% of participants in the methadone arm had negative urinalysis for methadone at each visit, which can indicate some patients were not taking the methadone consistently. This made differentiation of the effect of OT and methadone challenging. Although, the specificity of urine test for opioids including methadone is less than perfect (189). Fifth, missing data in the study may have resulted in some levels of imprecision in our findings. This   110 occurred despite all the efforts of the research team to minimize the missing datain these vulnerable and sometimes difficult-to-engage participants. Finally, the majority of participants, 76%, were able to correctly guess the type of treatment they were receiving. This indicated that many participants may not have been blind to the treatment arm. This could also have been due to the differences in the subjective euphoric effects of the medications.  4.4.3 Generalisability Opium (and its derivatives) is both often the opioid of choice in Iran and the active ingredient of OT. This may result in better outcomes of OST with OT in Iran compared to other parts of the world, where heroin or prescription opioids are more widely used. To make dosing strategies similar in two arms and improve blinding, both methadone and OT were prescribed twice daily. This dosing strategy may have decreased medication compliance. To mitigate this, take-home doses for the afternoon were offered from day 4 onwards. However, some participants took the afternoon doses earlier in the day possibly increasing the rate of side-effects in the OT arm. Definition of the retention in treatment in this study used the proportion of participation in all the visits throughout the study rather than only looking at a certain number of visits closer to the end of the follow up period. This method was chosen because it provided a more complete and accurate account of how much participants benefited from the OST. However, this method may decrease the retention in treatment when compared to prior methods. Medications and other interventions were offered at no cost in the study and an honorarium was provided for participation in the follow up assessments. These may have increased the retention in treatment when compared to the real-world situation. It is worth mentioning that opium is the most common opioid of choice among patients with opioid use disorder in Iran. This may affect the   111 response to opium tincture for OST and needs to be considered when generalizing the findings of this study. An advantage of this study is purposely recruiting female participants to represent the sex ratio in population of patients with opioid dependence in Iran.   112  Tables and figures Figure 4.1 Dosing strategy for treatment with opium tincture or methadone in patients with opioid dependence, where one unit of medication is equal to 1 ml of opium tincture or 0.5 ml of methadone. a) day 1, morning b) day 1, afternoon c) day 2-3 d) day 4-84.    113 Figure 4.2 Consort flow diagram      114 Table 4.1 Frequency and contents of visits during the 12-week follow-up period in the opium trial. Activity Visit order Day 1- 3   End of 1st week       End of 2nd week    End of 3rd week    Start of 5th week     Start of 9th week     Final visit (Day 85)  1 2 3 4 5 6 7  8  9  10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 Document dispensed dose × × × × × × × × × × × × × × × × × × × × × × × × × × × × × × Adverse event Report Form × × × × × × × × × × × × × × × × × × × × × × × × × × × × × × Addiction Severity Index-5th edition                      ×    ×    × Urine toxicology1                      ×    ×    × 1 Methamphetamines, THC, and morphine, tramadol, and methadone     115 Table 4.2 Baseline characteristics of participants in the opium trial in both opium tincture (N=102) and methadone (N=102) arms.  OT (N=102) N (%) Methadone (N=102) N (%) Age (yrs.) [Mean (SD)] 37.7 (9.5) 37.2 (9.3) Sex (female) 11 (10.8) 12 (11.8) Married 68 (68.0) 62 (61.4) Secondary school or higher education 50 (50.0) 57 (56.4) Homeless 1 (1) 1 (1) Employed 56 (56.6) 66 (67.3) Lifetime history of incarceration 25 (25.3) 26 (26.8) Lifetime overdose 13 (13.3) 5 (5.0) Lifetime injection 8 (7.8) 6 (5.9) Past 30 days self-reported use of:   Alcohol 16 (15.8) 6 (5.9) Opioids 95 (95.0) 97 (95.1) Amphetamine type stimulants 32 (31.4) 31 (30.4) Cannabis 11 (11.0) 13 (12.9) Benzodiazepines 23 (22.5) 16 (15.7) Positive urine drug screen for:   Tramadol 3 (3.3) 12 (12.6) Methamphetamine 41 (43.6) 36 (37.5)   116  OT (N=102) N (%) Methadone (N=102) N (%) Cannabis 13 (14.0) 10 (10.6) Morphine 81 (82.7) 68 (69.4) Methadone 66 (66.7) 76 (77.6)      117 Figure 4.3 Relative retention rate of methadone arm compared to opium tincture.       118 Table 4.3Substance use outside treatment during the follow-up period of the opium trial at visits 22, 26, and 30.  Visit 22 (N = 142) Visit 26 (N = 133) Visit 30 (N = 126)  OT  (N = 64) Methadone (N = 78) OT  (N = 62) Methadone (N = 71) OT (N = 59) Methadone (N = 67)  N (%) N (%) N (%) N (%) N (%) N (%) Self-report Alcohol 7 (12.1) 4 (5.8) 4 (7.7) 4 (6.7) 1 (2.2) 4 (8.5) Heroin 1 (1.7) 6 (8.8) 1 (2.0) 3 (5.1) 2 (4.3) 5 (10.6) Opium 7 (12.1) 8 (11.9) 2 (4.0) 8 (14.5) 7 (14.3) 8 (18.6) Methadone 9 (15.3) 11 (15.9) 4 (8.0) 17 (28.8) 7 (15.2) 20 (40.8) Shireh/Sukhteh 7 (11.9) 8 (12.1) 4 (7.3) 10 (15.6) 3 (6.7) 7 (14.9) Crack heroin 0 (0) 0 (0) 0 (0) 1 (1.7) 0 (0) 1 (2.2) Tamjizak/norjizak 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Barbiturates 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Benzodiazepines 7 (11.9) 7 (10.0) 4 (7.7) 3 (5.1) 5 (10.9) 4 (8.3) Cocaine 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Amphetamines 10 (17.5) 17 (25.0) 10 (19.2) 18 (29.0) 9 (19.6) 15 (29.4) Cannabis 1 (1.7) 4 (5.9) 1 (2.0) 7 (11.7) 1 (2.2) 5 (10.6) Urine drug screen Tramadol 1 (1.8) 3 (4.6) 2 (3.8) 7 (12.3) 4 (7.3) 6 (10.7) Methamphetamine 23 (39.0) 21 (30.4) 14 (26.4) 18 (30.0) 19 (33.9) 19 (33.3) Cannabis 3 (5.5) 5 (7.6) 2 (3.8) 6 (10.5) 2 (3.6) 6 (10.3) Morphine 54 (91.5) 36 (52.9) 51 (94.4) 29 (48.3) 51 (87.9) 27 (45.0) Methadone 32 (53.3) 66 (91.7) 24 (45.3) 60 (93.8) 26 (45.6) 57 (91.9)   119 Table 4.4 Self-reported use of opioids in the past 30 days in follow-up visits 22, 26, and 30 in the opium trial.  Visit 22 Visit 26 Visit 30 Self- reported opioid use  Total  OT  Methadone Total  OT  Methadone Total  OT Methadone  N = 142 N = 64 N = 78 N = 133 N = 62 N = 71 N = 126 N = 59 N = 67 N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) Yes 48 (33.8) 21 (32.8) 27 (34.6) 38 (28.6) 10 (16.1) 28 (39.4) 43 (34.1) 15 (25.4) 28 (41.8) No 76 (53.5) 37 (57.8) 39 (50.0) 66 (49.6) 38 (61.3) 28 (39.4) 49 (38.9) 31 (52.5) 18 (26.9) Missing 18 (12.7) 6  (9.4) 12 (15.4) 29 (21.8) 14 (22.6) 15 (21.2) 34 (27.0)  13 (22.1) 21 (31.3)      120 Figure 4.4 Comparison of self-reported opioid use in follow up visits 22, 26, and 30 in the opium trial.       121 Figure 4.5 Survival analysis illustrating the trend of retention in treatment between methadone and opium tincture arms. Intention-to-treat sample  Log-rank p= .12  Per-protocol sample  Log-rank p= .11     122 Table 4.5 Type and frequency of adverse events in the opium tincture and methadone arms of the opium trial. Type of adverse event OT (N=102) Methadone (N=102) Nausea 7  Constipation 1  Headache 3 1 Allergic reaction 1  Rhinorrhea 1  Dizziness 1 1 Scalp pruritis 1  Urticaria 1  Restlessness 3  Drowsiness 1  Seizure  1 Unknown (drop-out) 2  Total  22 3    123 Chapter 5: Conclusion  Summary of introduction  Opioids, encompassing any chemical compound with morphine-like activity, have been known and used by people for thousands of years (9). Initially utilized for both medicinal and recreational purposes, their widespread use throughout the 18th and 19th centuries (in parallel with the invention of several potent opioids, like heroin, and the emergence of hypodermic syringes and hollow needles for injection in the 19th century) was increasingly regarded as a problematic social issue. As a result, international treaties and conventions in the 20th century were set up to dictate an approach, mostly based on the prohibition and criminalization of opioid use (17–19). Despite all of these international efforts to get rid of opioids, among other drugs, humans have never come close to the goal of a “drug-free world”. In fact, these efforts and naturalistic experiments have often proven to be counterproductive, escalating a multitude of harms related to opioid use. In contrast, certain states which have taken a different approach, relaxing prohibition laws and focussing on treatment and harm reduction measures, seem to have achieved better overall outcomes (19,23,25,26).  An estimated 1.16% (57.8 million people) and 0.61% (30.4 million people) of the global population aged 15–64 used opiates and opioids respectively at least once in 2018 (31). GBD study using a different methodology estimated the age-adjusted prevalence of opioid dependence at 510 per 100,000 population (40.5 million cases) in 2017 (23). Although second to cannabis in terms of prevalence, opioids rank first in terms of morbidity and mortality and, along with other drugs, they account for a significant burden of global disease, due to their egregious health consequences such as viral infections (HIV, HCV, and HBV) and overdose (2). Currently,   124 opioids are the culprits behind two major public health challenges around the world: the alarming rate of tramadol use among youth in West, Central, and North Africa as well as the tragic rate of mortality due to opioid overdoses across North America (2). The successful treatment of opioid dependence requires attention be paid to the complex and wide-ranging needs of patients, including the concurrent use of other substances, concurrent mental illnesses, medical comorbidities and their related harms, and patients’ social, residential, vocational, financial, and legal problems (50). Besides OST, the treatments available for opioid dependence can be categorized as withdrawal management, long-term treatment with naltrexone, psychosocial interventions, and harm reduction measures including (but not limited to) the distribution of naloxone kits and the provision of safe consumption facilities and needle exchange programs. There is a huge treatment gap for substance use disorder (only one out of every eight people with substance use disorder has access to a form of treatment); this figure drops to just 7.1% for ‘minimally effective’ treatment, which is subject to further substantial inequality across the world, with only 1% of patients in low-to-lower income countries accessing such treatment for substance use disorder (56). Opioid substitution treatment is a key part of the care plan for patients with opioid dependence. The term ‘methadone maintenance treatment’ was first coined in the early 1960s and the intervention underwent its first clinical trial between 1971 and 1976 (91). It became increasingly common to use OST to treat opioid dependence, owing to its role in addressing two major public health challenges in the late 20th century: the dramatic increase in the number of people who used heroin in Europe in 1980s and the HIV epidemic in the 1990s (91). Currently, OST has expanded beyond the use of methadone racemate alone and includes a range of medications such as Polamidone (the active isomer of the racemate), buprenorphine and its   125 combination with naloxone, slow-release oral morphine, Opium tincture, and injectable forms, heroin, hydromorphone, and codeine. A growing body of evidence demonstrates that in addition to alleviating craving and withdrawal, OST improves a multitude of treatment outcomes among patients with opioid dependence: retention in treatment (94–100), the use of substances outside treatment (94,95,97–99), high-risk behaviours (injection and sharing needles) (101,104,105), psychological health (114,115), physical health (particularly the incidence of HIV (101,102) and HCV infection (103)), quality of life (115), overdose (118,120), suicide (120), and all-cause mortality (23,94,118,120). 5.1.1 The case of Iran The area now known as Iran was among the first places in the world in which opium was used (8). Historically, opium use has been deeply rooted in Persian culture and medical practices (190). The production and availability of opium in Iran has varied throughout history as a result of the changing political and economic climate (8). Following the global trend, the production, trade, and consumption of opium and its products were all prohibited in Iran in 1955 (8,190). The Iranian Revolution in 1979 took this further and launched a zero-tolerance criminalizing approach to all forms of opium cultivation, possession, use, and trafficking in the country (29). This approach drastically limited the availability of any sort of treatment for substance use, and it remained in force until 1994 (27,30,77,124). The UNODC’s best estimates for the annual prevalence of opioid and opiate use in Iran were 3.0% (2011) and 3.3% (2015), the latter being the highest reported prevalence of opiate use in the world (2). Iran also had the highest rate of opioid seizures in the world (644 tons of opium, 21 tons of morphine, and 25 tons of heroin) in 2018 (2). The official 2011 statistic for the 12-  126 month prevalence of opioid dependence in Iran was 2.2% (41). The population of patients with opioid dependence in Iran can be characterized as predominantly male, married, and employed individuals whose most common opioid of choice is opium and its derivatives (37–42). Opioid use and dependence are a significant burden on the Iranian healthcare system. In 2017, according to a GBD study, opioid dependence contributed to a total number of 791,339 lost DALYs (corresponding to 3.88% of total lost DALYs) in Iran (20,376,961) (36). It is estimated that around 260,000 people inject drugs in Iran (43) and that the prevalence of HIV, HCV and HBV is 13% (43), 47% (44) and 4.9% (45) respectively among this population. Lead poisoning, due to the adulteration of street opium, is a less commonly documented harm related to opioid dependence in Iran (46–48), with case reports of egregious consequences such as unnecessary laparotomies (49).  According to the Iranian Mental Health Survey, among patients with opioid dependence, 59% and 29% reported ‘any service use’ and ‘any healthcare service use’ respectively in the past 12 months (41). The treatment of drug use in (post-Revolution) Iran only began in 1994 after a legislative change in Iranian law exempted patients with substance use disorder in treatment centres from prosecution (77). The forms of treatment currently available in Iran are OST (27,30,41,124), withdrawal management (78,79), ultrarapid detoxification (77,80,81), oral naltrexone (77,82), various forms of psychosocial interventions including peer-based programs like NA (30,77,83,84), and harm reduction measures such as needle and syringe exchange programs (27); these services can be accessed in various different settings such as private and public treatment clinics, drop-in centres (27,85), and triangular clinics (27), and through different institutions and organizations such as outreach teams, women-only drug treatment and harm reduction services (86–88), prisons (27,30), NGO-based programs (27,30,84,89,124), and   127 residential treatments (27,30,124). Compulsory residential treatment settings, also known as ‘camps’, are a controversial and criticized aspect of the treatment for opioid dependence in Iran (90). Traces of OST in Iran date back to the spring of 1968 when the government of Iran embarked on a new program to provide regulated opium to opium-dependent individuals, over 60 years of age, who were presumed unfit to undergo detoxification and rehabilitation due to their frailty (122). By 1975, around 185,000 registered clients with opioid dependence were registered in the program (123); However, the Revolution put an end to this treatment-based approach to drug use, and all of the voluntary treatment programs were gradually closed down for almost 15 years (124). Substitution treatment was only reinstated as part of the care for patients with opioid dependence in 2002 (124), when the first substitution program with methadone was piloted in Iran (77). This was followed by buprenorphine in 2006 (124), and OT in 2010 (30,124). As of March 2018, there were about one million patients in OST (including 11-month treatment with OT) in over 7,000 public and private centres (97.3% private centres) as well as in prisons across the country (124). The medications offered in OST centres were methadone (78%), buprenorphine (12%), and OT (10%) in the order of frequency (124). The OT number pertains to both forms of long-term treatment with OT: OST and the model used in Congress 60 with gradual tapering over a period of 11 months (124).  Summary of chapter 2: systematic review (131)  Given the growing interest (prior to 2016) in using OT to treat opioid dependence in certain regions of the world, a systematic review aimed to assess the evidence regarding its safety and efficacy. The last search was run on February 31, 2016 with no language limitations,   128 and two reviewers selected RCTs, cohort/case-control/cross-sectional studies and case series on the safety or efficacy of OT for treating opioid dependence before extracting the reported measures of mentioned outcomes from these selected studies. The Effective Public Health Practice Project Quality Assessment tool (135) was used for the appraisal of the selected articles.  Nine studies were selected; in three RCTs and one cohort analytical study on detoxification, 110 patients were treated with 15-140 morphine equivalents/day (mEq/d) of OT; in four prospective and one retrospective uncontrolled case series on long-term/maintenance treatment, 570 patients were treated with 100-400 mEq/d of OT. Only the two studies on detoxification included a comparison: one concluded the equal efficacy of OT and methadone in suppressing withdrawal symptoms (p= .32), and the other concluded that OT was less efficacious than buprenorphine/naloxone in suppressing withdrawal (OT = 12.20, 95% CI [11.00, 13.40]; control = 5.20, 95% CI [4.69, 5.71] and craving (OT = 303.0, 95% CI [-144.664, 750.664]; control = 0.0), though not significantly different (p= .26) with regards to retaining participants in treatment. No major AEs were reported.  In conclusion, although a few existent studies showed promising results when assessing the safety and efficacy of OT for treating opioid dependence—especially for detoxification—it was not possible to make conclusive recommendations at the time. Thus, future clinical trials were recommended to provide adequate evidence about the safety and efficacy of OT for treating opioid dependence, particularly for OST.  Opium trial    In the next step, a randomized clinical trial (the opium trial) was designed to compare the safety and efficacy of OT with methadone for the treatment of opioid dependence. In this   129 multicenter, double-blind, non-inferiority, controlled trial, participants with opioid dependence were recruited from community outreach programs, drop-in centers, and triangular clinics. Participants were excluded in the case of hypersensitivity to trial medications, pregnancy, and certain serious medical conditions. Between July 2017 and January 2018, a total of 204 participants (128 in urban Sari, 52 in rural Sari, 15 in Shiraz, and 9 in Isfahan were recruited for the trial. Participants were then randomized to receive either OT or methadone with an allocation ratio of 1:1 using a patient-centered flexible dosing strategy. Eligible participants were followed for a period of 12 weeks. The primary outcome was the difference in the proportion of patients retained in the treatment. Secondary outcomes were craving, withdrawal symptoms, physical and mental health, quality of life, severity of substance use problems, cognitive function, safety profile, cost-effectiveness, and participants' satisfaction. Both ITT and PP analyses were conducted.  Summary of chapter 3: patterns of substance use among patients with opioid dependence in Iran.   In the next stage of the research, a study used the data from the opium trial to assess the pattern of substance use among participants at baseline from a sample of treatment-seeking patients with opioid dependence in Iran. The study also compared the characteristics of participants between urban and rural centres. Baseline assessments involved ASI–5, blood tests, urine toxicology, and a sociodemographic questionnaire. With regards to lifelong substance use (excluding nicotine), the highest numbers were reported for opium (82%), Shireh/Sukhteh (72%) and methadone (69%). Lifelong polysubstance use, overdoses, and injections were reported by 76%, 9%, and 7% of participants respectively. Urban centers reported a significantly higher   130 proportion of heroin and methamphetamine use, but also lower rates of opium use, than the rural centre. Moreover, participants in urban areas demonstrated a higher proportion of overdoses in their lifetimes (12% vs. 0, p= .01) but lower unemployment (18% vs. 45%, p < .01) and incarceration rates (14% vs. 30%, p= .02) in comparison to the rural centre. In conclusion, after comparison with international samples, patterns of substance use and related risky behaviours were significantly different between Iran and other regions. They also differed between rural and urban areas. This finding suggested that the optimal treatment of opioid dependence may require tailoring the approach to these jurisdictional differences.  Summary of chapter 4: comparing opium tincture with methadone for opioid substitution treatment. Using the data from the opium trial, the next step aimed to assess if OT was non-inferior to methadone at retaining participants in OST.  Retention in treatment was the primary outcome and self-reported opioid use was measured by ASI every 4 weeks. In addition, the occurrence of AEs was also compared between the two arms. Although an essence was added to the methadone syrups to make them similar to OT in terms of smell, color, and taste, the majority of participants (76%) were able to guess their treatment assignment correctly, therefore the study was not completely blind.  Intention-To-Treat and Per-Protocol analyses of the primary outcome were performed for 204 and 202 participants respectively. The average daily doses for OT and methadone in this study were 273.42 mg, 95% CI [245.14 mg, 301.71mg] and 79.53 mg, 95% CI [69.64 mg, 89.42 mg], respectively. A total of 70 participants (68.6% in ITT and 69.3% in PP analyses) in the methadone arm and 61 participants (59.8% in ITT and 60.4% in PP analyses) in the OT arm   131 remained in treatment at the end of the 12-week follow-up period. The relative retention rate of methadone to OT was 1.15 (0.97, 1.36) and 1.15 (0.97, 1.36) in both ITT and PP analysis; hence, the upper bound ruled out M1 (3.26) but not M2 (1.25). For opioid use outside of treatment, 46 out of 152 (30.3%) responses were positive in the OT arm and 83 out of 168 (49.4%) responses were positive in the methadone arm.  The difference in these two proportions (OT-methadone) was -19%, 90% CI [-28%, -10%]. There were 22 AEs in the OT arm and three AEs in the methadone arm; the proportion of patients experiencing AEs were nine (8.8%) in the OT arm and two (2.0 %) in the methadone arm. There was no serious AE in the OT arm. There was a non-significant difference in the proportion of patients who experienced AEs between the two arms (p= .06).  In conclusion, OT proved to be a clinically effective medication; however, this study could not conclude if OT was non-inferior to methadone at retaining participants in treatment. OT was better than methadone at reducing opioid use outside of treatment; however, this must be interpreted cautiously given the acknowledged limitations (see the discussion section in Chapter 5). Although a high number of AEs was observed in the OT arm, the difference in the number of people with AEs was not statistically significant. No major AE was observed in the OT arm.   Significance This research provided evidence regarding the treatment of opioid dependence, which is of the utmost importance now, given the significant global burden of this condition and the tragic number of deaths resulting from overdoses across the world (particularly in North America). Iran is a key place for this type of research, as it has the highest rates of opiate dependence and opioid seizure in the world, neighbours the major global producer of opium (Afghanistan), and has   132 struggled with the problematic use of opioids for decades. Moreover, the use of opium is deeply rooted in Persian popular and medical culture. Despite the increasing number of publications on opioid dependence coming out of Iran (124), the area remains under-researched due to the ideological, political, and economic sensitivities surrounding the topic.  The introductory chapter provided the context by laying out an overview of the history of opioids and their use, the prevalence of opioid use and its related burdens, the current treatments for opioid dependence, and a more detailed discussion of OST, with additional remarks about Iran at each step, describing the widespread use of OT for OST towards the end. The systematic review was the first study—to our knowledge—to analyze evidence regarding the safety and efficacy of OT in the treatment of opioid dependence, highlighting the related treatment gap. Likewise, the opium trial was the first clinical trial to assess the safety and efficacy of OT in OST, comparing it to the most commonly used medication for OST: methadone. Despite a lack of random sampling, the baseline characteristics of participants in the opium trial were described and compared to international samples to facilitate the generalization of the opium trial’s findings to other contexts and, also, to discuss the broad picture of opioid dependence in Iran in more detail, adding to the body of existing literature on this topic. Furthermore, the trial helped to understand a difficult-to-engage and vulnerable population (i.e., patients with opioid dependence) by administering a comprehensive sequence of assessments. In addition, the trial purposively recruited female patients, who are often under-researched in existing studies on addiction (180). Finally, Chapter 6 strived to provide more context beyond the first two chapters, with personal anecdotes to further contextualize the results of the opium trial.  Beyond the scope of the trial, the relevance of OT to the overall picture of treatment for opioid dependence (discussed in detail in Chapter 6) can be summarized as follows : Firstly,    133 although an under-researched area, the critical role of cultural acceptability has been emphasized in pharmacotherapy for opioid dependence when analyzing the existing practices across different jurisdictions (191); opium tincture is a culturally acceptable medication in Iran, likely due to people’s more positive attitude towards opium, the main ingredient of this medication (129). This may be due to its recurring image in famous Persian literature, its status in Islam as opposed to prohibited alcohol, and its widespread use as a panacea in Iran (129), as in many other parts of the world (192). This was shown in a qualitative study about opium demonstrating the popular belief in the effectiveness of opium when treating a number of chronic medical problems such as premature ejaculation, diabetes mellitus, high blood pressure, and chronic pain (193). More specifically, the attitudes towards OT among patients in treatment with OT were explored in a preliminary qualitative study affirming their positive attitude towards the medication; patients cited reasons such as the chemical nature of methadone as opposed to the herbal nature of OT, methadone dependence, and the long duration of methadone treatment as opposed to the improvements regarding cravings, withdrawal, and general health with OT (130). Although some were misconceptions, these reasons may still contribute to a better uptake of the medication among patients as some participants cited them as their strong motivations for entering treatment. Besides treatment initiation, cultural acceptability may also improve other outcomes such as the rate of retention and satisfaction, allowing for more collaborative engagement with the patient’s family, community, and other stakeholders in the treatment process. Secondly, opium, the main precursor of OT, is widely available in Iran due to the country having the highest rate of global opium seizures (2). This may result in the wide availability and low cost of OT, which can then facilitate the acceptance and endorsement of OT treatment by the stakeholders, eventually advancing the harm reduction agenda in the region. However, during the study period, OT’s   134 retail price was higher than methadone (approximately four times), probably as a result of the addition of ancillary costs—such as those incurred from the seizure of opium—to its retail price, which warrants a a separate, closer economic analysis of the matter. Thirdly, OT can diversify the treatment options for opioid dependence. Compared to other mental illnesses with comparable prevalence, such as depressive or psychotic disorders, the number of pharmacotherapy options for opioid dependence is much more limited (a fact which has practical implications), with only a handful of medications currently available. To elaborate, more treatment options can provide patients with an increased number of choices, which then may help to better engage patients and improve their satisfaction with treatment services. In addition, in the case of side-effects or contraindication to one of the medications, it will equip the care providers with more options to offer to the patients, which may increase the chance of retaining patients in treatment. The aforementioned rationales may also justify (to a variable extent) the use of OT for OST in other jurisdictions, especially those with similar cultural practices and high availabilities of opium, as well as in areas with ethnic minorities who have been displaced or migrated from these regions.  Limitations  The research experienced financial struggles, partly because the structures for research funding in Iran are not accustomed to studies like clinical trials which demand substantial funding. In addition, attracting international funding was extremely difficult for this project due to multiple factors including (but not limited to) the international sanctions on Iran, which made financial transactions with Iran unappealing for donors outside the country. In response, the investigators had to make certain compromises in the study design, such as reducing the sample   135 size within the acceptable methodological framework. Further involvement of the clinical staff and people with lived experiences in the framework of this research could improve the design. A qualitative component in the study provided additional insight and enriched the interpretations.   The limitations of every stage in the research process were acknowledged in each chapter but are also summarized below. The limitations of the systematic review resulted from the small number of available studies; the low quality of existing evidence; the heterogeneity of the interventions in both the OT and the control groups as well as in the methods of outcome measurement; the incomplete reporting of outcomes; the fact that more high-quality evidence related to withdrawal management rather than to OST; the limitation of the results to certain regions of the world; and the omission of female participants. A major limitation of the baseline paper was the fact that the sample was not a representative sample (recruited through random sampling methods) but a convenient sample of treatment-seeking individuals with opioid dependence. However, given the hard-to-reach nature of the population with opioid dependence in Iran, the description of this sample was found to be of merit to the literature. Regarding the opium trial, a larger sample size could determine the non-inferiority of OT compared to methadone; unfortunately, this was not possible due to the aforementioned logistical limitations. Theoretically, a more efficient blinding of participants would have reduced the risk of bias in the opium trial; however, it might be extremely difficult, or even impossible, to blind participants given the differences between the subjective euphoric effects of the two medications. Furthermore, the extensive list of assessments increased the likelihood of study dropouts and missing data despite all of the efforts by the research and clinical staff to minimize the attrition. In addition, poor adherence to the medication in the methadone arm and the illicit use of methadone in the OT arm made differentiating the effects of the two medications difficult,   136 although these are well-recognized realities of OST. The use of self-reporting to measure substance use outside treatment also had its own limitations. However, the urine screen test was not a feasible option in this trial (refer to chapter 5 for the reason). Furthermore, the study’s more relaxed criteria for take-home doses compared with the Iranian national protocol needs to be considered when generalizing the results. Although clinical trials function as the gold-standard for assessing medications prior to their clinical approval, they often tend to provide a controlled setting, one that is different from the real world in many aspects, which can limit the generalizability of their findings.  Future directions  Concerning OST with OT, future trials with larger sample sizes and follow-up periods exceeding 12 weeks are required to test the effects of OT; ideally, these trials would be in more controlled settings such as inpatient clinics or in settings of daily-witnessed OST in a jurisdiction where opium and its derivatives (Shireh, Sukhteh, etc) are not the opioid of choice. The results of such trials can be pooled with the opium trial results to determine the non-inferiority comparison with methadone which was not possible in this study; further analyses of the other outcomes from the opium trial could also provide a more complete picture and a comprehensive comparison of OT and methadone. Furthermore, qualitative interviews with patients receiving OT could enrich the understanding of the effects of this medication. The twice daily dosing strategy was used for OT in this study because previous studies had recommended it; however, given the short half-life of morphine, the active ingredient of OT, further studies are required to optimize the dosing strategy of this medication. It would also be prudent to analyze the characteristics of participants who benefit from OT as opposed to other agonist medications   137 since one size may not fit all in this case. Moreover, it would be important to study the treatment outcomes with OT in other settings, especially regarding the use of OT with an 11-month taper model and its combination with psychosocial interventions in Congress 60.  In a broader sense, other areas of particular interest in the coming years will be the role of culture in the treatment of opioid dependence; predictors and measures to improve the rate of retention in OST; the treatment of concurrent stimulant use disorder in OST; the role of cannabis use and its interaction with opioid dependence and OST given the legalization of cannabis in various jurisdictions; the role of psychosocial interventions in OST; novel treatments such as HEANTOS (194,195); novel forms of treatment such as long-acting naltrexone and buprenorphine; novel methods for induction such as microdosing buprenorphine (196); the close monitoring of the surge in opioid overdose fatalities in other jurisdictions; the role of various disciplines in the treatment of opioid dependence; innovative measures, such as technology-based interventions, to close the huge global treatment gap in the care of opioid dependence; and the feasibility of the wider implementation of established harm reduction measures such as substitution with injectable opioids or safe consumption facilities in Iran.  Concluding remarks  Opioids, one of the most effective medications for pain control, have been around for thousands of years; in more recent human history, they have been the subject of several international conflicts, treaties, and conventions because their widespread use and associated harms, such as overdose and viral infections, can also compromise the functioning of societies. Iran was one of the first places where opioids were known and used and has its own history of social, political, and economic struggles with opioids and their influences. Despite their   138 medicinal use, opioids cause significant morbidity and mortality both in Iran and across the globe. There is a wide range of treatments for opioid dependence, and Iran has continued to adopt several of these interventions at varying speed, depending on the political climate. Opioid substitution treatment is one of the most well documented and evidence-based treatments for opioid dependence, which has shown to improve a multitude of treatment outcomes outcomes for patients. OT is one of the medications which has been used for substitution, and only Iran has been using it for OST on a large scale. This research project first conducted a systematic review and determined that, although a few studies existed assessing the safety and efficacy of OT for treating opioid dependence with promising results (especially for detoxification), it was not possible to make conclusive recommendations at that point. In the following stage, the opium trial compared the safety and efficacy of OT with methadone in the treatment of opioid dependence. A study of participants at baseline showed that, after comparison with international samples, patterns of substance use and related risk behaviours were significantly different between Iran and other regions of the world, as well as between rural and urban areas in Iran itself. The subsequent comparison of outcomes between the two opium trial arms showed that OT was a clinically effective medication, but the study could not conclude if it was non-inferior methadone at retaining participants in treatment; however, OT was superior to methadone when it came to reducing opioid use outside the treatment. Although a high number of AEs was observed in the OT arm, the difference in the number of people with AEs did not reach statistical significance. No major AE was observed in the OT arm. 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J Glob Oncol [Internet]. 2018 Sep 28;4(Supplement 2):192s-192s. Available from: https://doi.org/10.1200/jgo.18.79401   170 Appendices Appendix A. Appraisal of studies included in the systematic review  1. Tabasomi F et al. (138,139) Question Reviewer 1 rating Quote (s) Reviewer 2 rating Quote (s) Final Decision  Selection Bias      Are the individuals selected to participate in the study likely to be representative of the target population? Somewhat likely Zare Hospital in Sari- Mazandaran-Iran, between April and October 2013. 2 -somewhat likely   2 -somewhat likely  What percentage of selected individuals agreed to participate? Can’t tell  1 - 80-100% agree    97 referred for detox treatment to the hospital were screened during study period.  17 did not meet inclusion criteria and 6 declined to participate in study. 74 completed study.  (74/80 = 92.5%)  1 - 80-100% agree  Study design      Indicate the study design Randomized controlled trial  1-Randomized control trial   1-Randomized control trial    171 Question Reviewer 1 rating Quote (s) Reviewer 2 rating Quote (s) Final Decision  Was the study described as randomized? Yes  Yes   Yes  If Yes, was the method of randomization described? Yes They were assigned to two groups by simple randomization/ according to the computer-generated list. Yes  They were assigned to two groups by simple randomization. Each patient received either OT (group A) or methadone syrup (group B), according to the computer generated list.  Yes  If Yes, was the method appropriate? Yes  Yes   Yes  Confounders      Were there important differences between groups prior to the intervention? No There was no statistically significant difference between the two groups regarding these demographic 2 - No  Table 1-demographics, addiction duration and ASI scores had no statistically significant difference  2 - No  If yes, indicate the percentage of relevant confounders that were controlled (either in the design (e.g. stratification, matching) or analysis)?    -     Blinding      Was (were) the outcome assessor(s) aware of the intervention or exposure status of participants?  No Appearance, color, and odor of both medications were matched by pharmaceutical industry experts. 2 - No  Assessments were done by a resident who was blind to group assignment before prescribing the morning doses of medicines.    2 - No    172 Question Reviewer 1 rating Quote (s) Reviewer 2 rating Quote (s) Final Decision  Were the study participants aware of the research question? No Appearance, color, and odor of both medications were matched by pharmaceutical industry experts. 2 - No  Appearance, color, and odor of both medications were matched by pharmaceutical industry experts 2 - No  Data collection methods      Were data collection tools shown to be valid? Yes The Objective Opioid Withdrawal Scale (OOWS) was used to assess withdrawal symptoms. This scale is a valid and reliable indicator of the severity of the opiate withdrawal syndrome over a wide range of common signs and symptoms. 1 - Yes  The Objective Opioid Withdrawal Scale (OOWS) was used to assess withdrawal symptoms.  This scale is a valid and reliable indicator of the severity of the opiate withdrawal syndrome  1 - Yes  Were data collection tools shown to be reliable? Yes The Objective Opioid Withdrawal Scale (OOWS) was used to assess withdrawal symptoms. This scale is a valid and reliable indicator of the severity of the opiate withdrawal syndrome over a wide range of common signs and symptoms. 1 - Yes  The Objective Opioid Withdrawal Scale (OOWS) was used to assess withdrawal symptoms.  This scale is a valid and reliable indicator of the severity of the opiate withdrawal syndrome  1 - Yes  Withdrawals and drop-outs      Were withdrawals and dropouts reported in terms of numbers and/or reasons per group? Yes In total, 74 patients completed the present study and data from all 1 - yes  Figure 1: 74 Randomized (Group A: 35, Group B: 39) Lost to followup: 0    173 Question Reviewer 1 rating Quote (s) Reviewer 2 rating Quote (s) Final Decision  these patients were analyzed  Indicate the percentage of participants completing the study. (If the percentage differs by groups, record the lowest). 80-100%  1 - 80-100%    Intervention integrity      What percentage of participants received the allocated intervention or exposure of interest? Can’t tell  1 - 80-100%   1 - 80-100% Was the consistency of the intervention measured? Can’t tell  1 - Yes  Starting doses were maintained for 5 consecutive days.  Thereafter, detoxification was initiated by tapered dose reductions (20% every day) over a period of 5 days, to reach abstinence.  At the end of 10th day the medications were discontinued.  1 - Yes  Is it likely that subjects received an unintended intervention (contamination or co-intervention) that may influence the results? Can’t tell  6 - Can't tell   6 - Can't tell  Analyses      Indicate the unit of allocation practice/office    individual   individual  Indicate the unit of analysis practice/office    individual   individual  Are the statistical methods appropriate for the study design?  Can’t tell  1 - Yes  Analyzed by ANOVA, independent samples t-test, Mann-Whitney U test & Wilcoxon test.   1 - Yes    174 Question Reviewer 1 rating Quote (s) Reviewer 2 rating Quote (s) Final Decision   Is the analysis performed by intervention allocation status (i.e. intention to treat) rather than the actual intervention received? Can’t tell  1 - Yes  74 patients randomized into 2 groups, 74 completed the present study and data from all these patients were analyzed. 1 - Yes   Is there a discrepancy between the two reviewers with respect to the component (A-F) ratings? Yes If yes, indicate the reason for the discrepancy: Differences in interpretation of criteria      175 2. Seiri L., et al. 2014 (141) Question Reviewer 1 rating Quote (s) Reviewer 2 rating Quote (s) Final Decision  Selection Bias      Are the individuals selected to participate in the study likely to be representative of the target population? Can’t tell  2 - somewhat likely  226 male opiate dependent clients referring to a private treatment service in Tehran, entered the study 2 - somewhat likely  What percentage of selected individuals agreed to participate? Can’t tell  5 - can't tell   5 - can't tell  Study design      Indicate the study design uncontrolled prospective case series  7 - consecutive case series  after 12 months of follow up, 37 (16.4%) of cases had dropped off treatment and had relapsed to illicit drug use.  22 (9.8%) had voluntarily tapered their TO and abstained from any licit or illicit opiate use, as confirmed through urine analysis… 167 clients (74%) continued to receive TO on a daily basis.  uncontrolled prospective case series Was the study described as randomized? No  no   No If Yes, was the method of randomization described?      If Yes, was the method appropriate?      Confounders      Were there important differences between groups prior to the intervention? Can’t tell  3 - can't tell  Single group  3 - can't tell    176 Question Reviewer 1 rating Quote (s) Reviewer 2 rating Quote (s) Final Decision  If yes, indicate the percentage of relevant confounders that were controlled (either in the design (e.g. stratification, matching) or analysis)?    -    Blinding      Was (were) the outcome assessor(s) aware of the intervention or exposure status of participants?  Yes  1 - yes   1 - yes  Were the study participants aware of the research question? Yes  1 - yes   1 - yes  Data collection methods      Were data collection tools shown to be valid? Can’t tell  3 - can't tell  ??Based on continual study enrolment and licit or illicit opiate use as confirmed through urine analysis  3 - can't tell  Were data collection tools shown to be reliable? Can't tell  3 - can't tell   3 - can't tell  Withdrawals and drop-outs      Were withdrawals and dropouts reported in terms of numbers and/or reasons per group? Yes  1 - yes   1 - yes  Indicate the percentage of participants completing the study. (If the percentage differs by groups, record the lowest). 80 -100% 37 (16.4% of cases had dropped off treatment 1 - 80-100%  37 (16.4%) of cases had dropped off treatment  1 - 80-100%  Intervention integrity      What percentage of participants received the allocated intervention or exposure of interest? Can’t tell  1 - 80-100%  The clients were initially stabilized on an equivalent dose of TO and in case of consent, their doses were tapered by 10% every 21 days. 1 - 80-100%    177 Question Reviewer 1 rating Quote (s) Reviewer 2 rating Quote (s) Final Decision  Was the consistency of the intervention measured? Can't tell  3 - can't tell   3 - can't tell  Is it likely that subjects received an unintended intervention (contamination or co-intervention) that may influence the results? Yes  In addition to TO all individuals participated in self-help programs including peer counseling and recreational activities initiated by Congress 60, an NGO for opium abusers. 4 - yes  In addition to TO all individuals participated in self-help programs including peer counseling and recreational activities initiated by Congress 60, an NGO for opium abusers.  4 - yes  Analyses      Indicate the unit of allocation practice/office    individual   individual  Indicate the unit of analysis practice/office    individual   individual  Are the statistical methods appropriate for the study design?  Can't tell  3 - can't tell   3 - can't tell  Is the analysis performed by intervention allocation status (i.e. intention to treat) rather than the actual intervention received? Can't tell  3 - can't tell   3 - can't tell  Is there a discrepancy between the two reviewers with respect to the component (A-F) ratings? Yes If yes, indicate the reason for the discrepancy: Differences in interpretation of criteria    178 3. Mehrjerdi ZA (2013) (142) Question Reviewer 1 rating Quote (s) Reviewer 2 rating Quote (s) Final Decision  Selection Bias      Are the individuals selected to participate in the study likely to be representative of the target population? Somewhat likely  Among a community-recruited sample of women who were simultaneously dependent on opium smoking and non-prescribed use of benzodiazepines. 2 - somewhat likely  Among a community-recruited sample of women who were simultaneously dependent on opium smoking and non-prescribed use of benzodiazepines.  2 - somewhat likely  What percentage of selected individuals agreed to participate? Can’t tell  5 - can't tell   5 - can't tell  Study design      Indicate the study design Uncontrolled prospective case series  7 - consecutive case series   Uncontrolled prospective case series Was the study described as randomized? No  no   No If Yes, was the method of randomization described?      If Yes, was the method appropriate?      Confounders      Were there important differences between groups prior to the intervention? Can’t tell Only one group 3 - can't tell   single group  Can’t tell If yes, indicate the percentage of relevant confounders that were controlled (either in the        179 Question Reviewer 1 rating Quote (s) Reviewer 2 rating Quote (s) Final Decision  design (e.g. stratification, matching) or analysis)? Blinding      Was (were) the outcome assessor(s) aware of the intervention or exposure status of participants?  Yes  1 - yes  1 - yes Were the study participants aware of the research question? Yes  1 - yes  1 - yes Data collection methods      Were data collection tools shown to be valid? Yes both ASI and random urine samples are valid and reliable tools. 1 - yes Addiction Severity Index (ASI-5th) and urine specimens  1 - yes Were data collection tools shown to be reliable? Yes both ASI and random urine samples are valid and reliable tools. 1 - yes Addiction Severity Index (ASI-5th) and urine specimens 1 - yes Withdrawals and drop-outs      Were withdrawals and dropouts reported in terms of numbers and/or reasons per group? Yes 86% became abstinent from simultaneous use of opium and benzodiazepines after completing the treatment and 71% remained abstinent after 6 months of treatment. 1 - yes  Among 283 clients, 221 completed the treatment (78%).  1 - yes  Indicate the percentage of participants completing the study. (If the percentage differs by groups, record the lowest). 60-79%  2 - 60-79%  Among 283 clients, 221 completed the treatment (78%). 2 - 60-79%  Intervention integrity      What percentage of participants received the allocated intervention or exposure of interest? Can’t tell  1 - 80-100%   1 - 80-100%   180 Question Reviewer 1 rating Quote (s) Reviewer 2 rating Quote (s) Final Decision  Was the consistency of the intervention measured? Can’t tell  3 - can't tell   3 - can't tell Is it likely that subjects received an unintended intervention (contamination or co-intervention) that may influence the results? Can’t tell  4 - yes  Attending psychotherapeutic meetings (AOR=1.85, 95% CI [1.04, 2.19]), and family support for treatment (AOR=1.61, 95% CI [1.24, 2.49]) were associated with treatment successs *Unintended intervention? 4 - yes  Analyses      Indicate the unit of allocation Community A community-recruited sample of women  individual individual Indicate the unit of analysis Community A community-recruited sample of women  individual individual Are the statistical methods appropriate for the study design?  Can’t tell  3 - can't tell  3 - can't tell Is the analysis performed by intervention allocation status (i.e. intention to treat) rather than the actual intervention received? Can’t tell  3 - can't tell  3 - can't tell  Is there a discrepancy between the two reviewers with respect to the component (A-F) ratings? Yes If yes, indicate the reason for the discrepancy: Differences in interpretation of criteria    181 4. Tavakoli M., et al. 2012 (136,137)  Question Reviewer 1 rating Quote (s) Reviewer 2 rating Quote (s) Final Decision  Selection Bias      Are the individuals selected to participate in the study likely to be representative of the target population? Somewhat likely All patients over 40 who came to congress 60 for detoxification or treatment 2 - somewhat likely All patients over 40 who came to congress 60 for detoxification or treatment 2 - somewhat likely What percentage of selected individuals agreed to participate? Can't tell  5 - can't tell   5 - can't tell  Study design      Indicate the study design Cohort analytic (two group pre + post)  7 - consecutive case series   Uncontrolled prospective case series Was the study described as randomized? No  no   No If Yes, was the method of randomization described?      If Yes, was the method appropriate?      Confounders      Were there important differences between groups prior to the intervention? Can’t tell There is only one group 3 - can't tell   single group  Can’t tell If yes, indicate the percentage of relevant confounders that were controlled (either in the design (e.g. stratification, matching) or analysis)?      Blinding        182 Question Reviewer 1 rating Quote (s) Reviewer 2 rating Quote (s) Final Decision  Was (were) the outcome assessor(s) aware of the intervention or exposure status of participants?  Yes  1 - yes  1 - yes Were the study participants aware of the research question? Yes  1 - yes  1 - yes Data collection methods      Were data collection tools shown to be valid? Yes SF-36 is valid and reliable tool. 1 - yes SF-36 1 - yes Were data collection tools shown to be reliable? Yes SF-36 is valid and reliable tool. 1 - yes SF-36 1 - yes Withdrawals and drop-outs      Were withdrawals and dropouts reported in terms of numbers and/or reasons per group? No  No  No Indicate the percentage of participants completing the study. (If the percentage differs by groups, record the lowest). Can’t tell  Can’t tell  Can’t tell Intervention integrity      What percentage of participants received the allocated intervention or exposure of interest? Can't tell  Can't tell  Can't tell Was the consistency of the intervention measured? No  No  No Is it likely that subjects received an unintended intervention (contamination or co-intervention) that may influence the results? Can’t tell  Yes  Participation in Congress 60 which provides self-help interventions Yes Analyses      Indicate the unit of allocation Organization/institution     individual  individual Indicate the unit of analysis Organization/institution     individual  individual Are the statistical methods appropriate for the study design?  Yes  Yes  Yes   183 Question Reviewer 1 rating Quote (s) Reviewer 2 rating Quote (s) Final Decision  Is the analysis performed by intervention allocation status (i.e. intention to treat) rather than the actual intervention received? Can’t tell  3 - can't tell 3 - can't tell 3 - can't tell  Is there a discrepancy between the two reviewers with respect to the component (A-F) ratings? Yes If yes, indicate the reason for the discrepancy: Difference in interpretation of Criteria  5. Somogyi AA, et al. 2008 (144) Question Reviewer 1 rating Quote (s) Reviewer 2 rating Quote (s) Final Decision  Selection Bias      Are the individuals selected to participate in the study likely to be representative of the target population? Somewhat likely Subjects were recruited from the Northern Drug Dependence Treatment Centre, Chiang Mai, Thailand. 2 - somewhat likely   2 - somewhat likely  What percentage of selected individuals agreed to participate? 80 - 100% agreement Forty-five Thai subjects dependent on opium were recruited, with no subject having to withdraw. 1 - 80-100% agree  45 Thai subjects dependent on opium were recruited, with no subject having to withdraw.  1 - 80-100% agree  Study design      Indicate the study design Controlled clinical trial Initially, subjects were randomly allocated to the following three treatment groups 2 - controlled clinical trial   2 - controlled clinical trial   184 Question Reviewer 1 rating Quote (s) Reviewer 2 rating Quote (s) Final Decision   Was the study described as randomized? Yes  no  Initially, subjects were randomly allocated to the following 3 tx groups; 6.66mg, 13.3mg, 20mg, twice a day…. However, those subjects who reported using relatively small amounts of opium prior to starting tx experience sedation when given 20 and 30ml TOP... Thus, a flexible dosing regimen was used, where the TOP dose was adjusted according to patients' self-reported prior opium smoking use as amount/day.  Yes  If Yes, was the method of randomization described? No  -   If Yes, was the method appropriate?   -   Confounders      Were there important differences between groups prior to the intervention? Yes Thus, a flexible dosing regimen was used, where the TOP dose was adjusted according to patients’ self-reported prior opium smoking use as amount per day. / Table 2. 1 - yes  There were differences between groups for prior daily opium  use (p<0.0001), so that subjects in Groups 2 and 3 self-reported significantly greater daily opium use than those in Group1 (p<0.001).  There 1 - yes    185 Question Reviewer 1 rating Quote (s) Reviewer 2 rating Quote (s) Final Decision  were no other between group difference for any other demographic vairable (p>0.05).  If yes, indicate the percentage of relevant confounders that were controlled (either in the design (e.g. stratification, matching) or analysis)? Less than 60% (few or none)     2 - 60-79% (some)   2 - 60-79% (some)  Blinding      Was (were) the outcome assessor(s) aware of the intervention or exposure status of participants?  Yes This open-label study was approved by the Royal Adelaide Hospital Research Ethics Committee 1 - yes  Open-label study  1 - yes  Were the study participants aware of the research question? Yes  1 - yes   1 - yes  Data collection methods      Were data collection tools shown to be valid? Yes Dyer study 1 - yes  pharmacodynamic measures and methadone symptoms checklist according to previous study (Dyer et al., 1999).  1 - yes  Were data collection tools shown to be reliable? Yes Dyer study 1 - yes  pharmacodynamic measures and methadone symptoms checklist according to previous study (Dyer et al., 1999).  1 - yes  Withdrawals and drop-outs      Were withdrawals and dropouts reported in terms of numbers and/or reasons per group? Yes Forty-five Thai subjects dependent on opium 1 - yes  32 subjects completed the requirements of the 1 - yes    186 Question Reviewer 1 rating Quote (s) Reviewer 2 rating Quote (s) Final Decision  were recruited, with no subject having to withdraw. /  In total, 32 subjects (31 male and one female) completed the requirements of the interdosing study, with transcription errors and incomplete blood samples occurring in 13 of the original 45 subjects. interdosing study, with transcription errors and incomplete blood samples occuring in 13 of the original 45 subjects.  Indicate the percentage of participants completing the study. (If the percentage differs by groups, record the lowest). 60-79 %  2 - 60-79% (71.1%)   2 - 60-79% (71.1%)  Intervention integrity      What percentage of participants received the allocated intervention or exposure of interest? Can’t tell  1 - 80-100%   Can’t tell Was the consistency of the intervention measured? No  1 - yes  no patient had reported taking medications known to alter the pharmacokinetics of morphine…Each subject was studied for an 8-h period during the 12-h interdosing interval study and was required to be at steady state (unchanged dose for >=4 days) prior to participating.  Can’t tell   187 Question Reviewer 1 rating Quote (s) Reviewer 2 rating Quote (s) Final Decision  Is it likely that subjects received an unintended intervention (contamination or co-intervention) that may influence the results? Can’t tell  5 - no  no patient had reported taking medications known to alter the pharmacokinetics of morphine 5 - no  Analyses      Indicate the unit of allocation organization/institution     individual   individual  Indicate the unit of analysis organization/institution     individual   individual  Are the statistical methods appropriate for the study design?  Yes  1-yes   1-yes  Is the analysis performed by intervention allocation status (i.e. intention to treat) rather than the actual intervention received? No  2 - no  32 of original 45 subjects analyzed  2 - no   Is there a discrepancy between the two reviewers with respect to the component (A-F) ratings? Yes If yes, indicate the reason for the discrepancy: Differences in interpretation of criteria/ Differences in interpretation of study      188 6. Mokri A, et al. 2007 (140) Question Reviewer 1 rating Quote (s) Reviewer 2 rating Quote (s) Final Decision  Selection Bias      Are the individuals selected to participate in the study likely to be representative of the target population? Somewhat likely  Opium dependent clients referring to the INCAS clinic after attaining informed written consent 2 - somewhat likely  opium dependent clients referring to the INCAS clinic after attaining informed written consent  2 - somewhat likely  What percentage of selected individuals agreed to participate? Can't tell  5 - can't tell   5 - can't tell  Study design      Indicate the study design uncontrolled prospective case series  7 - consecutive case series   uncontrolled prospective case series Was the study described as randomized? No  no   no  If Yes, was the method of randomization described?   -   If Yes, was the method appropriate?   -   Confounders      Were there important differences between groups prior to the intervention? Can’t tell  3 - can't tell   3 - can't tell If yes, indicate the percentage of relevant confounders that were controlled (either in the design (e.g. stratification, matching) or analysis)?   -   Blinding        189 Question Reviewer 1 rating Quote (s) Reviewer 2 rating Quote (s) Final Decision  Was (were) the outcome assessor(s) aware of the intervention or exposure status of participants?  Yes an open label trial study was implemented. 1 - yes  preliminary results of an open label clinical trial  1 - yes  Were the study participants aware of the research question? Yes an open label trial study was implemented. 1 - yes  preliminary results of an open label clinical trial  1 - yes  Data collection methods      Were data collection tools shown to be valid? Yes ASI, Beck depression inventory are valid questionnaires 1 - yes  ASI, Aids Risk Inventory, Beck Depression Scale (need references)  1 - yes  Were data collection tools shown to be reliable? Yes ASI, Beck depression inventory are reliable questionnaires 1 - yes  ASI, Aids Risk Inventory, Beck Depression Scale (need references)  1 - yes  Withdrawals and drop-outs      Were withdrawals and dropouts reported in terms of numbers and/or reasons per group? Yes  1 - yes   1 - yes  Indicate the percentage of participants completing the study. (If the percentage differs by groups, record the lowest). 6079% the 6-month retention rate reached 780 -100%   % (87% excluding first week drop outs). 2 - 60-79% (71%)  * Assessment based on preliminary results, trial still in progress at time of publication?* Since March 2006 till present 22 clients have been recruited.  3 clients dropped out of treatment in the 1st week but thereafter attrition rates decreased dramatically as the 6-month retention rate reached 71% (87% excluding 1st week drop outs). 2 - 60-79% (71%)    190 Question Reviewer 1 rating Quote (s) Reviewer 2 rating Quote (s) Final Decision   Intervention integrity      What percentage of participants received the allocated intervention or exposure of interest? Can’t tell  4 - can't tell   4 - can't tell  Was the consistency of the intervention measured? Can’t tell  4 - can't tell   4 - can't tell  Is it likely that subjects received an unintended intervention (contamination or co-intervention) that may influence the results? Can’t tell  4 - can't tell   4 - can't tell  Analyses      Indicate the unit of allocation organization/institution     individual   individual  Indicate the unit of analysis organization/institution     individual   individual  Are the statistical methods appropriate for the study design?  Can’t tell  3 - can't tell   3 - can't tell  Is the analysis performed by intervention allocation status (i.e. intention to treat) rather than the actual intervention received? Can’t tell  3 - can't tell   3 - can't tell   Is there a discrepancy between the two reviewers with respect to the component (A-F) ratings? Yes If yes, indicate the reason for the discrepancy: Differences in interpretation of criteria     191 7. Jittiwutikarn J, et al. 2004 (143) Question Reviewer 1 rating Quote (s) Reviewer 2 rating Quote (s) Final Decision  Selection Bias      Are the individuals selected to participate in the study likely to be representative of the target population? Somewhat likely All subjects were inpatients at the Northern Drug Dependence Treatment Centre, Chiang Mai, Thailand. / Open label, parallel group study in an inpatient facility compared 15 former heroin users with 15 former opium smokers receiving TOP. 2 - somewhat likely  All subjects were inpatients at the Northern Drug dependence Treatment Centre, Chiang mai, Thailand.    2 - somewhat likely What percentage of selected individuals agreed to participate? Can’t tell   5 - can't tell   5 - can't tell Study design      Indicate the study design Cohort analytic (two group pre + post)  Open label, parallel group study 7 - open label, parallel group study   Cohort analytic (two group pre + post) Was the study described as randomized? No  no   No If Yes, was the method of randomization described?      If Yes, was the method appropriate?      Confounders      Were there important differences between groups prior to the intervention? Yes Open label, parallel group study in an inpatient facility 1 - Yes  parallel group study in an inpatient facility compared 15 former 1 - Yes    192 Question Reviewer 1 rating Quote (s) Reviewer 2 rating Quote (s) Final Decision  compared 15 former heroin users with 15 former opium smokers receiving TOP heroin users receiving methadone with 15 former opium smokers receiving tincture of opium  If yes, indicate the percentage of relevant confounders that were controlled (either in the design (e.g. stratification, matching) or analysis)? Less than 60% (few or none)   3 - less than 60% (few or none)   3 - less than 60% (few or none)  Blinding      Was (were) the outcome assessor(s) aware of the intervention or exposure status of participants?  Yes  1 - yes   1 - yes  Were the study participants aware of the research question? Yes  1 - yes   1 - yes  Data collection methods      Were data collection tools shown to be valid? Yes  (Dyer study) 1 - yes  blood sample, physiological measures, self-reported opioid effects and opioid withdrawal symptoms recorded, protocol according to previous study (Dyer & White, 1997).  1 - yes  Were data collection tools shown to be reliable? Yes  (Dyer study) 1- yes  blood sample, physiological measures, self-reported opioid effects and opioid withdrawal symptoms 1- yes    193 Question Reviewer 1 rating Quote (s) Reviewer 2 rating Quote (s) Final Decision  recorded, protocol according to previous study (Dyer & White, 1997).  Withdrawals and drop-outs      Were withdrawals and dropouts reported in terms of numbers and/or reasons per group? Yes All patients had received a minimum of 4 days’ treatment of either methadone or tincture of opium at their constant dose prior to being studied. 1 - yes   1 - yes  Indicate the percentage of participants completing the study. (If the percentage differs by groups, record the lowest). 80 -100%     1 - 80-100%   1 - 80-100%  Intervention integrity      What percentage of participants received the allocated intervention or exposure of interest? 80 -100%    Measurements during part of one dosing interval in 15 Thai patients taking tincture of opium every 12 h (four subjects as 3.33    mg, 10 subjects as 6.66 mg, one subject as 10 mg, morphine equivalents). 1 - 80-100%  Methadone group: 1-  5mg, 5- 10mg, 4- 15mg, 5- 20mg. For tincture of opium: 4- 3.33mg morphine equivalents, 10- 6.66mg, 1-10mg + 10mg morphine. Each patient's dosage of either methadone or tincture of opium was based on their reported herion or opium usage and are those usually employed in this centre.     194 Question Reviewer 1 rating Quote (s) Reviewer 2 rating Quote (s) Final Decision  Was the consistency of the intervention measured? No  1 - yes  Methadone group: 1-  5mg, 5- 10mg, 4- 15mg, 5- 20mg. For tincture of opium: 4- 3.33mg morphine equivalents, 10- 6.66mg, 1-10mg + 10mg morphine. Each patient's dosage of either methadone or tincture of opium was based on their reported herion or opium usage and are those usually employed in this centre.  1 - yes  Is it likely that subjects received an unintended intervention (contamination or co-intervention) that may influence the results? Can’t tell  6 - can't tell   6 - can't tell  Analyses      Indicate the unit of allocation organization/institution     individual   individual  Indicate the unit of analysis organization/institution     individual   individual  Are the statistical methods appropriate for the study design?  Yes  1 - yes   1 - yes  Is the analysis performed by intervention allocation status (i.e. intention to treat) rather than the actual intervention received? Yes  1 - yes   1 - yes   Is there a discrepancy between the two reviewers with respect to the component (A-F) ratings? Yes If yes, indicate the reason for the discrepancy: Differences in interpretation of criteria   195 8. He M, et al. 1996 (145) Question Reviewer 1 rating Quote (s) Reviewer 2 rating Quote (s) Final Decision  Selection Bias      Are the individuals selected to participate in the study likely to be representative of the target population? Somewhat likely Subjects were voluntary drug-addicted patients, who were admitted to Changsha Drug Addiction Treatment Centre. 2 - somewhat likely  Subjects were voluntary drug-addicted patients, who were admitted to Changsha Drug Addiction Treatment Centre.  2 - somewhat likely  What percentage of selected individuals agreed to participate? Can’t tell  5 - can't tell   5 - can't tell Study design      Indicate the study design Controlled clinical trial     2 - controlled clinical trial   2 - controlled clinical trial  Was the study described as randomized? No  no   no  If Yes, was the method of randomization described?      If Yes, was the method appropriate?      Confounders      Were there important differences between groups prior to the intervention? Yes There were 28 subjects in the control group, which were similar in background conditions with those in the treatment group without significant differences. 1 - yes  14 patients were assigned to buprenorphine plus naloxon group and 28 patients to opium tincture group.   1 - yes    196 Question Reviewer 1 rating Quote (s) Reviewer 2 rating Quote (s) Final Decision  If yes, indicate the percentage of relevant confounders that were controlled (either in the design (e.g. stratification, matching) or analysis)? 80100% (most)    Drug users were categorized according to gender, age, occupation, drug histories, drug daily usage, methods of use, and allocated to the treatment group and control group in the ratio of 1:2. 1 - 80-100% (most)  14 patients were assigned to buprenorphine plus naloxon group and 28 patients to opium tincture group.  The 2 group patients were matched with sex, age, employment condition, heroin using route and history.  1 - 80-100% (most)  Blinding      Was (were) the outcome assessor(s) aware of the intervention or exposure status of participants?  Can’t tell  1 - yes  single blind control study 1 - yes  Were the study participants aware of the research question? No On the other hand, oral placeboes (Soup of Coptis chinensis and Rehmannia glutinosa) were first given to subjects in the treatment group, and intravenous drop infusion of normal saline and intramuscular injection of benzyl alcohol were administered to those in the control group. 2 - no  oral placeboes were first given to subjects in the treatment group, and intravenous drop infusion of normal saline and intramuscular injection of benzyl alcohol were admistered to those in the control group.  2 - no  Data collection methods      Were data collection tools shown to be valid? Yes The original symptom scale (claimed to be present in Farell’s paper; but rather in Gossop et 1 - yes  opiate withdrawal scale and craving rating scale were administered (original symptom scale 1 - yes    197 Question Reviewer 1 rating Quote (s) Reviewer 2 rating Quote (s) Final Decision  al.’s in British Journal of Psichiatry) / Cite study for Minnesota craving scale claimed to be present in Farell's paper; but rather in Gossop et al.'s in British Journal of Psychiatry).  Minnesota Cocaine Craving Scale (Halikas, Kuhn & Crosby, 1991).  Were data collection tools shown to be reliable? Yes The original symptom scale (claimed to be present in Farell’s paper; but rather in Gossop et al.’s in British Journal of Psichiatry) / Cite study for Minnesota craving scale 1 - yes  opiate withdrawal scale and craving rating scale were administered (original symptom scale claimed to be present in Farell's paper; but rather in Gossop et al.'s in British Journal of Psychiatry).  Minnesota Cocaine Craving Scale (Halikas, Kuhn & Crosby, 1991).  1 - yes  Withdrawals and drop-outs      Were withdrawals and dropouts reported in terms of numbers and/or reasons per group? Yes During consolidated treatment, 7 cases in treatment group applied for termination of treatment (naloxone daily usage is 1.26 ± 0.15mg when they left), 6 cases in control group applied for termination and 1 is processed as 1 - yes  During 1st 10 days of active tx, treatment group all finished (14/14), while 24 patients in control group accomplished with 4 withdrawing (24/28)... During consolidated tx, 7 cases in treatment group applied for termination of tx (naloxone daily usage 1 - yes    198 Question Reviewer 1 rating Quote (s) Reviewer 2 rating Quote (s) Final Decision  inapplicable case. These patients in both control and treatment groups applied for termination because they believed they got clean and did not need the treatment anymore. is 1.26 ± 0.15mg when they left), 6 cases in control group applied for termination and 1 is processed as inapplicable case.  These patients in both control and treatment groups applied for termination because they believed they got clean and did not need the treatment anymore.  Indicate the percentage of participants completing the study. (If the percentage differs by groups, record the lowest). less than 60%    There were 7/14 cases in treatment group and 17/28 cases in control group. 3 - less than 60% (50% &  60.7%)  Final- tx group:7/14, control 17/28.  3 - less than 60% (50% &  60.7%)  Intervention integrity      What percentage of participants received the allocated intervention or exposure of interest? less than 60%    During consolidated treatment, 7 cases in treatment group applied for termination of treatment (naloxone daily usage is 1.26 ± 0.15mg when they left), 6 cases in control group applied for termination and 1 is processed as inapplicable case. These patients in both control and treatment groups applied for termination because they believed 3 - less than 60%  During consolidated tx, 7 cases in treatment group applied for termination of tx (naloxone daily usage is 1.26 ± 0.15mg when they left), 6 cases in control group applied for termination and 1 is processed as inapplicable case.  These patients in both control and treatment groups applied for termination because they believed they got clean and did not need the 3 - less than 60%    199 Question Reviewer 1 rating Quote (s) Reviewer 2 rating Quote (s) Final Decision  they got clean and did not need the treatment anymore. treatment anymore. Final- tx group:7/14, control 17/28.  Was the consistency of the intervention measured? Can’t tell  1 - yes  Buprenorphine was administered through intravenous drop infusion and intramuscular injection…After the 5th day of hospitalization, naloxone hydrochloride was administered through intravenous drop infusion… opium tincture was administered from the 1st day of hospitalization...  Can’t tell Is it likely that subjects received an unintended intervention (contamination or co-intervention) that may influence the results? Can’t tell  5 - no   Can’t tell Analyses      Indicate the unit of allocation organization/institution     individual   individual  Indicate the unit of analysis organization/institution     individual   individual  Are the statistical methods appropriate for the study design?  Yes  1 - yes   1 - yes  Is the analysis performed by intervention allocation status (i.e. intention to treat) rather than the actual intervention received? Yes Analysis was presented both ways (intention to treat/ per protocol) 1 - yes (both)  compare patients who finished 15-day treatment 1 - yes (both)    200 Question Reviewer 1 rating Quote (s) Reviewer 2 rating Quote (s) Final Decision  with the unaccomplished in 2 groups respectively.   Is there a discrepancy between the two reviewers with respect to the component (A-F) ratings? Yes If yes, indicate the reason for the discrepancy: Oversight/ Differences in interpretation of criteria  9. Auriacombe M, et al. 1994 (146) Question Reviewer 1 rating Quote (s) Reviewer 2 rating Quote (s) Final Decision  Selection Bias      Are the individuals selected to participate in the study likely to be representative of the target population? Not likely  This is a cross-sectional evaluation of all the patients on OMP at the private-practice-based clinic at one time point. Eighteen patients were asked by their therapist to participate in this study 2 - somewhat likely  Abstract: This group of patients was selected because of persistent relapse and impairment after an average of 5.7 drug-free-oriented txs over a period of 6.8 yrs.   This is a cross-sectional evaluation of all the patients on OMP at the private-practice-based clinic at one time point. 2 - somewhat likely What percentage of selected individuals agreed to participate? Can’t tell      1 - 80-100% agree  18 patients were asked by their therapist to participate in this study and were evaluated after acquisition of informed consent. .  Can’t tell      201 Question Reviewer 1 rating Quote (s) Reviewer 2 rating Quote (s) Final Decision  Study design      Indicate the study design Cohort analytic (two group pre + post)     3 - cohort analytic (2 group pre + post)   Cohort analytic (two group pre + post)    Was the study described as randomized? No    no   No   If Yes, was the method of randomization described?      If Yes, was the method appropriate?      Confounders      Were there important differences between groups prior to the intervention? Can't tell  3 - can't tell   3 - can't tell  If yes, indicate the percentage of relevant confounders that were controlled (either in the design (e.g. stratification, matching) or analysis)?      Blinding      Was (were) the outcome assessor(s) aware of the intervention or exposure status of participants?  Yes  1 - yes   1 - yes  Were the study participants aware of the research question? Yes  1 - yes   1 - yes  Data collection methods        202 Question Reviewer 1 rating Quote (s) Reviewer 2 rating Quote (s) Final Decision  Were data collection tools shown to be valid? Yes Lifetime Retrospective Evaluation Score Table (LREST; Grabot, Auriacombe, Martin, & Tignol, Yes990) is administered. / a French language adaptation (IGT, Michel Landry, Centre DomrCmy- MontrCal, Montreal) of the Addiction Severity Index (ASI) was administered (Grabot et al., Yes99No; McLellan et al., Yes985; McLellan, Luborsky, Woody, & O’Brien, Yes980). 1 - yes  Lifetime Retrospective Evaluation Score Table (LREST) from previous study (Grabot, Auriacombe, Martin, & Tignol, 1990.  A French language adaptation of the Addiction Severity Index (ASI) (IGT, Michel Landry, Centre Domremy-Montreal, Montreal; Grabot et al., 1992; McLellan et al., 1985; McLellan, Luborsky, Woody, & O'Brien, 1980).     1 - yes  Were data collection tools shown to be reliable? Yes Lifetime Retrospective Evaluation Score Table (LREST; Grabot, Auriacombe, Martin, & Tignol, Yes990) is administered. / a French language adaptation (IGT, Michel Landry, Centre DomrCmy- MontrCal, Montreal) of the Addiction Severity Index (ASI) was administered (Grabot et al., Yes99No; McLellan et al., Yes985; McLellan, Luborsky, Woody, & O’Brien, Yes980). 1 - yes  Lifetime Retrospective Evaluation Score Table (LREST) from previous study (Grabot, Auriacombe, Martin, & Tignol, 1990.  A French language adaptation of the Addiction Severity Index (ASI) (IGT, Michel Landry, Centre Domremy-Montreal, Montreal; Grabot et al., 1992; McLellan et al., 1985; McLellan, Luborsky, Woody, & O'Brien, 1980).     1 - yes  Withdrawals and drop-outs      Were withdrawals and dropouts reported in terms of numbers and/or reasons per group? No  4 - Not applicable  all subjects were evaluated by the same experimental psychologist during a 150-4 - Not applicable   203 Question Reviewer 1 rating Quote (s) Reviewer 2 rating Quote (s) Final Decision  min, 3-part, semi-structured interview. And Retrospective.   Indicate the percentage of participants completing the study. (If the percentage differs by groups, record the lowest). Can’t tell    5 - Not applicable   5 - Not applicable  Intervention integrity      What percentage of participants received the allocated intervention or exposure of interest? Can’t tell    1 - 80-100%  6 patients received laudanum p.o., 15g daily; 12 patients received buprenorphine sublingual 2-4 mg daily.  1 - 80-100%  Was the consistency of the intervention measured? Can’t tell    2 - No   Can’t tell   Is it likely that subjects received an unintended intervention (contamination or co-intervention) that may influence the results? Can’t tell    6 - can't tell   Can’t tell   Analyses      Indicate the unit of allocation practice/office    individual   individual  Indicate the unit of analysis practice/office    individual   individual  Are the statistical methods appropriate for the study design?  Yes  1 - yes   1 - yes  Is the analysis performed by intervention allocation status (i.e. No  2 - no   2 - no    204 Question Reviewer 1 rating Quote (s) Reviewer 2 rating Quote (s) Final Decision  intention to treat) rather than the actual intervention received?  Is there a discrepancy between the two reviewers with respect to the component (A-F) ratings? Yes If yes, indicate the reason for the discrepancy: Differences in interpretation of criteria  205 Appendix B. Comparing tincture of opium and methadone for opioid substitution treatment: protocol for a multi-center parallel group non-inferiority double-blind randomized controlled trial Introduction Background While methadone is the most widely administered OST across the globe, OT has gained increasing popularity in certain countries (132,133). In Iran, approximately 64,000 patients were receiving OT in 2014 and OT, after methadone (with half a million patients being treated with methadone) was the second most used medication for OST (30,85,134).   Opium tincture is an interesting candidate in Iran and Middle East and the Golden Triangle region of Southeast Asia for several reasons. First, the retail prices of opium in these areas (0.1-2.1 US dollars per gram) are prominently lower than other parts of the world (22-184 US dollars per gram) (127). Secondly, the major production sites of opium are in these regions, which increases its availability (128). Thirdly, opium is culturally more acceptable and less stigmatized in these countries which can result in an increased compliance with the treatment (129). Even more, many patients are inclined towards using OT rather than methadone due to false beliefs and misconceptions about methadone (130). Finally, limited variety and the side-effect profile of the current treatment options for opioid dependence has provoked continuous investigations for expanding the repository of available treatments. Considering the scarcity of evidence on safety and efficacy of OT compared with other treatment options (e.g. methadone)   206 (131), further investigations are required and may conclude advantages of OT not confined to the above-mentioned regions, but also in other parts of the world. According to a recent systematic review (131), only a few number of reports are available on treatment with OT in patients with opioid dependence. The 3 existing randomized clinical trials investigated only detoxification with OT but not its use in the OST. Beyond that, while OT demonstrated an acceptable retention rate of 71-78% in previous reports, there is no comparison between OT and other standard treatments, in particular methadone, using a controlled design. Aims This chapter describes the design of a trial to compare the safety and efficacy of OT with methadone for OST. Methods This is prepared based on the 4th amendment of the opium trial protocol. More information is available as supporting information and at two ICMJE recognized registry databases of clinical trials (ClinicalTrials.gov: NCT02502175; IRCT.ir: IRCT201506261556N78). Hypothesis and objectives The primary objective of the opium trial was to determine whether or not OT is equally as effective as methadone at retaining patients with opioid dependence in OST using a patient-centered flexible dosing strategy. The primary hypothesis is that OT is equally as effective as methadone for retaining participants in OST. Our secondary objectives were to compare OT and methadone in terms of other health-related outcomes including AEs, craving, withdrawal   207 symptoms, abstinence from illicit use of drugs, physical health, psychological health, cognitive function, quality of life, cost-effectiveness, and patient satisfaction (Table 3.1).  Research design In this phase 3 multi-center, parallel-group, double-blind, non-inferiority randomized clinical trial (182), patients with opioid dependence were randomized to receive either OT or methadone using a patient-centered flexible dosing strategy for 12-weeks, complying with the Iranian national protocol for OST. The Clinical Research Ethics Board of University of British Columbia (UBC-CREB) (H15-00220) and Tehran University of Medical Sciences Ethics Committee (28099) approved the study. Sampling, eligibility, and recruitment Recruitment centers were four private outpatient OST clinics located in major cities in Iran: Sari and Tehran in the north, Isfahan in the center, and Shiraz in the south. To achieve the target sample size, the brochures and flyers were distributed in community outreach, general and mental hospitals, NGO-run communities, colleges and universities, drop-in centers, and specialized clinics for treatment of participants with HIV and HCV. In addition, flyers were posted on the billboard of bus/subway and local stores as well as in the aforementioned places. The estimated recruitment period was 1 year which began in July 2017. Participants provided informed consent before any study-related procedure. Eligible participants were willing and able to adhere to the treatment protocol based on their consent and assessment by the experienced physician at each clinic. Participants were selected from patients with opioid dependence based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria (4). Female participants of childbearing age were included only if   208 they agreed to use an acceptable method of contraception approved by the research physician during the study follow-up period. Participants were excluded if they met any of the following criteria: active participation in another treatment program for opioid dependence within the last 14 days before inclusion in this study; severe hepatic impairment; hypersensitivity to methadone, opium, or their ingredients; pregnancy; severe chronic respiratory disease; head injuries and raised intracranial pressure; biliary tract disease; consumption of monoamine oxidase inhibitors within the last 14 days prior to the study.  Randomization, allocation concealment, and blinding Participants were randomized with a 1:1 allocation ratio to methadone or OT treatment arms using stratified randomization block technique with block sizes of 2 and stratification on sex (F/M ratio = 1/9) and age (younger than 30/ 30-49/ 50 and older ~ 1: 2: 2). This stratification was based on age and gender distribution of the population with opioid-dependence in Iran according to the results of Iranian Mental Health survey in 2011 (41). Sealed Envelope Ltd. 2015 created the blocked randomization list (https://www.sealedenvelope.com/simple-randomiser/v1/lists [Accessed 17 June 2017]; seed number: 276524980879508). Randomization list was uploaded on the trial website (metopitrial.ir). The clinic pharmacist logged in to trial website which assigned each participant to a unique randomization code and retrieved the intervention arm when dispensing the medications. The pharmacists were the only persons aware of both allocation label and randomization code of each participant. The patients, investigators, treatment team (except pharmacist), and assessors were only aware of the randomization code for each participant, but not the allocation label or randomization tables. An essence was added to   209 methadone syrups to make them similar to OT in terms of smell, color, and taste.  No procedure or test in the study, distinctively different between two arms for instance in frequency or the method of sample collection, etc. that could potentially reveal participants’ arms to themselves, clinicians, or researchers was planned in this study. Randomization and allocation concealment were broken in the emergency situations at the discretion of the responsible physician. Treatment interventions After obtaining informed consent, participants who fulfilled the eligibility criteria were invited for Baseline Visit. In this visit, participants were assessed using several assessment batteries in a structured clinical interview and then randomized into either OT (10mg/ ml) or methadone (5mg/ml) treatment arms. Both treatments were manufactured by DaruPakhsh.co, Tehran, Iran, in accordance with instructions provided by WHO on Good Manufacture Practice. The essence was added to the methadone syrup after strict laboratory evaluations for stabilization and lack of interaction with other ingredients. Also, the volume of essence-contained methadone syrups was controlled during production not to be different from normal methadone syrups in terms of concentration of active ingredients. Medications were monitored regularly by the pharmacist at each center. Patients received their treatment based on patient-centered flexible dosing strategy using the following flowcharts where one unit of medication was equal to 1 ml (10mg) of OT or 0.5 ml (2.5mg) of methadone [Figure 3.1]. The treatment was discontinued in case the participant voluntarily chooses not to continue, or the research physician decided to discontinue the treatment based on the predefined criteria discussed in the safety section.  All the relevant assessments, treatments, and laboratory tests were free of charge for all participants. Furthermore, all the participants received routine psychological therapies provided   210 by the psychologist at the clinic based on an individual’s need. Also, participants received concomitant prescription medications other than opioids on a need basis according to the physician’s opinion and instructions. The type, duration, and reason for all the psychological therapies and prescribed medications were documented. Outcomes, instruments, and timeline Table 3.2 and Figure 3.2 represent the study schedule as well as participants’ flow throughout the study. In brief, patients had 30 visits during the 12 weeks of follow up period, starting from the point they start their treatment. Table 3.1 demonstrates study outcomes as well as methods for their assessment. Primary outcome Retention in treatment: Retention in treatment was defined as participating in a certain proportion of scheduled treatment sessions. Since frequencies of visits were different in various stages of the study, we had to set the cut-off for each stage separately. A previous study had defined retention in treatment as receiving treatment for 10 out of last 14 (71.4%) days of follow-up period (99). So, we set 70% of the visits at each stage after rounding them up as the cut-off for retention in treatment. So, participants who attended a minimum of 4 (out of 6) visits in the first 3 days, 6 (out of 9) visits from day 4 to 14, 4 (out of 6) visits from day 15 to 28, and 6 (out of 9) visits in the next 8 weeks were considered “retained in the treatment”. Retention in treatment has been consistently used in several previous trials in OST (94). Secondary outcomes   211 Craving, withdrawal symptoms, abstinence from illicit use of drugs, physical health, psychological health, quality of life, cognitive function, severity of problems related to substance use, client satisfaction and cost-effectiveness were secondary outcomes in this study. Behavioral stages of change and childhood traumatic experiences were measured at baseline. Table 3.1 summarizes the measured outcomes, measurement instruments and the methods of analysis.  Secondary outcomes in this study provide a holistic and in-depth understanding of the OST treatment effect: 1) alleviation of withdrawal symptoms is one of the fundamental merits of OST, which helps patients reduce their use of opioids outside treatment and its related harms; however, residual withdrawal symptoms between doses of OST is a well-established phenomenon, associated with increased substance use outside treatment and poor psychosocial outcomes (155), 2) craving can result in continued use of opioids outside the treatment despite being in OST. It can be triggered by stress or exposure to drug cues and is a subjective phenomenon, which might be perpetuated by negative reinforcement i.e., an increased desire to use opioids to alleviate residual withdrawal symptoms or positive reinforcement i.e., an increased desire for missing euphoric effects of certain opioids such as heroin (197), 3) concurrent use of other substances outside treatment, which is quite common, poses a challenge for OST, is an indicator of severity of patients’ condition, and a predictor of poor engagement, drop-out, and risk of post-treatment relapse. It can be rooted in patients’ need for self-medication of their withdrawal distress or emotional troubles, pleasure-seeking, and/or a co-occurring substance use disorder (198), 4) psychological health with can be impacted by OST and is frequently under-reported in previous studies, is a key indicator of patients’ overall health and well-being regardless of its association with substance use outcomes, especially given the pervasiveness of psychiatric comorbidities among patient in OST (199), 5) physical health is   212 another key contributor to patients’ overall health, yet frequently underreported in previous OST studies. Poor physical health among patients in OST can be due to direct effect of opioid use, accompanied high-risk behaviours such as injection, traumatic brain injury, residential instability, food insecurity, and domestic violence (common conditions among patients with opioid dependence) and their barriers for accessing the health services including the stigma they face, which can be addressed with successful institution of OST  (200,201), 6) cognitive function can impact both treatment outcomes and everyday functioning of patients in OST. Previous OST studies have yielded controversial results about the impact of OST on cognitive function (202), 7) addiction severity index instrument, which was used in opium trial is probably the most widely-used standardised instrument in OST setting. It is used to holistically measure the severity of potential problem areas among participants at baseline and also monitored and quantified the changes in these areas during the follow-up period in a standardized way (147), 8-9) quality of life can be severely compromised among patients with opioid dependence and can be improved with OST. Its measurement in opium trial quantifies the impact of OST on burden of opioid dependence among patients and allows the comparison of this burden with other interventions in various conditions. Combined with cost assessment (also performed in opium trial), it also provides the ground for health economic evaluation to show the cost-effectiveness of OST and inform an efficient resource-allocation and policymaking (203), 10) treatment satisfaction reflects patients’ perception and evaluation of the treatment quality compared to their expectation and is the measure in the study to incorporate patients’ view in the overall evaluation of OST and foster the patient-centred perspective on treatment (204).   Setting and personnel   213 Trial centers were private outpatient centers that fulfilled the personnel and equipment requirements set by national guidelines. Each center had a director, one full-time general practitioner, one full-time psychologist, one full-time pharmacist, and one secretary. They were equipped with outpatient as well as basic emergency care facilities. All research physicians had at least 5 years of experience in treatment of patients with opioid dependence. Also, clinical psychologists were experienced and/or trained in the implementation of assessment batteries used in this study. Quality assurance, data collection, monitoring, and confidentiality At each study center, the staff were trained by the investigators on  both the Tri-council Policy Statement 2, Canadian Code of Ethics (205) and ethics code of Iran as well as for appropriate methods of assessment, completion of case report forms (CRF), and data management procedures using face to face lectures and role playing with the staff. Independent entities at data center, review confirmed CRFs and contact the clinics for clarification if incomplete or inaccurate data are found in CRFs. Data were collected on paper (i.e. CRF). Paper documents were kept in a locked place in the clinic office with authorized access. Electronic data were entered into a safely secured, encrypted and password-protected database with regular synching and back-ups. All documents are kept for 25 years after completing the study after which paper forms will be shredded and electronic data will be permanently deleted.  A unique study code not derived from or related to the information about the individual were used on all study documents except randomization lists, consent form, and screening log. This code could not be translated to identify the individual and investigators or their institutions   214 could not use or disclose the unique study code for other purposes or disclose the mechanism for re-identification. Participant’s medical information obtained during the study was confidential and disclosure to third parties was prohibited. No identifying participant information, including names, were disclosed in reports, publications or presentations. At the participant’s written request, medical information could have been given to his/her personal physician.  Access to data and associated documentation were permitted only if user agreed to use the data for research purpose, commit to confidentiality principles, and destroy the data after completing the analyses. Principal investigator, co-investigators and clinic staff in Iran had direct access to the paper forms.  Consent, safety, and adverse events Trained staff in codes of ethics were responsible for obtaining informed written consent at each study site. Screened participants received paper consents with full details including but not limited to potential adverse events, potential benefits, timelines and procedures, and contact information of responsible bodies in accordance to the guidelines by UBC-CREB and TUMS-EC. Participants were provided with adequate time, were able to discuss any issues regarding the consent with the clinic physician, and were free to withdraw their consent at any time during the trial without affecting their relationship with the healthcare providers. Any untoward medical occurrence in a participant during the study whether or not considered  drug-related was defined as an AE. Adverse events were recorded according to the spontaneous reports by the patients/caregivers/clinic personnel, clinical examination, monthly lab tests, and a comprehensive checklist which was used to capture all events, their severity, and their relatedness to the study procedures by the clinic physician from the baseline visit throughout all   215 subsequent visits. The physician followed AEs until resolution, stabilization, or study end, and serious study-related AEs were followed beyond study end until the resolution of AE and its related impact on the participant. AEs are included in the reports to DSMB as well as investigators and ethics committees at sponsor institutions. The reports followed the regulations set by the Iranian Ministry of Health Adverse Drug Reporting Center. The research physician was authorized decide to discontinue the treatment because of adverse reactions to study medications, a serious change in medical status which threats patient’s safety if the treatment was continued, violence against treatment team members without convincing evidence of mental illness like psychosis or delirium, or criminal behavior with resultant imprisonment during the study period. Early termination of treatment and data collection occurred in case a participant withdrew his/her consent to participate. In any of the abovementioned cases the relationship between healthcare team and the patient was not affected, but the participant received information on alternative options to continue his treatment out of the study. In addition, data concerning treatment discontinuation or termination of participation was recorded in full including the reason and the number of the session for such a decision. Also, participants were informed about financial costs associated with their participation in the study that are paid by the sponsors, and their potential options to continue their self-paid treatment after the trial period. Investigators held the responsibility for any costs for medical treatment incurred as a result of a study-related injury. Patients had access to the investigators through the contact information provided in the consent forms for at least 5 years after the trial was completed. Feasibility   216 Feasibility review was conducted after recruitment of first 60 patients.  The interim analyses were carried out every 6 months after beginning of the study and reported to the Data and Safety Monitoring Board (DSMB). Accordingly, the DSMB made a decision on any necessary changes to the ongoing protocol concerning patients’ safety or data integrity after discussing the issue with investigators. Recommendations were made to principal investigators regarding continuation, modification, or termination of the trial in case of serious safety concerns or devaluation of clinical equipoise that justified the initiation of the trial. Sample size The sample size was calculated using the Food and Drug Administration (FDA) guidelines for non-inferiority clinical trials using a fixed margin (95%-95%) approach (182). To calculate the active control effect, data was obtained from a Cochrane systematic review in which, retention in treatment with methadone has been compared with placebo. The meta-analysis of the 4 new studies has yielded a pooled 95% CI for retention ratio of methadone to placebo of 4.44 [3.26, 6.04] (94). The lower bound of the above CI i.e., 3.26 was selected as M1, which yields a treatment effect of 2.26. A very conservative clinical non-inferiority margin i.e., M2 equal to 1.25 (11% of M1) was chosen. To calculate the sample size, we assumed retention rate for participants in OST with methadone to be 77.7% at 3 months based on a systematic review of retention in treatment among participants in OST in low and middle-income countries (96). Using the following formula (Zhong, 2009) and assuming a power of 90% and Type I error set at 5%, the total sample size was calculated to be 240 participants, 120 in each group. N1 = 2 × "!	"#$"!"#%#& 	$$ × 	%	 × (1 − %)= 2	 ×	 "%.'("%.$)%(.*( 	$$ × 	77.7 × (1 − 77.7)	= 120   217 Due to limitation of the resources for continuing the trial, we decided to adjust the sample size with the power of 80%, which yielded a sample size of 174: N2 = 2 × "!	"#$"!"#%#& 	$$ 	× 	%	 × (1 − %)	= "%.'("+.),%(.*( 	$$ 	× 77.7 × (100 − 77.7)= 87 Given the existing resources, clinics agreed to continue the recruitment up to a sample size of N = 200, which surpasses the power of 80% but does not reach the power of 90% as set initially. N = sample size in each arm  Zx = The standard normal deviance for a two-sided x . = Type I error = 0.05 /	=	Type	II	error	=	0.1	&	0.2	P = Anticipated retention rate in each arm, assumed to be equal in two arms = 77.7% M2 = Clinical non-inferiority margin in percentages = P - (P/1.25) = 15.75 Given the existing resources, clinics agreed to continue the recruitment up to a sample size of N = 204, which surpasses the power of 80% but did not reach the power of 90% as set initially. Statistical analysis Analyses were based on both intention-to-treat (ITT) and per-protocol (PP) methods. A CI procedure was conducted to evaluate whether the upper bound of 95% CI of retention ratio of methadone to OT passes the non-inferiority margin i.e. 1.25.  Dissemination of results After completion of data collection and confirmed accuracy of data by DSMB and auditing committee, investigators analyzed the complete dataset and prepare the final reports in accordance   218 with the approved protocol as well as later amendments. The reports were provided to all the related committees and boards as well as principal investigators and consultant statistician to be reviewed. Public communication of the results was in the form of journal articles, conference abstracts, and update of the clinical trial registries.  10. Results A total of 204 participants, 128 in Sari-urban, 52 in Sari-rural, 15 in Shiraz and 9 in Isfahan were randomized equally to 2 arms. Results of this clinical trial are to be reported after final analysis. 11. Discussion This was the first trial to assess the safety and efficacy of OT for OST compared with methadone, the most-widely administered treatment for this condition. Results of previous studies on OT in patients with opioid dependence were inconclusive (131).  This trial was also subject to some limitations. First, we stratified our sample based on the age and gender distributions of patients with opioid dependence in Iran, with men to women ratio of 9:1 and almost half the sample selected from patients with age range of 30-39 years old, which may be different from other countries (134). Second, while we used every effort to make the two treatments similar, patients might be able to guess the treatment they receive based on the characteristics that is different between OT and methadone such as the timing and intensity of resultant euphoric effect. Third, providing free medication and care might increase the retention in treatment in both groups compared to usual treatment settings.    219 Among the strengths of this study were a sufficiently large sample size compared to previous studies on OST with opium and the comprehensive battery of assessments with repeated measurements. Furthermore, this clinical trial was unique in that it provided a potential basis for estimation of conversion ratio between methadone and OT for treatment of opioid dependence. In more details, since the scant evidence on optimum dosing strategy for OT in opioid dependence was not as firm as the buck of evidence for methadone, we primarily considered each 1mg of methadone approximately equal to 4mg of opium in terms of analgesic effects based on the available literature of pain research; however, knowing that effectiveness of medications on alleviating symptoms and retaining patients in treatment during withdrawal phase in opioid dependence is different from physical pain conditions, further strong evidence is needed for estimation of a reliable conversion ratio and dosing for OT. The patient-centered flexible dosing strategy in this study provided a mean for comparison of required mean dose of medication between OT and methadone treatment arms. This in turn served as a basis for both practice with OT in patients with opioid dependence and future similar studies.         220 12. Tables and figures Table 1. Secondary outcomes, method of measurement and analysis Measures Tool Description of tool Main reference Application in Iranian population Illicit drug use Self-report and urine toxicology Self-reports for all drugs, and urine toxicology for methamphetamines, THC, and cocaine will be applied using ABON 5 panel multi drug urine test kit  Company  Craving Visual Analogue Scale (VAS) (0-10)  marking on a 10-centimiter line in proportion to their craving from 0 (no carving) to 10 (the highest level of craving) Wewers and Love, 1990 (206)  Withdrawal Subjective Opioid Withdrawal Scale (SOWS) a self-administered scale containing 16 symptom items each on a scale of 0 (not at all) to 4 (extremely) Handelsman et al., 1987 (181) Assadi et al., 2004 (207); Kheirabadi et al., 2008 (208) Physical health Opiate Treatment Index (OTI)  A structured interview designed to provide a measure of the effectiveness of drug treatments through six outcomes including drug use, HIV risk-taking behavior, social functioning, criminality, health status, and psychological functioning. We only use the health section of the OTI, which is composed of items addressing signs and symptoms in major organ systems as well as injection-related health problems, and is designed to give an indication of the subject’s current state of health, especially in relation to those areas within which the individual drug user usually develops problems  Darke et al., 1992 (209) Esmaeili et al., 2014 (210); Azizi et al., 2010 (211)   221 Measures Tool Description of tool Main reference Application in Iranian population Psychological health Symptom Checklist-90-Revised (SCL-90-R)  A 90-item, brief, multidimensional checklist designed to assess psychopathology and psychological distress using 9 primary symptom dimensions: somatization, obsessive compulsive, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation, psychoticism. It is then expressed through three intensities: Global Severity Index, Positive Symptom Distress Index, and positive symptom total  Drogatis, 1994 (212) Noorbala et al., 2007 (213); Bagheriyazdi et al., 1994 (214) Severity of substance use problem Addiction Severity Index-5th (ASI-5th)  A semi-structured interview consisted of 200 items designed to address recent and lifetime problems in substance users in seven domains: medical status, employment and support, drug use, alcohol use, legal status, family/social status, and psychiatric status. The final score is calculated based on the manual in a range of 0-1  McLellan et al., 1992 (147) Ahmadi 2002 (125), 2003 (215) Cognitive function Montreal Cognitive Assessment (MOCA)  A brief screening measure designed to identify cognitive impairment using a one-page 30-point test format. Assessment domains include short-term memory, visuospatial abilities, executive function, attention, concentration, language, and orientation  Nasreddine et al., 2005 (216) Emsaki et al., 2011 (217)   222 Measures Tool Description of tool Main reference Application in Iranian population Quality of life World Health Organization Quality of Life-BREF (WHOQOL-BREF) Field Trial Version provides a short form quality of life assessment that includes 26 questions, among which 24 items come from the 24 facets contained in WHOQOL-100, and two other items represent overall quality of life and general health. Also, Quality-Adjusted Life-Month (QALM) and Quality-Adjusted Life-Year (QALY) will be calculated based on the WHOQOL-BEF World Health Organization 1996 (218) Nejat et al., 2006 (219); Jahanlou and Karami, 2011 (220) Client satisfaction Treatment Perception Questionnaire (TPQ) A 10-item scale for assessment of patients’ satisfaction in an addiction treatment program in two domains: perception of the clients towards the nature and extent of their contact with the program staff, and aspects of the treatment service and its operation and rules and regulations. Items are scored on a Likert scale of 1 (strongly agree) to 5 (strongly disagree) Marsden et al., 2000 (221) Ali et al., 2005 (222) Childhood trauma Childhood Trauma Questionnaire (CTQ) A standardized, retrospective 28-item self-report inventory that measures the severity of different types of childhood trauma. It contains five clinical subscales each comprised of five items scores on a Likert scale of 1(never) to 5(very often): emotional abuse, physical abuse, sexual abuse, emotional neglect, and physical neglect. The measure also includes a three-item minimization/denial subscale indicating the potential underreporting of maltreatment. These tree items are dichotomized as 0(never) or 1(all other responses) and summed up  Bernstein and Fink, 1998 (223) Naqavi, Mohammadi, Salari, & Nakhaee, 2011 (224)   223 Measures Tool Description of tool Main reference Application in Iranian population Stages of change University of Rhode Island Change Assessment Scale (URICA)  A 32-item measure with 4 subscales measuring the stages of change in an interview or self-report format: pre-contemplation, contemplation, action, and maintenance. Items are score on a Likert scale of 1 (strong disagreement) to 5 (strong agreement). Subscale scores are combined arithmetically to yield a second-order Readiness to Change score at entrance to treatment DiClemente et al., 2004 (225); McConnaughy et al., 1983 (226) Ghannadiasl et al., 2014 (227); Jafari et al., 2012 (228) Cost-effectiveness Substance Abuse Services Cost Analysis Program (SASCAP) Cost per QALM and QALY will be calculated using SASCAP and the methodology applied by Vanagas et al. (2010) for cost-utility analysis for each treatment arm Zarkin et al., 2004 (229); Vanagas et al. (2010) (230) Unavailable      224 Table 2. Schedule of study procedures Activity  Visit order  Day 1 -3   End of 1st week      End of 2nd week   End of 3rd week    Start of 5th week    Start of 9th week    Final visit (Day 85)   Screening and Baseline visits  1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 Informed consent form ×                               Medical history × × × × × × × × × × × × × × × × × × × × × × × × × × × × × × × Physical examination × × × × × × × × × × × × × × × × × × × × × × × × × × × × × × × Pregnancy test ×                      ×    ×    × Randomization ×                               Adverse event Report Form   × × × × × × × × × × × × × × × × × × × × × × × × × × × × × × Opiate Treatment Index (OTI) ×                      ×    ×    × Montreal Cognitive Assessment (MOCA)  ×                      ×    ×    × Addiction Severity Index-5th edition ×                      ×    ×    × World Health Organization Quality of Life-BREF ×                      ×    ×    × Symptom Checklist–90–Revised ×                      ×    ×    × Childhood Trauma Questionnaire ×                               Craving Visual analogue scale (0-10)  × × × × × × × × × × × × × × × × × × × × × × × × × × × × × × Subjective Opioid Withdrawal Scale  × × × × × × × × × × × × × × × × × × × × × × × × × × × × × × Treatment Perception Questionnaire (TPQ)                               ×   225 Activity Visit order  Day 1-3   End of 1st week      End of 2nd week   End of 3rd week     Start of 5th week    Start of 9th week    Final visit (Day 85) University of Rhode Island Change Assessment Scale (URICA) ×                               Blood tests1 ×                              × Urine toxicology2 ×                      ×    ×    ×  Viral profile3 ×                              × ECG ×                      ×    ×    × Visit Duration (minutes) 200 50-60  130 50-60  130 50-60  130 1 Hemoglobin, fasting blood sugar, liver function test (ALT, AST, Bilirubin (direct and indirect), albumin, total protein), renal function test (BUN, creatinine), lipid profile (LDL, HDL, Cholesterol, Triglyceride), viral infections (HBs antigen, HCV antibody, HIV EISA)  2 for methamphetamines, THC, and morphine, tramadol, 3 viral infections (HBS antigen, HCV antibody, HIV ELISA   226 Appendix C. Substitution treatment with opium tincture in Iran: learnings for harm reduction on a global scale. 1. Context  City, region and/or country  Located in the Middle East and with a population of more than 80 million people, Iran is the 19th most populous and the 16th largest country in the world (231). The official religion and language of the country are Islam and Persian (Farsi) respectively (232). Figure 1. Map of Iran     This map was obtained from Nations Online Project website (https://www.nationsonline.org/oneworld/map/iran_map.htm) on November 10, 2020  and was identified free to use for educational purposes.     227    Core mental health issues and subpopulation  With an annual prevalence of 3.31%, Iran has the highest rate of opiate consumption in the world (233). This is partly due to the widespread availability and low cost of opiates, given Iran’s close proximity to Afghanistan, the world’s largest producer of opiates (86% of global opium production in 2017) (233). Opium is the most popular opioid in Iran as its use is less stigmatized than the use of other opioids, including prescription opiates. Iran also has the highest rate of opium seizure (528,928 kg = 80% of total global seizures) and the second highest rate of morphine and heroin seizures (51,636 kg = 33% of total global seizure in 2016) globally, which reflects both the amount of trafficking and the level of law enforcement (233). In response to this high rate of consumption, Iran has developed one of the largest OST programs. The agonist medications on offer are methadone (~ 480,000 registered patients as of 2014), buprenorphine (~ 100,000 registered patients as of 2014) and OT (~26,000 registered patients as of 2014) in the order of frequency (85). Aside from Iran, there are reports of OT use for the treatment of opioid dependence in only a few other regions of the world (recently or historically) including Afghanistan, China,  Thailand, and France (though it is not used on as large a scale in any of these other places) (131). As such, this chapter aims to describe the case for using OT for OST in Iran. According to the Iranian Mental Health Survey (183), the 12-month prevalence of any psychiatric disorder was 23.6% in Iran; anxiety disorders, mood disorders, and substance use disorders were the most frequent psychiatric disorders respectively. Opioid dependence, with an   228 estimated prevalence of 2.23%, accounted for the majority of illicit substance use disorders (2.44%). Cannabis and amphetamine-type stimulants were the second and third most commonly used substances respectively (41). The use of the latter seems, alarmingly, to be on the rise (172). Crack heroin D (174) and Norjizak E (175) are substances which are largely unique to the Iranian drug market. Opioid dependence was more common among men, the divorced, the unemployed, and those with low socio-economic statuses (41).  This survey found that the opioid of choice for the majority of individuals with opioid dependence was opium, followed by opium extracts, methadone, heroin/crack heroin, and morphine  (41). The prevalence of injection in the last 12 months was 5%  (41). Concurrent mood and anxiety disorders were reported by 36% and 30% of those with opioid dependence respectively. Among those with opioid dependence (n =116) in this survey, 67% (n=80) reported any perceived need to use healthcare services, 60% (n=68) had used any services, and 30% (n=33) had used any healthcare services in the past 12 months. The most common services were self-help groups (40%), outpatient treatment (27%), and residential treatment (19%) (41).  2. Description of the intervention/program Defining the problem/situation leading up to the intervention/program  D Crack heroin is a heroin-based narcotic with a significant amount of acetyl codeine combined with heroin, codeine, caffeine, morphine, thebaine, and acetaminophen; it is different from cocaine-based crack, known as crack in most other countries’ drug markets. Iranian crack is taken both by sniffing and injection, and it differs from heroin since it is odorless and can be injected without the need for preheating.  E Norjizak is a combination of opioids with Dexamethasone or benzodiazepines. It is mainly injected and has been associated with a wide range of side effects including extensive skin infections and abscesses, corticosteroid side effects, significant risk of bloodborne infections, such as HCV, and increased mortality.   229 The history of using opium to treat opioid dependence in Iran goes back to 1968 when the government embarked on a 9-year program aimed at the treatment and control of substance use disorder. In this program, coupons were issued to approximately 180,000 registered patients who were either aged 60 and above or were diagnosed with a severe chronic illness. Registered patients were able to receive opium legally from the government for personal use. In 1977 (nine years after its establishment), the program underwent a formal evaluation and more restrictions were imposed, especially for young patients, as a result of the illegal spillover of opium distributed to non-registered individuals (122).  After the 1979 Revolution, drug policy shifted significantly in the country, leading to the criminalization of drug use and treatment. This was changed after a legislative initiative concerning substance use in 1994 opened the door to the development of treatment programs for substance use disorder for the first time since the government had changed. Initially limited to 14-day detoxification with clonidine, pharmacotherapy for patients with opioid dependence later included naltrexone in 1999. The program incorporated agonist treatments (methadone and buprenorphine) in 2001 (77).  Implementation and delivery Opium tincture is a clear, reddish-brown hydro alcoholic solution with a characteristic odor and bitter taste. Each 100 ml contains 1 g of anhydrous morphine in a 19% water solution of ethanol alcohol. Morphine is the active ingredient of OT with the chemical formula of C17H19NO3. Opium tincture, historically also known as laudanum, was first piloted as an agonist treatment for opioid dependence in Iran in 2005. The existing literature has documented the use of OT in the treatment of opioid dependence in other regions of the world, such as   230 Afghanistan, the Golden Triangle (Thailand, Laos, and Myanmar), China, and France (132,143–146). However, adequate robust evidence supporting its safety and efficacy for this purpose has not yet been published (131).  Opium tincture is a culturally acceptable medication for OST in Iran. Historically, famous Persian literature (which still has a strong influence on popular culture in Iran to this day) portrayed opium use in a positive way, describing it as a cure for every disease. Although the same is true for alcohol as well, its forbidden status in Islam prevented a similar rise in its use in Iran (129). However, these beliefs were not completely grounded on myth. In fact, opium and its tincture have been used as a panacea for many ailments throughout history, not only in Iran but also around the world (192). This practice dramatically increased during the 19th century in Iran due to the increased availability of opium and the lack of health services. Due to this historical use, opium still retains its reputation as a panacea in Iran, as several studies have shown (28). In a qualitative study by Jafari et al., chronic medical problems such as premature ejaculation, diabetes mellitus, high blood pressure, or pain were the second most commonly reported factors which prompted the initiation of opium use in a rural area in Iran (193). In another cross-sectional study of patients with diabetes, among whom 10.9% were currently using opium, 63.6% had started to use opium after being diagnosed and the rest had increased their use of the drug since then. A large percentage of these patients (72%) were advised to use opium to treat diabetes (234).  Given its cultural acceptability, it was theorized that OT may yield successful treatment outcomes for OST. This theory was first tested in a pilot 6-month study with 31 participants who were seeking treatment. In this study, 63% of the participants remained in treatment after 6 months and no major AE was observed among the participants (235). This is compared with a 6-  231 month retention in treatment of 69.2% and 71.7% for OST with buprenorphine and methadone respectively in low and middle-income countries (96). In 2010, OT was officially integrated by the Iranian Ministry of Health into the protocol for agonist treatments of opioid dependence (126). Within four years of its introduction, around 26,000 patients were being treated with this medication in Iran. A few key factors likely explain this widespread implementation within a relatively short period of time. Firstly, the provision of OT was facilitated in late 2011 by revisions to the protocol for agonist treatments, including an increased number of take-home doses and a reduced number of the unnecessary monitoring of staff and surveillance cameras in the designated clinics, making access to treatment less cumbersome for patients. Secondly, OT was exclusively administered as a pharmacotherapy by the NGO Congress 60, using a distinctive method devised by the founder of the NGO. With around 20,000 members (as of 2011), Congress 60 is one of the largest NGOs serving patients with substance use disorder in Iran, and it provides a multitude of services such as faith-based programs, designed in consecutive steps, peer-support programs, and pharmacotherapy with OT, tapered over 11 months (89). Thirdly, given the substantial amounts of opium seized in the country, OST with OT could be a cost-effective public health solution if seized opium is redirected towards the treatment of patients. Lastly, the pressures on resources for agonist treatments in Iran, caused by international sanctions which jeopardized the treatment of hundreds of thousands of patients in the country, persuaded the government to promote the widespread use of potential alternatives such as OT.  During the implementation of OST with OT in Iran, some studies (although not rigorously designed, conducted and/or reported) showed promising preliminary results on the outcomes of OT programs. These studies showed that OST with OT had a reasonable retention   232 rate, improved the quality of life among participants, was a cost-effective treatment, and was not associated with any major AEs. However, according to a systematic review in 2016, the results of studies on the safety and efficacy of OT in the treatment of opioid dependence were not conclusive at the time (131). In summary, this review identified nine completed studies with available reports on the use of OT for the treatment of opioid dependence; among these studies, only five (with a total sample size of 570 participants—four prospective and one retrospective uncontrolled case series) were related to the long-term/maintenance treatment of opioid dependence as opposed to detoxification/withdrawal management. Although the retention rates of these studies were high (7178%), all of the study designs were uncontrolled, the outcome measurements were inconsistent across the board, the overall risk of bias was high, and the details of the intervention were poorly reported.   Given the inconclusive published evidence on OST, the opium trial was designed to compare OT with methadone with regards to retaining participants in treatment (161). The opium trial was a multicentre, randomized, double-blind, controlled clinical trial which recruited 204 participants between July 2017 and January 2018 and was concluded in April 2018. Patients were randomized to receive OT or methadone using a patient-centered flexible dosing strategy and were followed for 12 weeks. In each group, 101 individuals received the allocated intervention. In ITT analysis (n =102 in each arm), 70 (68.6%) and 61 (58.8%) participants remained in treatment until the end of the 12-week follow-up period. Similarly, in PP analysis (n=101 in each arm), 70 (69.3%) and 61 (60.3%) participants remained in treatment. The relative rate of retention in methadone to opium in both ITT and PP analyses was 1.15, 90% CI [0.97, 1.36 corresponding to one-sided 95% CI. This CI ruled out the M1 (3.26) indicating that OT is a clinically effective medication for OST. However, the upper bound did not rule out M2 (1.25),   233 indicating that the study was not able to determine whether or not OT is equally as effective as methadone when it comes to retaining patients in treatment. To clarify, M1 is equal to the entire effect of the active control (methadone in this case) compared to the placebo. M1 is not directly measured in non-inferiority studies and is estimated based on the performance of the active control in previous studies. M2, often a smaller margin with a set equal to a certain proportion of the M1, is then defined as the largest clinically-acceptable difference of the test drug (OT) compared to the active control (182). No major AE was observed in the study.   3. Concluding the case, presentation and identification of follow-up issues to be examined   Given the growing body of evidence on the use of OT for OST, it seems very likely that it will remain one of the medications for opioid dependence, at least in those parts of the world where the availability of opium is widespread. As described above, the opium trial did not have enough evidence to conclude the non-inferiority of OT compared to methadone. This gap will necessitate further trials which are able to determine this comparison or, if further trials are not feasible, the accumulation of additional data which can be merged with the opium trial data to determine this comparison using meta-analytic approaches. Further research can also explore and determine which patients are the ideal candidates for treatment with OT and which candidates may benefit less from this option.    A cautionary note on the further use of OT for pharmacotherapy is the body of evidence which has found an association between illicit opium use and certain cancers (236–238). However, these studies are mostly exploring this association for illicit opium, which is not exactly the same substance as OT, as it is often adulterated with various substances, such as lead,   234 and often smoked in addition to oral use. Nonetheless, further study into this association is still warranted for individuals who are receiving OT as a medication.  Discussion Questions (x3) 1) What are the potential benefits of including OT in the repository of medications for OST on a global level? 2) What are the potential criteria for patients with opioid dependence who might respond either well or poorly to treatment with OT? 3) What are the lessons learnt from this case study for harm reduction on a global level? Supplemental Reading (x3) 1) Nikoo M, Nikoo N, Anbardan SJ, Amiri A, Vogel M, Choi F, et al. Tincture of opium for treating opioid dependence: a systematic review of safety and efficacy. Addiction. 2017 Mar;112(3):415–29.  2) White WL. Congress 60: An addiction recovery community within the Islamic republic of Iran. Alcohol Treat Q. 2015 DOI: 10.1080/07347324.2015.1050929 3) Ekhtiari H, Noroozi A, Farhoudian A, Radfar SR, Hajebi A, Sefatian S, et al. The evolution of addiction treatment and harm reduction programs in Iran: a chaotic response or a synergistic diversity? Addiction. 2020 DOI: 10.1111/add.14905      235 4. Tables and figures Table 1. Basic Socioeconomic and Demographic Indicators INDICATOR  YEAR UN Human Development Index ranking         60 (out of) 189 2017 Population (thousands) 81,162,788 2017 Urban population (%) 74.4 2017 Drinking water coverage (%) 94.9 2015 Poverty rate (% living under USD 1.25 per day) 1.5 2005 Gini index 40 2016 GDP per capita in PPP (constant 2005 international dollars) 1484945934180 2017 GDP per capita (constant 2000 USD) 6734  2017 Literacy (total/female/male) (%) (86/81/90) 2016      236 Table 2. Health System and Epidemiologic Indicators INDICATOR  YEAR Average life expectancy at birth (total/female/male) (76/77/75) 2017 Infant mortality rate (per 1,000 live births)  13 2017 Government expenditure on health as % of GDP 8.1 2016 Government mental health spending as % of Government expenditure on health 3% 2011 % of mental health expenditures spent on mental hospitals 17% 2011 MNSS DALYs as a % of total DALYs 22% 2017 Mental health workforce (per 100,000) 65 2011 Psychiatrists working in mental health sector (per 100,000) 1 2017 Nurses working in mental health sector (per 100,000) 8 2017 Social workers working in mental health sector (per 100,000) 1 2017 Psychologists working in mental health sector (per 100,000) 2 2017 **(other case specific indicators of interest)     

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