Graduate and Postdoctoral Studies
DSpace
UBCV
Pilarinos, Andreas
Doctor of Philosophy - PhD
University of British Columbia
Background: Adolescents and young adults (AYA) continue to be impacted by the toxic drug crisis. This dissertation sought to examine AYAs’ experiences with opioid agonist treatment (OAT) to inform treatment programming and improve health outcomes and well-being among AYA who use opioids. Methods: A systematic review of literature examining access to medications for opioid use disorder (MOUD), including prescription and non-prescription opioids, was conducted from electronic database inception until May 3, 2021. Quantitative analyses derived data from the At-Risk Youth Study, an open, prospective cohort of street-involved AYA who use drugs in Vancouver, Canada, to examine OAT access and outcomes, interest in buprenorphine-naloxone, and factors associated with methadone maintenance therapy (MMT) discontinuation between December 2005 and June 2018. Longitudinal qualitative exploration into experiences navigating OAT and barriers to engagement, retention, and completion were conducted with AYA between January 2018 and August 2020. Results: Systematic review findings suggest AYA are less likely to access MOUD versus adults, and that adolescents are more likely to be prescribed partial opioid agonists. In before and after analysis of OAT outcomes among 454 AYA, greater reductions in daily illicit opioid were observed among AYA retained in OAT versus AYA who did not initiate OAT (-1.83 vs. -0.63, p=0.015), but no other reductions were observed. Low levels of initial buprenorphine-naloxone interest were reported (n=60, 13.4%), which was negatively associated with self-reported Indigenous identity, and racial or ethnic identity, while later study follow-up period was negatively associated with buprenorphine-naloxone interest over time. A majority of 160 AYA who initiated MMT over the study period discontinued MMT (n=102, 63.8%), which was found to be positively associated with crystal methamphetamine use. Lastly, qualitative findings demonstrate barriers experienced by AYA navigating OAT and highlight ways to improve OAT access, engagement, and discontinuation. Conclusions: Findings from this dissertation suggest OAT alone is insufficient for helping AYA to meet their treatment goals. AYA require access to essential socioeconomic supports alongside culturally safe and patient-centered treatments and a broader range of OAT. Clinical treatment guidelines require updating to align with AYAs’ needs while recognizing the potential harms of overmedicalizing treatment.
Medications for opioid use disorder among young people: evidence to improve treatment experiences and outcomes in Vancouver, Canada by Andreas Pilarinos B.Sc., Simon Fraser University, 2013 M.P.P., Simon Fraser University, 2016 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Interdisciplinary Studies) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) December 2022 © Andreas Pilarinos, 2022 ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the dissertation entitled: Medications for opioid use disorder among young people: evidence to improve treatment experiences and outcomes in Vancouver, Canada submitted by Andreas Pilarinos in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Interdisciplinary Studies Examining Committee: Dr. Jane Buxton, Professor, School of Population and Public Health, UBC Co-Supervisor Dr. Kora DeBeck, Associate Professor, School of Public Policy, Simon Fraser University Co-Supervisor Dr. Danya Fast, Assistant Professor, Department of Medicine, UBC Supervisory Committee Member Dr. Patricia Sptittal, Professor, School of Population and Public Health, UBC University Examiner Dr. Carolyn Szostak, Associate Professor, Department of Psychology, UBC Okanagan University Examiner iii Abstract Background: Adolescents and young adults (AYA) continue to be impacted by the toxic drug crisis. This dissertation sought to examine AYAs’ experiences with opioid agonist treatment (OAT) to inform treatment programming and improve health outcomes and well-being among AYA who use opioids. Methods: A systematic review of literature examining access to medications for opioid use disorder (MOUD), including prescription and non-prescription opioids, was conducted from electronic database inception until May 3, 2021. Quantitative analyses derived data from the At-Risk Youth Study, an open, prospective cohort of street-involved AYA who use drugs in Vancouver, Canada, to examine OAT access and outcomes, interest in buprenorphine-naloxone, and factors associated with methadone maintenance therapy (MMT) discontinuation between December 2005 and June 2018. Longitudinal qualitative exploration into experiences navigating OAT and barriers to engagement, retention, and completion were conducted with AYA between January 2018 and August 2020. Results: Systematic review findings suggest AYA are less likely to access MOUD versus adults, and that adolescents are more likely to be prescribed partial opioid agonists. In before and after analysis of OAT outcomes among 454 AYA, greater reductions in daily illicit opioid were observed among AYA retained in OAT versus AYA who did not initiate OAT (-1.83 vs. -0.63, p=0.015), but no other reductions were observed. Low levels of initial buprenorphine-naloxone interest were reported (n=60, 13.4%), which was negatively associated with self-reported iv Indigenous identity, and racial or ethnic identity, while later study follow-up period was negatively associated with buprenorphine-naloxone interest over time. A majority of 160 AYA who initiated MMT over the study period discontinued MMT (n=102, 63.8%), which was found to be positively associated with crystal methamphetamine use. Lastly, qualitative findings demonstrate barriers experienced by AYA navigating OAT and highlight ways to improve OAT access, engagement, and discontinuation. Conclusions: Findings from this dissertation suggest OAT alone is insufficient for helping AYA to meet their treatment goals. AYA require access to essential socioeconomic supports alongside culturally safe and patient-centered treatments and a broader range of OAT. Clinical treatment guidelines require updating to align with AYAs’ needs while recognizing the potential harms of overmedicalizing treatment. v Lay summary Opioid-related overdose is the leading cause of unintentional injury death, which continues to impact young people. This dissertation examined the experiences of young people who use opioids when accessing medications for opioid use disorder (MOUD) using quantitative and qualitative data from a study of street-involved youth and treatment programs located in Vancouver, Canada between December 2005 and August 2020. Evidence from this dissertation found that MOUD are an important treatment for many street-involved young people, but that many young people are hesitant to start treatment or face challenges when trying to access, stay on, and stop using MOUD. Therefore, results suggest that to improve young peoples’ treatment experiences and outcomes, there is a need to: provide housing, education, employment, and other essential supports; provide culturally safe and patient-centered treatments, including a broad range of MOUDs; and, update treatment guidelines to reduce barriers to MOUD while raising caution around overmedicalizing treatment. vi Preface This statement is intended to certify that the work as presented in this dissertation was conceptualized, conducted, written, and disseminated by the candidate, Andreas Pilarinos (AP), with guidance from Dr. Jane Buxton (Supervisor), Dr. Kora DeBeck, and Dr. Danya Fast (Supervisory Committee Members). All co-authors of the manuscripts – Dr. Jane Buxton (JB), Dr. Kora DeBeck (KD), Dr. Danya Fast (DF), Dr. Brittany Bingham (BB), Dr. Ronald Joe (RJ), Yandi Kwa (YK), Dr. Ekaterina Nosova (EN), Dr. Huiru Dong (HD), Janet Mok (JM), Cameron Grant (CG), Dr. Mohammad Karamouzian (MK), and Daniel J. Bromberg (DJB) – made contributions consistent with co-investigator, collegial, or supervisory committee responsibilities. All empirical research conducted in Chapters 3-5 received approval from the University of British Columbia/Providence Health Care Research Ethics Board (study ID#: H05-50160). The quantitative data presented in Chapters 3-5 were derived from the At-Risk Youth Study (ARYS) and accessible to the Principal Investigator (KD), who takes responsibility for the accuracy of all analyses and the integrity of the research results. The qualitative data presented in Chapter 6 was collected by the ARYS Qualitative Research Team, led by DF. The contributions and status of each of the Chapters are outlined hereafter: A version of Chapter 2 has been published and is presented in accordance with journal and university guidelines: AP, DJB, MK. (2022). Access to medications for opioid use disorder (MOUD) among adolescents and young adults: a systematic review. JAMA Pediatrics. (Volume 176, Issue Number 3, Pages 220-332). AP conceptualized and was the lead investigator of this vii study, and responsible for the search strategy design, record screening, data extraction and interpretation, writing and preparing the manuscript. DJB and MK supported the search strategy design, record screening, interpretation of the findings, and providing feedback on the manuscript. Permission to publish parts of the manuscript in this dissertation has been granted by the publisher (AMA United States) through communication dated December 10, 2021 (License #: 5205530170172) A version of Chapter 3 has been published and is presented in accordance with journal and university guidelines: AP, DF, EN, YK, RJ, JB, KD. (2022). “Initiation of opioid agonist treatment and subsequent substance use and other patterns among adolescents and young adults in Vancouver, Canada”. Drug and Alcohol Dependence. (Volume 235, Page 109441). Chapter 3 was conceptualized by AP and KD, who guided the statistical analyses conducted by EN and JM. The initial draft was prepared by AP, and DF, EN, YK, RJ, JB, and KD provided critical feedback. All authors approved the final manuscript for submission. A version of Chapter 4 is under peer-review for publication: AP, BB, CG, YK, RJ, DF, JB, KD. “Willingness to use buprenorphine-naloxone among a prospective cohort of street-involved youth in Vancouver, Canada”. This analysis was conceptualized by AP and KD. AP significantly guided the statistical analyses conducted by CG, with the support of KD. The initial draft was prepared by AP, and BB, CG, YK, RJ, DF, JB, and KD provided critical feedback. All authors approved the final manuscript for submission. viii A version of Chapter 5 has been published and is presented in accordance with journal and university guidelines: AP, YK, RJ, HD, CG, DF, JB, KD. (2022). “Methadone maintenance treatment discontinuation among a prospective cohort of street-involved youth in Vancouver, Canada”. Canadian Journal of Psychiatry. This analysis was conceptualized by AP and KD. Statistical analyses were conducted by HD and CG, which AP guided with the support of KD. The initial draft was prepared by AP, and HD, CG, YK, RJ, DF, JB, and KD provided critical feedback. All authors approved the final manuscript for submission. A version of Chapter 6 has been published: AP, YK, RJ, MT, JB, KD, DF. (2022). “Navigating opioid agonist treatment among youth who use illicit opioids in Vancouver, Canada”. International Journal on Drug Policy. (Volume 107, Pages 103773). Participant recruitment and data collection were conducted by DF and MT. Thematic analysis was conducted by AP with the support of DF. The initial draft was prepared by AP, and DF, YK, RJ, MT, JB, and KD provided critical feedback. All authors approved the final manuscript for submission. ix Table of contents Abstract ........................................................................................................................................ iii Lay summary ................................................................................................................................. v Preface ........................................................................................................................................... vi Table of contents ........................................................................................................................... ix List of tables ................................................................................................................................. xv List of figures ........................................................................................................................... xviii List of abbreviations ................................................................................................................... xix Acknowledgements ...................................................................................................................... xx Dedication ................................................................................................................................. xxiii Chapter 1: Introduction ................................................................................................................ 1 1.1 The toxic drug crisis and the impact on young people .................................................... 1 1.2 Medications for opioid use disorder for adolescents and young adults ........................... 2 1.2.1 Opioid agonist treatments ........................................................................................ 3 1.2.1.1 Partial opioid agonist treatments ......................................................................... 4 1.2.1.2 Full opioid agonist treatments ............................................................................. 5 1.2.2 Opioid antagonist treatments ................................................................................... 6 1.3 Research on opioid agonist treatments among adolescents and young adults in Vancouver, Canada ...................................................................................................................... 7 1.4 Toxic drug crisis and policy changes over the study period ............................................ 9 1.4.1 Establishment of the Inner City Youth Program ..................................................... 9 1.4.2 Establishment of the Youth Intensive Case Management Team ........................... 10 1.4.3 Reformulation of methadone to Methadose™ ...................................................... 11 x 1.4.4 OxyContin™, fentanyl, and the declaration of the 'overdose crisis’ ..................... 12 1.4.4.1 Introduction of youth-specific clinical treatment guidelines for OUD .............. 13 1.4.4.2 COVID-19 and the implementation of interim Risk Mitigation Guidance ....... 14 1.5 Study justification .......................................................................................................... 15 1.6 Conceptual framework .................................................................................................. 16 1.7 Study objectives ............................................................................................................. 18 1.8 Study design & methods ................................................................................................ 22 1.9 Summary of dissertation chapters .................................................................................. 24 Chapter 2: Access to medications for opioid use disorder and associated factors among adolescents and young adults: a systematic review .................................................................. 29 2.1 Introduction ................................................................................................................... 29 2.2 Methods ......................................................................................................................... 30 2.2.1 Population, intervention, comparisons, outcomes ................................................. 30 2.2.2 Search strategy ....................................................................................................... 31 2.2.3 Screening, inclusion and exclusion criteria, and quality assessment .................... 32 2.3 Results ........................................................................................................................... 32 2.3.1 Access to MOUD ................................................................................................... 33 2.3.2 Age-related factors ................................................................................................ 34 2.3.3 MOUD access over time ........................................................................................ 35 2.3.4 Health and social systems related factors .............................................................. 36 2.3.5 Substance use and personal health related factors ................................................. 38 2.3.6 Socioeconomic and educational factors ................................................................ 40 2.3.7 Geographical or population-density factors .......................................................... 41 xi 2.3.8 Criminal justice system related factors .................................................................. 42 2.3.9 Racial or ethnic identity related factors ................................................................. 42 2.3.10 Sex-based factors ................................................................................................... 43 2.4 Discussion ...................................................................................................................... 44 2.5 Conclusions ................................................................................................................... 48 Chapter 3: Time to opioid agonist treatment initiation and before and after substance use and other patterns among adolescents and young adults in Vancouver, Canada ................. 75 3.1 Introduction ................................................................................................................... 75 3.2 Methods ......................................................................................................................... 76 3.2.1 Study Sample ......................................................................................................... 76 3.2.2 Study Variables ...................................................................................................... 76 3.2.3 Statistical approach ................................................................................................ 78 3.2.3.1 Baseline comparisons ........................................................................................ 79 3.2.3.2 Cox regression analysis ..................................................................................... 79 3.2.3.3 Non-linear growth curve analysis ...................................................................... 80 3.2.3.3.1 Case groups definition: ‘Retained’ and ‘discontinued’ OAT ...................... 81 3.2.3.3.2 Control group definition: ‘No OAT’ ........................................................... 81 3.2.3.4 Matching of cases to control trios ...................................................................... 82 3.2.3.5 Within-group changes among case and control groups ..................................... 82 3.2.3.6 Between-group changes between case and control groups ............................... 83 3.3 Results ........................................................................................................................... 83 3.4 Discussion ...................................................................................................................... 86 3.5 Conclusions ................................................................................................................... 89 xii Chapter 4: Buprenorphine-naloxone willingness among adolescents and young adults in Vancouver, Canada ..................................................................................................................... 97 4.1 Introduction ................................................................................................................... 97 4.2 Methods ......................................................................................................................... 99 4.2.1 Study Sample ......................................................................................................... 99 4.2.2 Study Variables .................................................................................................... 100 4.2.3 Statistical Analyses .............................................................................................. 102 4.2.3.1 Baseline comparisons ...................................................................................... 102 4.2.3.2 Logistic regression analysis ............................................................................. 103 4.2.3.3 Cox regression analysis ................................................................................... 103 4.3 Results ......................................................................................................................... 104 4.4 Discussion .................................................................................................................... 106 4.5 Conclusions ................................................................................................................. 112 Chapter 5: Methadone maintenance treatment discontinuation among adolescents and young adults in Vancouver, Canada ........................................................................................ 118 5.1 Introduction ................................................................................................................. 118 5.2 Methods ....................................................................................................................... 121 5.2.1 Study Sample ....................................................................................................... 121 5.2.2 Study Variables .................................................................................................... 123 5.2.3 Statistical analyses ............................................................................................... 124 5.2.3.1 Baseline comparisons ...................................................................................... 124 5.2.3.2 Extended Cox regression analysis ................................................................... 125 5.3 Results ......................................................................................................................... 126 xiii 5.4 Discussion .................................................................................................................... 128 5.5 Conclusions ................................................................................................................. 132 Chapter 6: Adolescent and young adults’ experiences navigating the OAT continuum in Vancouver, Canada ................................................................................................................... 138 6.1 Introduction ................................................................................................................. 138 6.2 Methods ....................................................................................................................... 139 6.2.1 Study Sample ....................................................................................................... 140 6.2.2 Study Procedures ................................................................................................. 140 6.2.3 Thematic Analysis ............................................................................................... 142 6.3 Results ......................................................................................................................... 143 6.3.1 OAT contemplation and initiation ....................................................................... 144 6.3.2 OAT maintenance and retention .......................................................................... 148 6.3.3 Tapering off and OAT discontinuation ............................................................... 152 6.4 Discussion .................................................................................................................... 154 6.5 Conclusions ................................................................................................................. 160 Chapter 7: Conclusions ............................................................................................................. 162 7.1 Summary of findings and contributions of this dissertation ........................................ 162 7.2 Overall contribution to the literature on OAT among AYA ....................................... 165 7.3 Policy implications and recommendations .................................................................. 170 7.4 Study strengths and limitations .................................................................................... 176 7.5 Recommendations for future research ......................................................................... 180 7.6 Knowledge translation plan ......................................................................................... 182 7.7 Conclusions ................................................................................................................. 183 xiv References ................................................................................................................................... 185 xv List of tables Table 2.1 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist for a systematic review of MOUD access and associated factors among adolescents and young adults who use opioids. ....................................................................................................... 50 Table 2.2 Population, exposures, comparisons, outcomes, and study design inclusion criteria. .. 53 Table 2.3 Medline search strategy for a systematic review on MOUD access and associated factors among adolescents and young adults who use opioids. ..................................................... 54 Table 2.4 Risk of bias assessment for cohort studies using the modified Newcastle-Ottawa Scale. ....................................................................................................................................................... 57 Table 2.5 Risk of bias assessment for cross-sectional studies using the modified Newcastle-Ottawa Scale. ................................................................................................................................. 58 Table 2.6 Risk of bias assessment for qualitative studies using the GRADE-CERQual Scale. .... 59 Table 2.7 Summary of included studies examining MOUD access and associated factors among adolescents and young adults who use opioids. ............................................................................ 60 Table 2.8 Summary of study findings from included studies examining MOUD access and associated factors among adolescents and young adults who use opioids. ................................... 66 Table 3.1 Baseline characteristics of AYA who reported recent weekly opioid use stratified by initiation of OAT over the study period (September 2005 to June 2018) (n=454). ...................... 91 Table 3.2 Cox Proportional Hazard regression analysis of factors associated with time to first opioid agonist treatment among AYA who reported recent weekly opioid use (n=454). ............. 92 Table 3.3 Substance use, difficulty accessing health services, incarceration, and homelessness patterns in the period before and after opioid agonist treatment (OAT) among participants who were retained in OAT (n=108) vs. controls who did not access OAT (n= 207). .......................... 93 xvi Table 3.4 Substance use, difficulty accessing health services, incarceration, and homelessness patterns in the period before and after opioid agonist treatment (OAT) among participants not retained in OAT (n=52) vs. controls who did not access OAT (n=95). ........................................ 94 Table 3.5 Non-linear growth curve analyses of substance use, difficulty accessing health services, incarceration, and homelessness patterns between cases retained on OAT (n=108) vs. controls who did not access OAT (n=207). ................................................................................... 95 Table 3.6 Non-linear growth curve analyses of substance use, difficulty accessing health services, incarceration, and homelessness patterns between cases retained on OAT (n=52) vs. controls who did not access OAT (n=95). ..................................................................................... 96 Table 4.1 Baseline characteristics of adolescents and young adults in Vancouver, Canada stratified by an interest in using buprenorphine-naloxone when first asked between December 2014 and June 2018 (n=447). ...................................................................................................... 114 Table 4.2 Bivariate and multivariable logistic regression of factors associated with an initial interest in using buprenorphine-naloxone among AYA between December 2014 and June 2018 (n=447). ....................................................................................................................................... 115 Table 4.3 Reasons for an initial disinterest in buprenorphine-naloxone (n=387, 402 observations) and over follow-up (n=163, 532 observations) among AYA between December 2014 and June 2018. ............................................................................................................................................ 116 Table 4.4 Bivariate and multivariable Cox proportional hazard model of factors associated with time to a change in interest in using or actual buprenorphine-naloxone enrolment among street-involved AYA between December 2014 and June 2018 (n=248). .............................................. 117 xvii Table 5.1 Baseline descriptive statistics of adolescents and young adults (AYA) who reported initiating methadone maintenance treatment (MMT) or Methadose stratified by ever reporting MMT discontinuation between December 2005 and June 2018 (n=160). .................................. 134 Table 5.2 Reasons for MMT discontinuation among a prospective cohort of street-involved AYA who initiated and discontinued MMT at some point between December 2005 and June 2018 in Vancouver, Canada (n=119). ....................................................................................................... 135 Table 5.3 Bivariate and multivariable extended Cox proportional hazard model of factors associated with time to MMT discontinuation among street-involved AYA who reported initiating MMT between December 2005 and June 2018 (n=137). ............................................ 136 Table 5.4 Bivariate and multivariable extended Cox proportional hazard model of factors associated with time to MMT discontinuation that could be addressed through policy change among AYA who reported initiating MMT between December 2005 and June 2018 (n=62). ... 137 xviii List of figures Figure 1.1. Timeline of policy and health-service delivery related changes over the study period of the proposed analyses. ............................................................................................................... 27 Figure 1.2. Conceptual framework to examine opioid agonist treatment (OAT) among adolesecnts and young adults who use opioids in Vancouver, Canada, as adapted from the risk environment’74 and patient-centered accessibility75 frameworks. ................................................. 28 Figure 2.1 The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Flow Diagram. ............................................................................................................................... 56 Figure 4.1 Flow-chart of disinterest in using buprenorphine-naloxone or enrolling in buprenorphine-naloxone among adolescents and young adults in Vancouver, Canada between December 2014 and June 2018. ................................................................................................... 113 xix List of abbreviations AHR Adjusted hazard ratio AIC Akaike information criterion AOR Adjusted odds ratio AYAs Adolescents and young adults ARYS At-Risk Youth Study BC British Columbia BCCSU British Columbia Centre on Substance Use CI Confidence interval CES-D Centre for Epidemiological Studies – Depression CM Crystal methamphetamine COVID-19 Coronavirus disease of 2019 DTES Downtown Eastside DSM-V Diagnostic and Statistical Manual of Mental Disorders – 5th Edition HCV Hepatitis C virus HIV Human immunodeficiency virus ICM Intensive Case Management ICY Inner City Youth IQR Interquartile range LGBTQIA2S+ Lesbian, gay, bisexual, transgender, queer or questioning, intersexual, asexual, and Two-Spirit L6M Last-six-months MAT Medication-assisted treatment or therapy MMT Methadone maintenance treatment or therapy MOUD Medications for opioid use disorder NA/CA/AA/SMART Narcotics Anonymous, Cocaine Anonymous, Alcoholics Anonymous, and Self-Management and Recovery Training NMPOU Non-medical prescription opioid use OAT Opioid agonist treatment OR Odds ratio OUD Opioid use disorder RCT Randomized controlled trial RMG Risk Mitigation Guidance SROM Slow-release oral morphine SUD Substance use disorder USA United States of America VCH Vancouver Coastal Health YAC Youth Advisory Council xx Acknowledgements I acknowledge the caretakers of the land where this research was conducted and extend my sincere appreciation and gratitude to the Musqueam, Squamish, and Tsleil-Waututh Nations for the opportunity to live and work on their occupied, ancestral territories as an uninvited guest and settler. I also extend my greatest thanks to all ARYS participants and young people who participated in this research. Your contributions to this dissertation have provided hope and inspiration to countless young people around the world, and it is a privilege and honor to have the opportunity to bring your experiences and perspectives to the forefront. To Dr. Kora DeBeck and Dr. Jane A. Buxton, I thank you for the growth you have fostered in me throughout my academic journey, and for your generosity, kindness, and patience. I am forever grateful for the opportunities that you have provided me and the knowledge you have imparted on me, and I am inspired and motivated by your tireless dedication to improving the health and well-being of people who use drugs. I would also like to extend my utmost gratitude to Dr. Danya Fast, whose knowledge and expertise has been central to guiding this dissertation and illuminating the voices of young people who use drugs. To Dr. Ronald Joe, Yandi Kwa and Lizzy Ambler, I thank you for the critical insights and perspectives you brought to this work. I also thank all BCCSU and ARYS staff and my fellow students for your support and camaraderie throughout this research, including Dr. Mohammad Karamouzian, Dr. Huiru Dong, Dr. Kate xxi Jaffee, Dr. Stephanie Lake, Dr. Brittany Barker, Dr. Tessa Cheng, Sanjana Mitra, Dr. Michelle Olding, Trevor Goodyear, Allison Laing, Dr. Tara Beaulieu, Dr. Ekaterina Nosova, Janet Mok, Cameron Grant, JinCheol Choi, Marina Abramishvili, Ana Prado, and Daniel J. Bromberg. I also extend my deepest gratitude to the Indigenous Health team at Vancouver Coastal Health for your unwavering support, including Dr. Brittany Bingham, Leslie Bonshor, Elder Roberta Price, Elder Doris Fox, Dr. Krisztina Vasarhelyi, Shannon Field, Chenoa Cassidy-Matthews, Sandra Fox, Nicole Dawydiuk, and everyone else on the Indigenous Health team. Your support and help were central to me completing my dissertation work, and I thank you all for your friendship and encouragement along the way. This research was funded through a Four-Year Fellowship from the University of British Columbia, and I am thankful to the Interdisciplinary Studies Graduate Program for providing me with this support. I particularly want to thank Enid Ho for supporting me throughout my studies and for the incredible and essential work she does to uplift and empower students. I also owe my progress to the endless love and motivation of the Pilarinos, Palis, Whiteman, Katsiamitas, and Cicek families, as well as my Eastside family, including the Karra, Mah, Ironside, and Carney families. I thank you for everything you have done for me and am grateful to have you as my family. xxii To Heather, you are the best companion and partner I could have ever asked for and it is a privilege to have you in my life. Your dedication, perseverance, and thoughtfulness have been an inspiration to me, and I will forever appreciate your encouragement and support. xxiii Dedication This work is dedicated to my family, friends, community members, and all others lost to the ongoing toxic drug crisis and War on Drugs.1 Chapter 1: Introduction 1.1 The toxic drug crisis and the impact on young people Across North America, toxic drug poisoning is the leading cause of unintentional injury death.1-4 According to public health experts, the sharp increase in toxic drug poisoning fatalities can be attributed to the heightened presence of potent synthetic opioids and opioid-analogues, such as fentanyl and carfentanil, within the illicit drug supply.5-7 In Vancouver, British Columbia, Canada, the study setting that this dissertation is situated within, it is therefore suspected that the existing supply of illicit “heroin” is largely composed of these synthetic opioids,8 which has contributed to a high number of toxic drug poisoning fatalities9. This toxic drug poisoning crisis, often referred to as the ‘overdose crisis’, has also been exacerbated by the ongoing COVID-19 pandemic, where recent research found that the number of toxic drug poisoning fatalities between March 17th, 2020 – when the COVID-19 pandemic was declared – to December 31st, 2020 (n=1,516) were over double the number of fatalities reported over the same period in 2019 (n=744).10 Evidence from North America indicates that adolescents and young adults (AYA) represent a significant proportion of toxic drug poisonings and deaths. For example, in the United States of America (USA), the toxic drug poisoning fatality rate for those aged 15-24 increased from 3.2 per 100,000 in 1999 to 12.6 per 100,000 in 2017, and from 8.1 per 100,000 in 1999 to 38.4 per 100,000 in 2017 for those aged 25-34.11 Estimates from Canada similarly suggest that between 2016 and 2018, approximately 21% of toxic drug poisoning fatalities were among adolescents and young adults (AYA) under the age of 30,12 while the recent British Columbia Coroners Service report, 2 titled Illicit Drug Toxicity Deaths in BC: January 1, 2012 – August 31, 2022, found that those under the age of 30 represent approximately 19% of all toxic drug poisoning deaths,9 despite evidence that AYA between the ages of 12-24 only represent 6.3% of all people diagnosed with an opioid use disorder (OUD) in British Columbia.13 Given that AYA who use drugs are experiencing several syndemics – that not only include the toxic drug poisoning crisis and the COVID-19 pandemic, but ongoing colonization, entrenched poverty, and unstable housing, among other forms of structural violence – urgent efforts have been taken to reduce harms and improve the health and well-being of this highly marginalized and stigmatized population.14-17 1.2 Medications for opioid use disorder for adolescents and young adults One intervention with the potential to reduce the harms of the toxic drug poisoning crisis includes expanding access to medications for opioid use disorder (MOUD). A growing body of literature has pointed to the potential benefits of MOUD in reducing illicit opioid use, improving treatment retention, and supporting long-term recovery.18-20 MOUD are a group of drugs that are used in the treatment of OUD, with the purpose of substituting illicitly-sourced and potentially contaminated drugs with pharmaceutical-grade alternatives. MOUD include opioid agonist treatments (OAT), which are also known as opioid agonist therapies (e.g., methadone, injectable diacetylmorphine, slow-release oral morphine, hydromorphone), partial opioid agonist treatments (e.g., buprenorphine-naloxone), and opioid antagonist treatments (e.g., naltrexone). These medications are an important part of the treatment continuum for people with OUD as they can help mitigate withdrawal symptoms, reduce cravings, and provide safer alternatives to the illicit drug supply. 3 While increasing evidence supports the use of MOUD among adult populations,21 similar attention to the experiences and perspectives of AYA who use opioids and engage in MOUD is limited. For example, some research on MOUD among AYA suggests that it is an effective and important intervention that can be used to treat OUD in this population;18-20 however, a 2013 study from the United States found that only 2.4% of adolescents seeking treatment for heroin use disorder received access to methadone maintenance treatment (MMT) or buprenorphine when compared to 26.3% of adults over the same period.22 Similarly, recent research from British Columbia found that a smaller proportion of AYA accessed OAT in comparison to adult populations,13 highlighting concerning discrepancies in OAT access between AYA and adults. Given concerns of prescribers’ reluctance to provide OAT to AYA,23 and evidence of some ambivalence towards OAT among AYA,24, 25 there are important gaps in our understanding of OAT among AYA that require further attention.26, 27 1.2.1 Opioid agonist treatments Opioid agonist treatments are a subgroup of MOUD with a good safety profile and tolerance among people with OUD.26 Due to their high affinity for mu-opioid receptor sites, OAT act as a substitute for illicit opioids thus preventing withdrawal symptoms, addressing cravings, and reducing the toxic drug poisoning risk among people who use opioids.26 Given the proven ability of OAT to reduce harms and improve treatment outcomes,26 OAT is recommended for AYA with moderate to severe OUD in existing pediatric treatment guidelines across North America.26, 28 4 There are two classes of OAT medication that are used for the treatment of OUD. The first is partial opioid agonists – which includes buprenorphine-naloxone (brand name: SuboxoneÒ) – that similarly has a high affinity for the mu-opioid receptor but is not as active as full opioid agonists at these sites. The second is full opioid agonists, which have a high affinity for and activity at the mu-opioid receptor sites. Examples of full opioid agonists include methadone maintenance treatment (MMT) (brand names: MethadoseÔ, Metadol-DÒ),29 slow-release oral morphine (brand name: KadianÒ),30 and injectable diacetylmorphine and hydromorphone (brand name: DilaudidÒ).31 Given the diverse mechanisms of action, there are clinically relevant differences in the induction and administration of full versus partial opioid agonists that are described hereafter. 1.2.1.1 Partial opioid agonist treatments Partial opioid agonists are recommended as a first line treatment for OUD among AYA in the study setting, which are deemed safer due to their displacing and a blocking effect on opioids at the mu-opioid receptor site.26 This includes buprenorphine-naloxone, which is also known by the brand name SuboxoneÒ. This improved safety has supported the justification for greater flexibility in treatment programming using partial opioid agonists, as the risk for toxic drug poisoning or death are lower when compared to full opioid agonists.32 Various formulations of partial opioid agonists are available in Canada, including subcutaneous buprenorphine implants, extended-release buprenorphine injections, buprenorphine buccal film, as well as combined, sublingual buprenorphine-naloxone.33 Clinical guidelines in the study setting currently recommend the 5 prescription of buprenorphine-naloxone, which has a better safety profile in comparison to other OAT; because of this, clinical guidelines also recommend providing AYA with take-home doses from 7 to 14 days.26, 34 Despite greater flexibility associated with partial opioid agonists, there are important barriers to treatment induction among people who use opioids. Because partial opioid agonists have a high affinity for mu-opioid receptors but low activity at these sites,35 it causes immediate, precipitated withdrawal symptoms among people who are actively using opioids.26, 36 For this reason, those seeking partial opioid agonists must typically remain abstinent from all opioids prior to treatment induction in order to prevent precipitated withdrawals and initiate treatment when natural withdrawal symptoms appear. To remedy this, buprenorphine-naloxone micro-dosing induction has been proposed as an alternative treatment induction method, which involves the co-prescription of full opioid agonists alongside buprenorphine-naloxone. Referred to as the ‘Bernese method’, patients are gradually titrated to a higher buprenorphine-naloxone dose while concurrently decreasing full opioid agonist dose until a therapeutic dose is achieved.36-39 This buprenorphine-naloxone induction approach has become increasingly available within the study setting, and while it provides a more comfortable transition to buprenorphine-naloxone without the need to cease opioid use prior to induction, it requires a longer treatment induction time and there is limited evidence on its use among AYA.36-39 1.2.1.2 Full opioid agonist treatments 6 Full opioid agonists do not require abstinence from opioids prior to treatment induction and they do not have a blocking effect on other opioids when taken concurrently. For this reason, there are additional safety concerns around the use of full opioid agonists among AYA given the potential for toxic drug poisonings, which is evident through restrictions on how these medications are administered. For example, full opioid agonists are listed as a second line treatment and only recommended in instances where AYA were unsuccessfully initiated onto partial opioid agonists, or in instances where AYA report high-intensity opioid use.26, 34 Additionally, full opioid agonists typically require daily witnessed dispensation at a pharmacy; however, existing clinical guidelines recommend approximately three days of take-home dosing, or twice-weekly witnessed ingestion at the time of carry pick-up, and at-home delivery services.40 Examples of full opioid agonists currently recommended for AYA in the study setting include methadone and slow-release oral morphine.26 1.2.2 Opioid antagonist treatments Whereas partial opioid agonists, like buprenorphine-naloxone, and full opioid agonists, like MMT, bind and have an activating effect at the mu-opioid receptor sites, opioid antagonist therapies have a blocking effect. Opioid antagonist treatments, like naltrexone (brand name: VivitrolÔ) also have a high affinity for receptor sites,35 but instead inhibit receptor site activity and thus block opioids from binding to them. Those initiating opioid antagonist treatment must also refrain from using opioids prior to initiating opioid antagonist treatments to prevent precipitated withdrawal symptoms that would have arisen if they were actively using opioids, although medically supervised withdrawal onto naltrexone is also available in some settings.41 Despite challenges 7 around initiating opioid antagonist treatments, take-home dosing is more readily permitted and available due to perceptions of the lower potential for diversion and misuse of opioid antagonists in comparison to partial and full OAT.42 Within the study setting, existing clinical guidelines do not recommend the use of opioid antagonist treatments due to the increased toxic drug poisoning risk associated with requiring abstinence prior to treatment induction and due to the absence of sufficient evidence of its use among AYA.26 One example of an opioid antagonist treatment is naltrexone, which is available in injectable and oral formulations.41 1.3 Research on opioid agonist treatments among adolescents and young adults in Vancouver, Canada There is emerging AYA-specific literature in Vancouver, Canada examining and characterizing OAT use among AYA. For example, a study conducted in 2009 among ARYS participants found that self-reported Indigenous identity, a high school education, mental illness, non-injection crack use, and spending >$50 on drugs per day were positively associated with attempting to access substance use treatment, including MMT.43 However, long wait times were the most commonly reported reason for failing to access substance use treatment, and failing to access treatment was positively associated with drug bingeing and homelessness.43 Another study among ARYS participants in 2014 found that self-reported Indigenous identity, homelessness, and being a victim of violence were positively associated with being unable to access MMT and other SUD treatment,44 while a 2015 ARYS analysis found that substance use treatment was one of the most difficult to access health and social services reported among AYA.45 8 More recently, a 2019 population-level study examining OAT prescription in British Columbia found that a lower proportion of AYA accessed OAT in comparison to adult populations. Additionally, findings indicate that adolescents were prescribed buprenorphine-naloxone at higher proportions than their adult counterparts, who were more likely to have received MMT.13 This may be attributable to recommendations that buprenorphine-naloxone be provided to AYA as a first line treatment within the clinical guideline for the treatment of OUD in British Columbia,26 which did not apply to adult populations that would have had continued access to MMT. In addition to quantitative research examining OAT among AYA in Vancouver, Canada, there is emerging qualitative research that has captured AYAs’ perspectives on OAT. For example, a 2017 study exploring injection cessation among AYA recruited from ARYS found that OAT was seen as a tool for supporting AYA in stopping their injection drug use.46 Additionally, a 2020 qualitative investigation into AYAs’ perspectives on OAT that included ARYS participants found some ambivalence towards OAT, with many AYA not identifying OAT as an integral part of their long-term treatment journey and recovery.24 Similarly, a 2021 qualitative study among AYA in Vancouver, Canada, found that the provision of OAT in the absence of addressing colonization and entrenched poverty trapped young people in cycles of perceived momentum (i.e., a sense that they were moving forward with their lives) and stagnation (i.e., a sense that they were going nowhere), generating deep ambivalence towards treatment, and in particular medicalized approaches such as OAT. 25 OAT did little to break the cycle of momentum that young people were enmeshed,25 and recent qualitative evidence from British Columbia suggests that such an approach can feel overmedicalizing.47 Overmedicalization refers to the emphasis on treating a specific condition without focusing on the contextual factors – such as entrenched poverty and 9 systemic racism – that are contributing to that specific condition.48 The overemphasis on prescribing OAT was also found to deter AYA from trusting and believing in the effectiveness of treatment.47 This was further compounded by the lack of socioeconomic supports, the sharing of AYAs’ personal or treatment history information between healthcare providers without their consent, and the negative and/or racist treatment AYA experienced.47 1.4 Toxic drug crisis and policy changes over the study period The timeline outlined in Figure 1.1 represents the study period for the analyses reported in this dissertation along with details of significant OAT policy and health service changes that occurred during this time. These events are presented with the intent of identifying external factors that may have impacted study findings (e.g., policy change impacts on treatment willingness). Due to limitations in the study questionnaire, we were not able to account for all contextual changes (e.g., questionnaire not updated to capture significant policy changes), but findings were interpreted with reference to these contextual factors as much as possible. These challenges have been further described in the limitations section of each analytic Chapter and at the end of this dissertation. 1.4.1 Establishment of the Inner City Youth Program Prior to the establishment of the At-Risk Youth Study (ARYS) in 2005, an open prospective cohort of street-involved AYA who use drugs from where data for this dissertation was derived, evidence suggests that there were limited AYA-specific health and substance use treatment services available to AYA within the study setting.49 Following calls from researchers and advocate for 10 investments in AYA-specific programming and services,49 the Inner City Youth (ICY) program was established in Downtown Vancouver in 2012 to provide needed mental health, health care, and substance use services to AYA,50, 51 including OAT. Then in 2015, the program became housed within the Granville Youth Health Centre, which was the first AYA-specific health care clinic available to AYA in Vancouver and remains a critical hub for AYA in search of health and social supports. This also contributed to the creation of the Foundry in 2015, which provides integrated prevention and early-intervention services for AYA with mental health challenges. As of 2020, the Foundry has been expanded to eight locations across the province of British Columbia, which includes the Granville Youth Health Centre that has since been renamed Vancouver-Granville Foundry. 1.4.2 Establishment of the Youth Intensive Case Management Team In addition to the funding of the ICY program, there was growing recognition of the need for more integrated, outreach supports, which resulted in the establishment of the first Youth Intensive Case Management team in Vancouver. This was a multi-disciplinary team of healthcare providers, cultural workers, allied health professionals, and outreach workers who provide AYA with complex needs case management support in community, acute, and residential treatment settings, with the aim of reducing harms and improving their connection with health and social services.51 This represented the first outreach team that sought to provide AYA within Vancouver with wrap-around supports, including primary care, housing, access to harm reduction supplies, as well as OAT prescriptions. 11 1.4.3 Reformulation of methadone to Methadose™ During this time period, the most commonly prescribed and accessible OAT was MMT;52 and although buprenorphine-naloxone was not available, it was approved by Health Canada, Canada’s federal health agency, for use in the treatment of OUD in 2007.53 While MMT was the most commonly prescribed treatment for OUD prior to the declaration of the toxic drug supply crisis, there was an important change in its formulation in February 2014 that has significant impacts on those who received MMT. Whereas MMT was previously prepared and distributed to patients by pharmacies, this change resulted in the distribution of a pre-prepared and 10-times more concentrated formulation, known as Methadose™, to pharmacies who then administered it to patients. This change was implemented with minimal consultation with people with lived and living experience and resulted in relapse, toxic drug poisoning, and disengagement from treatment altogether for many people who use opioids.54-57 The negative impacts of the changes from Methadone to Methadose™ resulted in patient-led advocacy that led to the introduction of third formulation in 2018, Metadol-D®, which is recognized as an effective, and typically more favorable, alternative to Methadose.54 Although Methadose™ and Metadol-D® contain equal proportions of methadone enantiomers and are equally bioavailable, there have been calls for additional research into pharmacokinetic or environmental factors that may have contributed to the negative outcomes observed with the change to and from Methadose™.54, 56 To date, both quantitative and qualitative research have sought to understand the impact of the formulation change on MMT patients. For example, a province-wide survey that found that a majority of patients were dissatisfied with the taste of Methadose™ and that the new formulation 12 was not effective at managing withdrawal symptoms and pain.55 Similarly, qualitative research with people who had transitioned to Methadose™ suggests that there may be a psychological component to experiences of withdrawal symptoms, and that the change in taste may have contributed to experiences of withdrawal symptoms and pain.57 Nonetheless, both studies recommend consulting patients prior to changes in medication formulations, which may increase satisfaction with and lessen the negative consequences of said policy changes.55, 57 1.4.4 OxyContin™, fentanyl, and the declaration of the 'overdose crisis’ Beginning in 2011, significant increases in toxic drug poisonings and fatalities were witnessed across the province of British Columbia.9 This coincided with the introduction of fentanyl and other highly toxic opioid analogues within the illicit drug supply, as well as with efforts to curb the prescription of licit opioids – and specifically OxyContin™, which is a slow-release oral formulation of oxycodone58 – given growing concerns around misleading and aggressive marketing campaigns targeted at prescribers that downplayed the addictiveness of prescription opioids and encouraged their provision for a range of conditions.2 As a result, it is suspected that the increase in prescription opioid provision between 1996 and 2014 contributed to a 10-fold increase in the number of people accessing OAT in British Columbia and Ontario;2 though for many people who had their opioid prescription discontinued, this resulted in their sourcing opioids from the illicit drug market at a time when fentanyl and other toxic opioid analogues were increasingly present within illicit opioid supply.2 This significantly increased people’s risk of experiencing a toxic drug poisoning or death, which is reinforced by evidence that fentanyl was present in approximately two-thirds of toxic drug fatalities in British Columbia in 2016.2 13 In British Columbia, the increased in drug-related toxic fatalities culminated in the declaration of a public health emergency by the Provincial Health Officer of British Columbia on April 14, 2016.59 The declaration recognized the increasing presence of synthetic opioid analogues within the illicit drug supply and sought to mobilize resources in reaction to the rapidly increasing toxic drug poisonings and fatalities.59 This included expanding access to naloxone, an opioid antagonist that is effective at reversing opioid-related poisonings, and contributed to the introduction of a Ministerial order that mandated the provision of overdose prevention services that would allow people to use their drugs in the presence of staff and peers trained to reverse opioid-related drug poisonings.60, 61 Additionally, free drug checking services were implemented where people who use drugs could identify the chemical makeup of their acquired substances to reduce potential harms.62 Despite efforts to expand access to harm reduction, OAT, and overdose prevention services to reduce toxic drug poisoning and deaths, access to such services has not been equitable – especially for AYA and people who reside in rural settings.13, 63-65 Additionally, although there was a decrease in the number of illicit drug toxicity deaths reported in 2019, they have continued to increase, reaching a record 2,265 fatalities in 2021.9 1.4.4.1 Introduction of youth-specific clinical treatment guidelines for OUD In addition to implementing harm reduction measures to reduce harms among people who use opioids, clinical guidelines for the treatment of OUD for AYA were published by the British Columbia Centre on Substance Use (BCCSU) on June 13, 2018.26 These guidelines acknowledged the importance of OAT in reducing toxic drug poisonings and deaths and provided guidance on 14 how to safely prescribe OAT to AYA in British Columbia. Buprenorphine-naloxone is the recommended first line treatment for severe to moderate OUD among AYA within these clinical guidelines, while MMT is recommended as a second line treatment for AYA who had previously attempted but disengaged from buprenorphine-naloxone. Additionally, the BCCSU guidelines acknowledge the added risk of toxic drug poisoning or death for AYA who report polysubstance use and therefore also recommend OAT for AYA who report concurrent stimulant and opioid use. 1.4.4.2 COVID-19 and the implementation of interim Risk Mitigation Guidance While evidence presented by the British Columbia Coroners Service suggested that the number of toxic drug poisoning deaths were beginning to decrease in 2019, the onset of the COVID-19 pandemic resulted in a continued increase in the number of toxic drug poisoning deaths, which has persisted.26 Given that a majority of toxic drug poisoning deaths were occurring in private residences, where people were often using substances alone,26 there were concerns that the public health measures seeking to reduce the transmission of SARS-CoV-2 contradicted efforts to dissuade people from using alone. In response, the BCCSU released Risk Mitigation in the Context of Dual Public Health Emergencies (hereafter referred to as Risk Mitigation Guidance (RMG)), which recommended the provision of a broader range of prescription alternatives to illicit and licit substances, including opioids, stimulants, benzodiazepines, and also tobacco and alcohol.66 The RMG was not intended as a treatment for substance use disorders, but as a temporary measure to encourage and support physical distancing in order to reduce the transmission of COVID-19 among marginalized and 15 vulnerable populations in community settings. This includes AYA <19 years of age who, if efforts to initiate OAT are unsuccessful, can participate in RMG if they provide informed consent and are educated on RMG.66 Nevertheless, the interim RMG also recommended higher OAT induction doses, increasing OAT dosages for people who are still using illicitly-sourced drugs, and encouraging the provision of take-home doses for those already on OAT.66 For people who were not interested or retained on OAT, the RMG recommended several other medications that could be alternatively prescribed. For opioids, these include hydromorphone, slow-release oral morphine, and sustained-release oral morphine, while dextroamphetamine and methylphenidate were recommended as substitutes for illicit stimulants.66 To date, preliminary evidence suggests that the RMG has been effective at reducing harms.67 Nevertheless, recent research in a COVID-19 isolation hotel found that higher doses than those recommended within RMG may be warranted to increase this intervention’s effectiveness at reducing toxic drug poisonings and death, in turn outlining ways that the RMG could be improved.67 To note, the quantitative analyses in this dissertation were conducted in the period preceding the declaration of the COVID-19 pandemic; however, the qualitative analysis was conducted both before and after the declaration of the COVID-19 pandemic and the introduction of RMG. 1.5 Study justification To date, some research indicates that AYA are significantly less likely to be initiated on to OAT when compared to adult populations,22 and are more likely to encounter detoxification and 16 abstinence-based treatments prior to qualifying for OAT.68 This is problematic considering the heightened toxic drug poisoning risk following detoxification service engagement69 and that this population continues to experience high levels of opioid-related overdose.9 As AYA report different drug use patterns and service needs when compared to adult populations,70-72 and given reports of challenges accessing substance use treatment,43, 45, 73 there is a need to better understand AYA perspectives on and experiences with OAT within Vancouver, Canada. Recognizing these critical knowledge gaps and the heightened overdose risk in the context of the ongoing toxic drug supply crisis, this proposed research seeks to provide further insight into AYAs’ perspectives on, experiences with, and barriers to accessing, being retained on, and tapering off of OAT in Vancouver, Canada. While Vancouver, Canada is considered a global leader in the provision of harm reduction, health and social supports for people who use drugs, there are known and persistent challenges to accessing, remaining engaged in, and tapering off of OAT among AYA in the treatment setting that require attention. In providing a better understanding of AYAs’ OAT experiences, the intent of this dissertation is to identify ways that existing services can be improved to meet the needs of AYA and reduce the ongoing impacts of the toxic drug crisis. 1.6 Conceptual framework This research employs Rhode’s risk environment framework74 and the patient-centered health care accessibility framework75 to examine AYA experiences with and their perspectives regarding OAT. The Risk Environment framework has been used to examine the way that micro- and macro-17 level components of social, economic, physical, and policy environments influence behaviours, disease risk, health care access, and drug-related harms among people who use drugs.76-80 The Risk Environment framework is rooted in Rhodes’ examination of interventions seeking to curb the transmission of Human Immunodeficiency Virus (HIV) among people who inject drugs, where Rhodes argues that some approaches individualize drug use and shift the responsibility of harm onto individuals. Instead, Rhodes suggests focusing on the broader, socio-political factors that aid in the transmission of HIV as opposed to focusing solely on individualistic behaviors and behavioural interventions.74 The patient-centered health care accessibility framework developed by Levesque, Harris & Russell is also employed throughout this dissertation.75 This framework conceptualizes five health care service accessibility-related dimensions that include approachability, acceptability, availability, accommodation, affordability, and appropriateness. Additionally, this framework also examines individual characteristics that interact with the health care dimensions of accessibility and include ability to perceive, ability to seek, ability to reach, ability to pay, and ability to engage. By examining accessibility-related factors around treatment access, this conceptual framework supports the identification of health service access experiences and challenges and barriers to OAT among AYA. In the context of this dissertation, the risk environment framework74 provides a basis for considering the impacts of socio-structural and environmental factors on OAT engagement among AYA who use drugs, while the patient-centered health care accessibility framework75 supports the examination of accessibility-related factors that influence AYAs’ OAT experiences. The overall 18 conceptual framework for this research is outlined in Figure 1.2, which combines both the Risk Environment and patient-centered health care accessibility frameworks. It was hypothesized that a combination of physical space (e.g., geography, drug scene characteristics, treatment approachability), social inequity (e.g., barriers to health or social services, incarceration, homelessness), economic (e.g., employment, treatment affordability), and policy environment factors (e.g., treatment availability) will influence OAT engagement among AYA. However, I acknowledge the overlap and interplay between these various ‘categories’ and that some of these factors fit within multiple categories. 1.7 Study objectives The purpose of this dissertation is to generate evidence to better understand the OAT experiences and perspectives of AYA who use opioids by examining existing barriers and challenges to OAT access and engagement within this population. Identifying barriers and challenges are expected to help identify specific treatment gaps that can be used to inform changes to health policies or treatment services. Hence, these findings could ultimately improve the treatment experiences and outcomes of AYA who use opioids. The following objectives and hypotheses were developed to guide this research: 1. To systematically review literature examining access to MOUD among adolescents and young adults. Emerging evidence suggests that AYA are less likely to be offered and access OAT when compared to adult populations.81 Despite a Cochrane review of two randomized controlled trials of MOUD among AYA and a systematic review examining 19 retention in MOUD among AYA,82-84 no systematic review that has sought to summarize existing evidence on OAT access among AYA. Chapter 2 outlines the findings of a systematic review examining access to MOUD in addition to identifying associated factors. Review findings informed the subsequent objectives of Chapters 3-6. 2. To identify factors associated with initiating OAT in the last six months among AYA who reported frequent opioid use but had not previously accessed OAT during the study period; and, 2) to compare the before and after substance use and other patterns between AYA who: a) recently accessed and were retained on OAT and b) recently accessed but subsequently discontinued OAT, to c) AYA that did not recently access OAT. Existing evidence on the substance use and other health-related outcomes among AYA who access OAT is limited or of low methodological quality.85 Given the need for more research examining OAT access and outcomes among AYA, it was hypothesized that recent non-fatal overdose, recent regular heroin or fentanyl use (last six months (L6M), ≥weekly), and later study follow-up period (per six month period) would be positively associated with time to OAT access, but negatively associated with older age (≥19 vs. <19) and recent homelessness. In before and after analysis, it was hypothesized that those who continue in OAT will experience significant reductions in opioid use and non-fatal overdose, while participants who accessed and discontinued OAT or who did not access OAT would not. 3. To examine factors associated with an initial buprenorphine-naloxone interest, as well as factors associated with the time to a positive change in buprenorphine-20 naloxone interest or actual enrolment among AYA who were initially disinterested in buprenorphine-naloxone. Buprenorphine-naloxone has proven effective among AYA who report injection drug use and who have mental illness,86 as well as among adults who report recent non-fatal overdose and illicit buprenorphine use.87 Research into factors associated with willingness to engage in buprenorphine-naloxone is limited to adult populations, despite evidence that AYA are more likely to be prescribed buprenorphine-naloxone. Therefore, it was hypothesized that initial willingness to use buprenorphine-naloxone would be positively associated with recent heroin or fentanyl use (L6M, ≥weekly), recent injection drug use (L6M), and any previous MMT treatment attempts, but negatively associated with older age (per year older) and recent homelessness (L6M). Among those participants who initially indicated they were unwilling to use buprenorphine-naloxone, it was hypothesized that recent homelessness (L6M) would be negatively associated with buprenorphine-naloxone interest or actual enrolment over follow-up. 4. To identify factors associated with time to MMT discontinuation among AYA who report initiating MMT over the study period, to describe reasons for MMT discontinuation, and examine factors associated with time to MMT discontinuation that can be addressed through policy or guideline changes. While evidence indicates that AYA are significantly less likely to be provided OAT,22 they are also significantly less likely to be retained in OAT when compared to adult populations.88-90 This higher risk of relapse is problematic because an abrupt disruption to OAT can result in relapse to using toxic street-sourced opioids that increase overdose risk.91 It was hypothesized that any 21 MMT discontinuation, which did not involve intentional tapering, would be positively associated with recent crystal methamphetamine use (L6M, ≥weekly), earlier age of ‘hard’ drug use initiation (per year older), having experienced childhood trauma, involvement in the child welfare system, difficulty accessing addiction treatment, engagement in non-pharmacological forms of addiction treatment (i.e., residential treatment, NA/AA, counselling), and younger age. In sub-analysis, it was hypothesized that ‘actionable’ MMT discontinuation – which includes missing a dose or being taken off by a healthcare providers, experiencing difficulty accessing a pharmacy, or cost-related barriers – would be associated with recent crystal methamphetamine use (L6M, ≥weekly), earlier age of ‘hard’ drug use initiation (per year longer), childhood trauma, involvement in the child welfare system, non-pharmacological treatment program access (i.e., residential treatment, NA/AA, counselling), and younger age. 5. To explore AYAs’ experiences navigating OAT, from treatment contemplation to tapering. A recent systematic review of the use of MOUD among AYA has emphasized the need for more qualitative research that examines OAT engagement and retention among AYA.85 Therefore, Chapter 6 qualitatively examines street-involved AYAs’ experiences navigating OAT, with the aim of better understanding barriers to OAT and improving existing clinical guidelines and policies to improve AYAs’ OAT experiences. 22 1.8 Study design & methods Data for the analyses presented in Chapters 3-6 were derived from an ongoing, open prospective cohort of street-involved adolescents and young adults. The details of the cohort are described hereafter in order to reduce replication within individual chapters, where eligibility criteria, procedures, and other relevant methodological information will be discussed instead. The ARYS is an open prospective cohort of street-involved youth in Vancouver, Canada, that was initiated in 2005 and is operated by the B.C. Centre on Substance Use. At the time of enrolment, the ARYS cohort requires that participants are between the ages of 14-26; have accessed street-based services intended for homeless or unstably housed AYA; have reported illicit “hard” drug use (e.g., fentanyl, heroin, prescription opioids, crack cocaine, crystal methamphetamine), other than (or in addition to) cannabis, in the last month; and provide informed consent to participate in the study. ARYS is a longitudinal cohort study funded by the US National Institutes of Health where it is classified as a U01 cohort study of the National Institute of Drug Abuse under the Vancouver Drug Users Study (V-DUS) and is additionally funded by the Canadian Institutes of Health Research. ARYS participants are recruited from the Downtown Eastside, Downtown South, and other neighborhoods where AYA are known to congregate in Vancouver using community-based recruitment strategies and snowball sampling to maximize the representativeness of the sample. Upon enrolment, participants complete an interviewer-administered baseline questionnaire and return semi-annually to conduct a follow-up questionnaire. Participants are asked questions about 23 their sociodemographic information, substance use patterns, substance use treatment engagement, incarceration, homelessness, among other topics, and are also asked to provide blood and urine samples for serological testing and analyses (e.g., fentanyl, HIV, Hepatitis-C Virus (HCV)) at baseline and over follow-up. In addition to conducting an interviewer-administered questionnaire, participants undergo a consultation with a study nurse and are referred to appropriate health care services if needed. For their time and insight, ARYS participants are re-imbursed with a $40 CAD honorarium per study visit. R Foundation for Statistical Computing (Version 3.2.4; Vienna, Austria) was used to conduct analyses in Chapter 3,92 while SAS software version 9.4 (SAS, Cary, NC) was used for Chapters 4 and 5. The ARYS study has received ethical approval from the University of British Columbia/Providence Health Care Research Ethics Board (study ID#: H05-50160). For Chapter 6, AYA who were not participants of the ARYS study were recruited to participate in the qualitative interviews. More specifically, AYA accessing services in various local drug treatment settings (e.g., youth-dedicated detoxification and treatment centers, safe houses) were recruited to participate in one-on-one interviews on a rolling basis over the duration of the study period. Interviews began in 2018, and participants were then invited to complete follow-up interviews at 6-month intervals. Co-authors DF and MT conducted in-person and telephone interviews in accordance with COVID-19 safety protocols, which took approximately 60 to 90 minutes to complete. Written informed consent was collected from participants prior to the commencement of their first interview and participants were reimbursed with a $30 CAD honorarium for each interview. Once completed, interviews were transcribed verbatim, deidentified, and reviewed to ensure that the transcripts corresponded with interview recordings. 24 Transcripts were then uploaded to NVivo 12 software93 where all data pertaining to OAT (i.e., buprenorphine-naloxone, methadone, slow-release oral morphine) was coded and retrieved for thematic analysis. This study received ethical approval from the University of British Columbia Research Ethics Board (H17-01726; H18-03529). 1.9 Summary of dissertation chapters This dissertation is composed of seven Chapters, the first providing an introduction into the use of MOUD among AYA. This includes an exploration of the context of OAT access and use among AYA in the study setting, as well as changes in policy and practice that have occurred over the study period of this dissertation. Additionally, this Chapter outlines the conceptual framework, objectives and hypotheses, and the design and methods employed for this dissertation. The research presented in Chapter 2 represents a version of a systematic review examining access to MOUD among adolescents and young adults, and associated factors. This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and examined a range of demographic, socioeconomic, treatment-related, and other factors associated with MOUD access among AYA. Chapter 3 examined whether demographics, substance use, and substance use disorder (SUD) treatment engagement patterns were associated with time to accessing OAT. Additionally, it employed a quasi-experimental study design to test whether remaining engaged in OAT was 25 associated with improved substance use and other patterns between AYA who initiated and did not initiate OAT. Given evidence that AYA are more likely to be prescribed buprenorphine-naloxone in comparison to MMT when compared to adults, Chapter 4 sought to investigate whether substance use and SUD treatment engagement patterns were associated with willingness to initiate buprenorphine-naloxone. This included examining whether these factors were associated with buprenorphine-naloxone interest or actual enrolment over study follow-up. Chapter 5 sought to address knowledge gaps surrounding MMT discontinuation among AYA, as existing evidence is largely limited to adult populations. Analyses sought to test whether substance use or non-pharmacological treatment engagement were associated with MMT discontinuation, including in a sub-analysis examining MMT discontinuation that was deemed ‘actionable’ – that refers to reasons for MMT discontinuation that could be addressed through guideline or policy changes. Chapter 6 responds to ongoing calls for qualitative research into AYAs’ perspectives and experiences when accessing OAT through longitudinal, one-on-one interviews with AYA at different points along the OAT continuum. These unique experiences provide insight into ways to reduce policy and practice barriers to treatment and support AYA in accessing, engaging, and tapering off of OAT when they are prepared to do so. 26 Lastly, Chapter 7 summarizes key findings and discusses the implications of this research on OUD treatment guidelines and policies. This includes the limitations, future areas for research, and conclusions of this dissertation. 27 Figure 1.1. Timeline of policy and health-service delivery related changes over the study period of the proposed analyses. Note: a Became housed within the Granville Youth Health Centre in 2015 and was subsequently renamed the “Vancouver-Granville Foundry” in the same year. Abbreviations: ARYS, At-Risk Youth Study; BC, British Columbia; BCCSU, British Columbia Centre on Substance Use; COVID-19, Coronavirus disease 2019; MOUD, medications for opioid use disorder; OAT, opioid agonist treatments. 28 Figure 1.2. Conceptual framework to examine opioid agonist treatment (OAT) among adolesecnts and young adults who use opioids in Vancouver, Canada, as adapted from the risk environment’74 and patient-centered accessibility75 frameworks. Notes: a Refers to factors in the physical space, including geographic or environmental factors that impact OAT-related outcomes; b Refers to social inequities, norms and rules that impact OAT-related outcomes; c Refers to the influence of economic factors that impact OAT-related outcomes; d Refers to policy-related factors that impact OAT-related outcomes. Abbreviations: DTES, Downtown Eastside; OAT, opioid agonist treatment. 29 Chapter 2: Access to medications for opioid use disorder and associated factors among adolescents and young adults: a systematic review 2.1 Introduction Toxic drug poisonings, primarily due to illicit opioids, are the leading cause of unintentional injury death across North America.1-4 In the study setting, adolescents and young adults have accounted for approximately 19% of overdose deaths, outlining the urgency of responding to this public health emergency.9 MOUD are one tool that have prevent a significant number of toxic drug poisonings and deaths,61, 94 and include full opioid agonists like MMT; partial opioid agonists like buprenorphine-naloxone; and full opioid antagonists like naltrexone. There is some evidence that indicates that AYA are significantly less likely to receive OAT for the treatment of OUD when compared to adults,22 and more likely to encounter detoxification and abstinence-based treatments when seeking care.68 This is problematic considering the heightened overdose risk following detoxification service engagement69 and that this population continues to experience high levels of opioid-related overdose,9 especially in the context of an increasingly toxic drug supply. Given research indicating that OAT is an effective and safe intervention for AYA who use opioids,95, 96 the absence of a systematic review on access to these potentially life-saving treatments among AYA is concerning. 30 Existing reviews examining MOUD among AYA have primarily focused on treatment retention and outcomes, demonstrating that OAT is effective at reducing substance use outcomes. However, there is limited research that has systematically reviewed access to MOUD among AYA, contributing to public health experts concerns that MOUD may be out of reach for many AYA.97, 98 In response to this knowledge gap, the purpose of this systematic review was to examine research on the access to or receipt of MOUD among AYA, in addition to summarizing factors that are associated with MOUD access in this population. 2.2 Methods The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used to guide this systematic review (Table 2.1) 2.2.1 Population, intervention, comparisons, outcomes For this review, the population was restricted to adolescents and young adults who use opioids, which included studies where the mean or median age of the study sample is between 10 to 30 years of age (Table 2.2). Studies were included if: more than 50% of the sample reported using opioids to a degree that was defined as problematic; a validated scale or diagnostic criteria (e.g., DSM-5)99 was used to diagnose participants with OUD; or if participants self-reported attempting to access MOUD. The exposure of interest included any MOUD, such as full opioid agonists, partial opioid agonists, and opioid antagonist treatments, and there was no restriction on the inclusion of controls. The outcomes of interest included access to MOUD and associated factors, 31 such as prescription receipt, availability of, and initiation of MOUD among AYA. All empirical study designs were included and considered, except for case studies or series, commentaries, and other systematic reviews. 2.2.2 Search strategy A comprehensive review strategy was developed an adapted to the following databases: CINAHL, EMBASE, Global Dissertations & Theses, MEDLINE, PsycINFO, Sociological Abstracts, and Web of Science (Table 2.3). The search period was from database inception up until May 3, 2021, and the search included a combination of subject heading MeSH and additions terms including “adolescents”, “young adults”, “youth”, “young people”, “opioid agonist treatment”, “medications for opioid use disorder”, “opioid antagonist treatment”, “prescription”, “access”, and “receipt”. The protocol for this review was registered in the Open Science Framework (osf.io/d7hvb). A grey literature search was conducted in order to identify any non-academic research conducted on MOUD access among AYA. Keywords were combined to search: opengrey.eu, the World Health Organization, the United Nations Office on Drugs and Crime, the United States Centre for Disease Control, the International Society of Addiction Medicine, Harm Reduction International, the National Institutes for Health and Care Excellence (United Kingdom), the Substance Abuse and Mental Health Services Administration (USA), the American Public Health Association, the Canadian Public Health Association, the Centre for Health Services and Policy Research (Canada), the Centre for Addiction and Mental Health (Canada), Sickkids Hospital Foundation (Canada), Google Scholar, and Google. 32 2.2.3 Screening, inclusion and exclusion criteria, and quality assessment References retrieved from bibliographic databases were imported to Endnote X9 for deduplication and subsequently exported to Covidence software. Peer-reviewed studies in English, French, Russian, or Spanish languages that examined the access, initiation, or prescription of MOUD were eligible for inclusion, based on the co-authors’ language capacity. Title and abstract screening for all records was completed by co-author AP, and co-author DJB randomly checked 20% of the identified records. Records identified during the title and abstract screening phase then proceeded to full-text review and underwent independent assessment by co-authors AP and MK (Figure 2.1). Studies on non-AYA populations or the general public were excluded from this review, as were studies that did not examine AYAs’ experiences separately from non-AYA populations. Additionally, studies where MOUD access was not the primary focus were excluded from this review. Co-authors AP and MK then conducted independent quality assessments of the identified studies using the modified Newcastle-Ottawa Scale100 for longitudinal (Table 2.4) and cross-sectional studies (Table 2.5) and the GRADE-CERQual tool for qualitative studies (Table 2.6).101 Disagreements between co-authors were discussed and resolved by consensus. 2.3 Results This review identified 11,278 unique records, of which 416 were eligible for full-text review. Of these, 37 studies met the study inclusion criteria and were included in this review. In summary, 33 studies were conducted between 1992102 and 2021,13 representing 179,785 AYA (mean: 4,859, median: 404, range: 5–82,992) and 3,243103-105 adolescent treatment facilities. Twenty-four studies were conducted in the USA,22, 81, 103-124 four in Canada,13, 46, 125, 126 three in Australia,102, 127, 128 two in England,129, 130 two in Ireland,96, 131 and one in Italy,132 while one study derived data from Austria, Canada, and the USA.133 Details on study design, setting, sample characteristics, inclusion and exclusion criteria, and study quality are presented in Table 2.7. Fourteen studies included participants with an OUD diagnosis,13, 81, 109, 111, 112, 114, 115, 117, 119-123, 133 nine examined heroin and other opioid use,22, 96, 106, 108, 124, 125, 128, 129, 132 and seven examined any opioid use.102, 110, 118, 126, 127, 130, 131 Additionally, two studies examined primary opioid use,107, 113 one non-medical prescription opioid use,116 and one any injection drug use.46 Sixteen studies included any opioid use over the study period,13, 46, 81, 109-112, 114, 115, 119-121, 123, 129, 130, 134 nine examined current opioid use,22, 96, 107, 108, 113, 117, 124, 131, 133 three examined past 30-day opioid use,116, 128, 132 two examined past year opioid use,118, 125 and one examined past 6-month opioid use.126 The remaining studies included opioid use in three months before and one month after an opioid-related overdose,103 upon incarceration,120, 127 and in the three days and eight or more years before treatment admission.102 2.3.1 Access to MOUD A majority of studies included an examination of MMT (n=30),13, 22, 46, 96, 102-104, 106-108, 110-115, 117, 118, 120-123, 125-131, 133 followed by buprenorphine (n=26),22, 81, 96, 103-109, 111-115, 118-124, 127, 128, 130, 133 naltrexone (n=10), 81, 103-106, 109, 111, 112, 118, 119 buprenorphine-naloxone (n=2),13, 119 lofexidine 34 (n=1),130 disulfiram and acamprosate (n=1),105 and slow-release oral morphine and injectable OAT (n=1).13 Three studies examined detoxification through the use of MOUD,120, 124, 130 while two studies did not report the type of MOUD being assessed.116, 132 The proportion of MOUD access across study samples ranged from 0.4%22 to 80.7%,102 which included 1.2%111 to 80.7%102 for MMT, 3%119 to 30%130 for buprenorphine, and 0.8%109 - 37%119 for naltrexone. Study findings and associated factors are presented in Table 2.8. 2.3.2 Age-related factors Eighteen studies found that younger age was negatively associated with MOUD access.13, 22, 81, 96, 102-104, 109, 111, 112, 114, 115, 118, 119, 123, 124, 126, 128 Additionally, some evidence suggests that in comparison to young adults and adults, adolescents were more likely to be prescribed partial opioid agonists and opioid antagonist treatments versus full opioid agonists.13, 111, 112, 118 This included a study from the study setting, which found that a low proportion of adolescents (12-18 years) versus young adults (19-24 years) received any OAT (36.5% vs. 71.4%) or MMT (38% vs. 49.5%), but that a higher proportion of adolescents received buprenorphine-naloxone (60.1%) in comparison to young adults (48.3%).13 These findings are supported by evidence that addiction treatment facilities that reported serving a greater proportion of adolescents were less likely to provide any MOUD,103 while one study found that adolescent-specific treatment facilities located in counties with older populations were more likely to provide MOUD in comparison to counties with younger populations.104 35 2.3.3 MOUD access over time MOUD access over time was considered in seven studies.81, 106, 114, 115, 123, 124, 128 Evidence suggests that the prescription of buprenorphine and naltrexone among AYA in the USA increased from 2% to 31.8% between 2002 and 2009, but decreased to 27.5% in 2014.81 This is complemented by a study among pregnant AYA that similarly reported increases in the prescription of buprenorphine between 2009 and 2015.115 This study also found decreases in the prescription of MMT over the same period,115 while another study among pregnant AYA found increases in buprenorphine prescription from 10.1% to 33.2% between 2009 and 2012 but no change in MMT prescription over the same period.114 A cross-sectional study from the USA conducted in 2020 examined the role of referral source on buprenorphine or MMT access among pregnant people, including AYA, between 1992 and 2017 and found significant increases in MOUD receipt among participants being referred to addiction treatment by friends, family, or by self-referral (59.1%, p<0.001) or by a healthcare provider (51.3%, p<0.001), although smaller increases in buprenorphine or MMT receipt among participants referred through the criminal justice (26.3%, p<0.001) were observed.123 A prospective study from Australia conducted in 2004 identified factors associated with time to treatment access and found that young adults were more likely to report a shorter time period between heroin initiation and MMT access when compared to adults.128 Additionally, a retrospective cohort study from the USA that was conducted in 2020 found that being diagnosed with OUD and previously receiving buprenorphine, MMT, and naltrexone were positively 36 associated with receiving any MOUD within 30 days of experiencing an opioid-related overdose.106 2.3.4 Health and social systems related factors Health and social systems related factors associated with MOUD access were identified in fourteen studies.46, 103, 105-107, 110, 114, 116, 120, 121, 125, 129, 132, 133 Four studies reported a positive association between previous MOUD attempts and future MOUD access.106, 110, 114, 132 One qualitative study conducted in 2009 in the USA reported that making information available to AYA about MMT encouraged treatment initiation,110 and three other studies identified treatment facility-related factors associated with MOUD access. This included a 2020 cross-sectional study of adolescent-serving treatment facilities in the USA that found that non-profit versus private status, the acceptance of insured versus free or subsidized treatment, providing inpatient versus outpatient services, and being licensed by a national authority versus being unlicensed were positively associated with buprenorphine, MMT, or naltrexone provision.103 Similarly, a 2015 cross-sectional study of adolescent-serving treatment facilities in the USA found that larger versus smaller, private versus public, accredited versus unaccredited facilities, as well as facilities with a greater versus smaller proportion of counsellors with Graduate degrees were more likely to provide MOUD.105 Another cross-sectional study from the USA also examined geographic and population-density factors associated with the provision of buprenorphine, MMT, and naltrexone in adolescent-serving treatment facilities that are discussed in a subsequent section.104 Lastly, another cross-sectional study from Austria, Canada, and the USA conducted in 2022 among pregnant AYA 37 found that already being on MMT was negatively associated with a willingness to participate in a randomized controlled trial (RCT) comparing the efficacy of buprenorphine to methadone.133 Six studies identified health and social systems related factors negatively associated with MOUD access, three of which included pregnant AYA.46, 116, 120, 121, 123, 129 One cross-sectional study conducted in 2020 that employed simulated-patient callers in the USA, including pregnant AYA, found that healthcare providers were less likely to prescribe buprenorphine or methadone to pregnant people, and that having Medicaid coverage versus private insurance was negatively associated with buprenorphine or methadone receipt among non-pregnant people.121 Additionally, a 2020 retrospective cohort study in the USA among incarcerated pregnant people that included AYA found higher odds of buprenorphine, methadone or oxycodone taper or brief maintenance receipt in the second and third trimester versus the first trimester.120 A 2020 cross-sectional study from the USA that included pregnant AYA found a negative association between criminal justice referral to addiction treatment facilities and buprenorphine or MMT receipt versus individual or other referral sources, although receiving a criminal justice referral to an addiction treatment facility in a State participating in Medicaid expansion was positively associated with buprenorphine or MMT receipt.123 Lastly, three studies identified additional health system related barriers and challenges to MOUD access including experiencing discrimination in the healthcare system due to substance use,116 treatment costs,46 difficulty finding a prescriber, and wait times to receiving MOUD.129 38 2.3.5 Substance use and personal health related factors Twelve studies identified an association between substance use and personal health-related factors and MOUD access. Of these, nine studies reported findings pertaining to personal health,46, 102, 110, 111, 114, 117, 122, 124, 126, 127, 129, 132 four of which qualitatively explored AYAs’ motivations for MOUD engagement.46, 110, 127, 129 This included a 2017 study among AYA in Canada who reported using MMT to support injecting drug use cessation,46 as well as a study from Australia conducted in 2017 among incarcerated people including AYA that found that wanting to reduce the risk of Hepatitis C infection associated with injection drug use was a central reason for accessing MMT.127 This aligns with findings from a 2011 prospective cohort study conducted in Canada, which found a positive association between Hepatitis-C seropositivity and MMT engagement among self-identifying Indigenous AYA.126 Another two qualitative studies, one from the United Kingdom conducted in 2014 and a 2009 study from the USA that both included AYA, found that feeling unwell and wanting to feel more stable were important reasons for MMT initiation,110, 129 while the former of the two studies also found that feeling pressured or coerced into treatment was seen to deter MMT initiation among AYA.110 Lastly, two quantitative studies investigated personal motivations for treatment entry among pregnant AYA, including one cross-sectional study that found that concerns of one’s baby’s health was a primary reason for MMT access117 and 2016 retrospective cohort study that found a positive association between having a partner with a SUD diagnosis and accessing MMT versus buprenorphine.114 Two studies identified mental health related factors,111, 122 which included a 2018 prospective cohort study of AYA in the USA that found a negative association between buprenorphine, MMT, 39 and naltrexone access and being diagnosed with depression.111 A retrospective cohort study in the USA that included pregnant AYA found that Black non-Hispanic and Hispanic people with depression or anxiety were less likely to consistently use OAT in the six months before their delivery and receive buprenorphine in comparison to white pregnant people.122 Substance use-related factors associated with MOUD access were identified in six studies.102, 111, 114, 124, 126, 132 This included a 2015 cross-sectional study conducted in Italy that included AYA, which found a positive association between illicit MMT, codeine, tramadol, oxycodone, heroin, and combined heroin and non-medical prescription opioid use (NMPOU) and OAT access.132 Additionally, a 2011 prospective cohort study of self-identifying Indigenous AYA in Canada found a positive association between MMT and daily injection drug use,126 while a 2012 prospective cohort study in the USA found that AYA accessing buprenorphine-based detoxification were more likely to report any injection drug use.124 Substance use-related factors negatively associated with OAT access were also identified, including a 1992 study from Australia where being rejected from an MMT program was positively associated with a positive urine drug screening test, ten or more criminal convictions, a shorter duration of substance use, and self-reported daily opioid use.102 A 2016 investigation into buprenorphine and MMT access among pregnant people in the USA, including AYA, found that those who reported benzodiazepine use were less likely to access buprenorphine versus MMT.114 Lastly, both a 2018 prospective cohort study among AYA in the USA and a 2011 prospective cohort study among self-identifying Indigenous AYA in Canada found that having an alcohol use disorder was negatively associated with buprenorphine, MMT, and naltrexone access or MMT access, respectively,111, 126 and the 40 former of the two studies also identified a negative association between buprenorphine, MMT, or naltrexone access and having a substance use disorder.111 2.3.6 Socioeconomic and educational factors Income-, employment-, and education-related factors associated with MOUD access were identified in six studies.81, 104, 114, 116, 124, 131 Of these, a 2020 retrospective cohort study among AYA in the USA found that adolescent-serving treatment facilities in low-income neighborhoods were more likely to provide buprenorphine, MMT, or naltrexone than those in high-income neighborhoods.104 However, these findings contradict evidence from a prospective cohort study among AYA conducted in the USA in 2017 that found AYA residing in high-middle- and high-poverty neighborhoods were less likely to receive buprenorphine or naltrexone in comparison to AYA residing in low-poverty neighborhoods. Findings also indicate that AYA residing in low- and low-to-middle educational level neighborhoods were less likely to receive buprenorphine or naltrexone in comparison to AYA residing in high-educational level neighborhoods, though findings were not statistically significant.81 Furthermore, this study also found that AYA residing in high, high-middle, middle-low poverty neighborhoods, as well as middle-low- and low-educational level neighborhoods, were more likely to receive naltrexone versus buprenorphine in comparison to AYA residing in low-poverty and high-educational level neighborhoods, respectively.81 The remaining studies examined individual socioeconomic and educational factors associated with MOUD access. This included a 2016 retrospective cohort study among pregnant people in the 41 USA that included AYA, which found that participants who were employed were more likely to access buprenorphine versus MMT.114 A 2016 cross-sectional study from the USA that included AYA found that participants with a higher monthly income ($501-$1,500 vs. ≤$500) were less likely to report attempting to access any MOUD and more likely to report unsuccessfully attempting to access MOUD.116 Additionally, one prospective cohort study from the USA conducted in 2012 that included AYA accessing buprenorphine-based detoxification found participants were less likely to report being employed,124 while a 2008 cross-sectional study among adolescents in Ireland entering an MMT program found that boys reported leaving school at an earlier age than girls (13.9 vs. 14.9 years, p=0.01).131 2.3.7 Geographical or population-density factors Six studies identified geographical or population density-related factors associated with MOUD access among AYA.81, 103, 104, 107, 113, 132 Although one prospective cohort study among AYA in the USA conducted in 2020 found that residing in the Mid-Atlantic and Mountain US versus the New England census region was positively associated with buprenorphine, MMT, or naltrexone access,104 a majority of studies that examined geographic factors found that residing in the US South was negatively associated with MOUD access in comparison to the US Northeast, Midwest, and West.81, 103, 107, 113 Two studies also examined population-density factors associated with MOUD access, including a 2017 prospective cohort study among AYA in the USA where residing in a non-metropolitan area was positively associated with buprenorphine versus naltrexone access.81 The second, a cross-sectional study conducted in 2020 in the USA, found that adolescent-serving treatment facilities in large metropolitan areas were less likely to provide buprenorphine, 42 MMT, and naltrexone in comparison to metropolitan, micropolitan, and non-core areas in the USA.104 Lastly, a 2015 study found that AYA were less likely to access MOUD in the Southern versus the Northern Italy.132 2.3.8 Criminal justice system related factors Criminal justice system related factors were identified in six studies.107, 114, 116, 120, 123 One cross-sectional study conducted in the USA in 2016 found that young adults who reported NMPOU and had been incarcerated were more likely to report successfully enrolling in MOUD,107 while a retrospective cohort study of pregnant people in the USA conducted in 2020 found that the receipt of buprenorphine, MMT, or an oxycodone taper or brief maintenance prior to incarceration was positively associated with receiving MOUD during incarceration.120 Additionally, a 2020 serial cross-sectional study of pregnant people, that included AYA, found that being referred to treatment through the criminal justice system was negatively associated with MOUD access, as did a 2016 cross-sectional study that included pregnant AYA in the USA.107 However, the former study also found that participants incarcerated in US States that participated in Medicaid expansion were more likely to received MOUD versus participants in States that did not.123 Additionally, residing in States that permit child abuse charges107 and the removal of custodial rights from pregnant people who use drugs,114 including AYA, was negatively associated with MOUD access. 2.3.9 Racial or ethnic identity related factors 43 Racial or ethnic identity related factors associated with MOUD access were observed in five studies from the USA,81, 111, 116, 122, 124 of which three identified a negative association between Black racial identity and buprenorphine, MMT, or naltrexone access.81, 111, 122 Additionally, a 2017 prospective cohort study81 and a 2020 retrospective cohort study among pregnant people conducted in the USA found negative associations between Latino ethnicity and buprenorphine, MMT, or naltrexone access,122 while a 2016 cross-sectional study in the USA found that Latino ethnicity was positively associated with successfully enrolling in versus never attempting MOUD.116 Additionally, a prospective cohort study conducted in 2012 in the USA that included AYA accessing buprenorphine-based detoxification found that a higher proportion of participants were white,124 while a 2011 prospective cohort study of self-identifying Indigenous AYA in Vancouver, Canada found that only 23.4% of participants reported accessing MMT over the study period.126 2.3.10 Sex-based factors An association between biological sex and MOUD access was identified in five studies,81, 111, 125, 126, 128 of which four reported higher levels of MOUD access among female versus male AYA.111, 125, 126, 128 Among these studies, a 2012 retrospective cohort study conducted in Ireland and a cross-sectional study conducted in 2020 in the USA found that female AYA who accessed MOUD were more likely to report being in a relationship as well as a history of suicide or self-harm,96, 131 while a qualitative study among AYA access buprenorphine or naltrexone in Canada in 2005 found female AYA were more likely to report polysubstance use, experiencing treatment barriers or stigma, as well as living in a group home or being housed at higher proportions than male AYA.125 44 In examining associations with MOUD access among male AYA in comparison to female AYA, two studies found a higher likelihood of male AYA reporting previous criminal conviction or incarceration as well as having siblings who used opiates or alcohol.96, 131 Additionally, two retrospective cohort studies from Ireland found male AYA accessing MMT were younger96 and reported a younger age of leaving school,131 while the 2005 qualitative study conducted in Canada found that male AYA were also more likely to report peer influence over their treatment decision-making, using heroin for the first time at an older age, and experiencing homelessness in comparison to female AYA.125 2.4 Discussion Consistent with existing literature examining MOUD access in the general population,22, 135-137 this review found younger age to be negatively associated with MOUD access. Additionally, findings suggest that younger age is positively associated with accessing opioid antagonists and partial opioid agonists, like naltrexone and buprenorphine-naloxone, respectively. One potential explanation for this is prescribers’ reluctance to provide MOUD to AYA,138-140 which may be due to concerns of diversion139, 140 or beliefs that OAT enables substance use and should be used as a last resort.138 More specifically, the use of value-based decision-making, whereby prescribers’ discriminatory views towards AYA who use drugs or their personal perspectives on treatment approaches may result in the prescription of MOUD that prescribers’ deem to have a lower potential for ‘abuse’. Despite this hesitancy, the toxicity of the illicit drug supply and associated overdose risk is far greater than the risk of prescribing MOUD27 and efforts should be made to address prescribers’ misconceptions around OUD and biases towards prescribing MOUD to AYA. 45 In the context of the conceptual framework employed in this dissertation, the tendency to prescribed certain types of OAT (i.e., buprenorphine and naltrexone) to AYA indicate OAT may not be approachable. Additionally, social factors, such as stigma towards AYA with OUD, may be shaping whether AYA deem OAT to be acceptable to meeting their treatment needs, especially when AYA may be unable to access the types of OAT that they deem essential to realizing their treatment goals. Some evidence from this review points to concerning racial identity-based differences in MOUD access. Given the known discrimination and structural racism that many Black, Indigenous, and people of colour (BIPOC) experience in the healthcare system,141 these findings emphasize the importance of improving the treatment experiences of BIPOC AYA. In the context of the risk environment, race-based stereotyping and discrimination are social factors that may be negatively influencing how BIPOC AYA experience and navigate OAT programming, emphasizing the importance of improving access to culturally safe treatment services.142, 143 Previous qualitative research among Indigenous AYA have indicated their preference and desire for culturally-safe treatment services, which are important to addressing the ongoing legacy of colonization.144 Furthermore, findings demonstrate increased access to MOUD in high-poverty and low educational level neighborhoods versus low poverty, high education level neighborhoods, which may be explained by the concentration of substance use treatment programs in low-income settings. Despite this, other findings demonstrated that treatment facilities in high-income neighborhoods were more likely to offer MOUD to AYA. This emphasizes the importance of ensuring that AYA have access to a continuum of supports – including health care, housing, 46 income assistance, and education, among others145 – alongside MOUD regardless of their socioeconomic background. Similarly, the significant geographic differences in MOUD access between the US South and other regions is problematic, especially given recommendations by the American Academy of Pediatrics urging the prescription of MOUD to AYA.28 These findings indicate the importance of understanding the discrepancies in MOUD access and identifying ways to improve MOUD access for AYA in this and other regions. These findings allude to the potential impact of policy-environment factors, whereby the concentration of OAT programming and services in certain neighborhoods or the provision of OAT in some jurisdictions but not others, can result in the inequitable availability of OAT. Potential solutions to this are communicating the benefits of MOUD to policymakers, healthcare providers, and AYA who use drugs, as well as establishing channels for AYA to access MOUD in underserved, rural or remote regions. Additionally, the sex-based differences in MOUD suggest that male AYA were less likely to access MOUD. This may be reflective of findings that male AYA are more likely to be influenced by their peer networks, which has been demonstrated in previous qualitative research among AYA.125 This is indicative of the strong influence of one’s social environment, influences, and factors on perceptions of treatment acceptability, and highlights the potential role of peers and peer networks in addressing misconceptions and cocnerns about OAT. To date, research has demonstrated the positive impact of peer networks on disseminating pertinent harm reduction and public health information,146 which may be another solution to addressing sex-based gaps in MOUD access. 47 Findings pertaining to the relationship between criminal justice system involvement and MOUD access require further attention. This relationship highlights the potential impacts of the policy environment, where carceral and punitive approaches to substance use have resulted in inequities in MOUD availability and accommodation within prison settings and other treatment-mandated programs. As MOUD remains illegal or out-of-reach in prison settings around the world,147 existing evidence demonstrates that many incarcerated OUD patients who discontinue opioid use in the absence of OAT relapse upon release,148 especially within the first two weeks of their release.149 Therefore, it is pertinent that access to MOUD be improved for incarcerated or treatment-mandated AYA in order to reduce the harms experienced by this population. Similarly, the criminalization of parents who use drugs, especially women who are pregnant or with children, and the negative association with MOUD access is concerning. One intervention that has proven successful is the implementation of a continuum of pre- and post-natal supports for women who use opioids, including community- and hospital-based “rooming in” interventions that provide MOUD and improve maternal and neonatal health outcomes.150 Lastly, the negative associations between other types of substance use and MOUD access provide insight into additional areas where treatment access can be improved. As evidence indicates that AYA have different substance use patterns and treatment needs versus non-AYA populations,70-72 review findings suggest that more intensive substance use (e.g., injection drug use, polysubstance use) may be negatively associated with MOUD access. This may be due to challenges that AYA with more intensive and entrenched substance use experience when accessing treatment, or due to stringent treatment requirements and expectations. This finding highlight the interplay between physical space (e.g., characteristics of a local drug scene) and social factors (e.g., barriers to health 48 and social services), and how these collectively influence how available and approachable AYA perceive MOUD to be. Therefore, it is important to better understand and offer treatment services that meet the needs of AYA who report polysubstance use, and research seeking to elucidate the relationship between substance use type and frequency would be beneficial. Additionally, for AYA who report both stimulant and opioid use, one promising approach is the provision of prescription stimulants alongside MOUD, which – when adequately dosed – have been found to reduce both illicit opioid and stimulant use.151-153 There are several limitations to this study that are important to note. Although relevant academic databases were searched, records may have nevertheless been missed in the search and screening process. Secondly, the heterogeneity between the included studies made it difficult to calculate pooled effect measures and so a narrative synthesis approach was utilized. Additionally, the different approaches to assessing age-related associations made it difficult to compare MOUD access between adolescents and young adults. Thirdly, identified studies were all derived from high-income countries and so findings are not generalizable to low- and middle-income settings. Despite these limitations, the quality of included studies was mostly moderate to high and identified studies point to ways to improve MOUD access among AYA. 2.5 Conclusions This review found that a majority of AYA who report OUD have limited access to MOUD, which is problematic given recommendations for their use.28 Findings suggest there is an urgent need to address barriers to MOUD access, including prescriber reluctance, which may be accomplished by 49 providing AYA with access to a continuum of health and social supports alongside MOUD. Similarly, determining ways to both encourage and reduce barriers to the prescription of MOUD may be helpful in improving MOUD access among this hard-to-reach population. 50 Table 2.1 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist for a systematic review of MOUD access and associated factors among adolescents and young adults who use opioids. Section/topic # Checklist item Reported on page # TITLE Title 1 Identify the report as a systematic review, meta-analysis, or both. 28 ABSTRACT Structured summary 2 Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number. N/A INTRODUCTION Rationale 3 Describe the rationale for the review in the context of what is already known. 28 Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS). 29 METHODS Protocol and registration 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number. 30 Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale. 29, 51 Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched. 30 Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated. 51-52 Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis). 31, 53 Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators. 31 51 Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made. 29, 51 Risk of bias in individual studies 12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis. 31, 54-56 Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means). NR Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I2) for each meta-analysis. NR Risk of bias across studies 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies). NR Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating which were pre-specified. NR RESULTS Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram. 31-32, 53 Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations. 31-43, 57-71 Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). 54-56 Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot. NR Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency. NR Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15). NR Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]). NR DISCUSSION Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; 43-46 52 consider their relevance to key groups (e.g., healthcare providers, users, and policy makers). Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias). 46 Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research. 43-46 FUNDING Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review. N/A 53 Table 2.2 Population, exposures, comparisons, outcomes, and study design inclusion criteria. Criteria Definition Population Adolescents and young adults with a mean or median sample age between 10 to 30 years and who report opioid use Exposures Medications for opioid use disorders including opioid agonist, partial agonist, and antagonist treatments Comparisons None stipulated, but could include placebo, non-exposed, or no interventions Outcomes Access to MOUD and associated factors; access includes any assessment of the availability, prescription receipt, or the initiation of MOUD Study designs All empirical study designs, excluding case series/studies and reviews 54 Table 2.3 Medline search strategy for a systematic review on MOUD access and associated factors among adolescents and young adults who use opioids. Ovid MEDLINE(R) ALL <Database inception to May 3, 2021> 1 [AYA MOUD access search in Ovid MEDLINE] 2 [Opioid use disorder concept] 3 exp opioid-related disorders/ or exp substance abuse, intravenous/ or exp substance abuse/ 4 ((Non-medical prescription$ or opi* prescription$ or prescription$ opi* or prescription$ drug$ or off-label) adj2 (abuse* or misuse* or disorder* or use* or addict* or depend*)).mp. 5 ((injection drug$ or intravenous drug$ or IV drug$ or injection opi* or intravenous opi*) adj2 (abuse* or misuse* or disorder* or use* or addict* or depend*)).mp. 6 ((opioid* or opiate* or drug$ or substance$ or heroin) adj2 (abuse* or misuse* or disorder* or use* or addict* or depend*)).mp. 7 ((poly-substance$ or poly-drug$) adj3 (abuse* or misuse* or disorder* or use* or addict* or depend*)).mp. 8 (PWID or PWUD or IDU or OUD or SUD or NMPOU).mp. 9 exp narcotics/ or exp Opiate Alkaloids/ or exp Fentanyl/ 10 exp controlled substances/ or exp prescription drugs/ or exp street drugs/ or exp Designer Drugs/ 11 ((illicit or street or recreational or illegal or regulated or hard or custom or designer or problem) adj2 (drug$ or substances$)).mp. 12 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 13 [MOUD concept] 14 exp Opiate Substitution Treatment/ 15 ((medically-assisted or opi* agonist or opi* antagonist or opiate$ or opioid$ or methado* or injectable opi*) adj2 (therap* or treatment* or pharmacotherap* or drug$ or substitution or replacement or maintenance)).mp. 16 (pharmacotherapy or OST or OAT or MAT or MMT or LAAM or iOAT or DAM or SROM).mp. 17 exp buprenorphine, naloxone drug combination/ or exp naltrexone/ or exp Buprenorphine/ or exp Methadone/ 18 (methado* or dolophine or buprenorphine or buprenorphine-naloxone or Suboxone or subutex or hydromorph* or diacetylmorph* or dilaudid or slow-release oral morphine or Kadian or levomethadyl acetate or clonidine or alpha-2-adrenergic agonists or naltrexone or vivitrol or revia).mp. 19 14 or 15 or 16 or 17 or 18 20 [MOUD access concept] 21 exp Health Services Accessibility/ 22 (uptake or access* or availab* or attempt* or engag* or enrol* or register* or continu* or prevalen*).mp. 23 21 or 22 24 [Adolescent and young adult concept] 25 exp Adolescent/ or exp Young Adult/ 55 26 (teen* or youth* or adolesc* or juvenile$ or child* or boy$ or girl$ or young adult* or emerg* adult* or young people* or young person* or young m*n or young wom*n or student$).mp. 27 25 or 26 28 [Summation & filters] 29 12 and 19 and 23 and 27 30 remove duplicates from 29 31 30 and animals 32 31 and humans 33 32 or (30 not 31) 56 Figure 2.1 The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Flow Diagram. 57 Table 2.4 Risk of bias assessment for cohort studies using the modified Newcastle-Ottawa Scale. Authors (Year) Q1 Q2 Q3 Q4 Q5 Q6 Q7 Q8 Q9 Total Alinsky (2020b)106 Yes Yes Yes Yes Yes Yes Yes Yes Yes L Bagley (2020)118 Yes Yes Yes Yes Yes Yes Yes Yes Yes L Bell (1992)102 - Yes - Yes - - Yes Yes Yes M Bell (2021)119 Yes Yes Yes Yes - Yes Yes Yes Yes L Chavez (2020)109 Yes Yes Yes Yes Yes - - Yes Yes L Hadland (2017)81 Yes Yes Yes Yes Yes Yes Yes Yes Yes L Hadland (2018a)112 Yes Yes Yes Yes Yes Yes Yes Yes Yes L Hadland (2018b)111 Yes Yes Yes Yes Yes Yes Yes Yes Yes L Knittel (2020)120 Yes Yes Yes Yes Yes Yes Yes Yes Yes L Krans (2016)114 Yes Yes Yes - - - Yes Yes Yes M Krans (2019)115 Yes Yes Yes - Yes Yes Yes Yes Yes L Krebs (2021)13 Yes Yes Yes Yes - - Yes Yes Yes L Mills (2004)128 Yes Yes Yes Yes - - - Yes Yes M Schiff (2020)122 Yes Yes Yes Yes - Yes Yes Yes Yes L Smyth (2012)96 Yes Yes Yes Yes - - Yes Yes Yes L Stancliff (2012)124 Yes Yes Yes Yes - - Yes Yes Yes L Yang (2011)126 Yes Yes Yes - Yes Yes - Yes Yes L Note: Q1 = Representativeness of the exposed cohort, Q2 = Selection of the non-exposed cohort, Q3 = Ascertainment of exposure, Q4 = Demonstrated that outcome of interest not present at start of study, Q5 = Comparability of cohorts on the bases of the design or analysis controlled for age, gender, ethnicity, Q6 = Comparability of cohorts on the bases of the design or analysis controlled for other important factors, Q7 = Assessment of outcome, Q8 = Was follow-up long enough for outcomes to occur, Q9 = Adequacy of follow-up of cohorts; L = low risk of bias; M = moderate risk of bias; H = high risk of bias. 58 Table 2.5 Risk of bias assessment for cross-sectional studies using the modified Newcastle-Ottawa Scale. Authors (Year) Q1 Q2 Q3 Q4 Q5 Q6 Q7 Q8 Q9 Q10 Total Alinsky (2020a)103 Yes Yes Yes Yes - Yes Yes Yes Yes Yes L Angelotta (2016)107 Yes Yes Yes Yes - - - Yes Yes Yes M Bachhuber (2017)108 Yes Yes Yes Yes - - - - Yes Yes M Bateman (2014)130 Yes Yes Yes Yes - - - - Yes Yes M Fagan (2008)131 Yes Yes - Yes - - - Yes Yes Yes M Feder (2017)22 Yes Yes - Yes - Yes Yes Yes Yes Yes L Hadland (2020)104 Yes Yes Yes - Yes Yes Yes Yes Yes Yes L Hand (2017)113 Yes Yes Yes - Yes - Yes Yes Yes Yes L Liebling (2016)116 Yes Yes - - Yes - Yes - Yes Yes M Maremmani (2015)132 Yes Yes - - Yes Yes Yes - Yes Yes M Paino (2015)105 Yes Yes Yes - Yes - Yes - Yes Yes M Patrick (2020)121 Yes Yes Yes - Yes - Yes - Yes Yes M Quigley (2012)117 - Yes Yes - - - - - Yes Yes H Stine (2009)133 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes L Winkelman (2020)123 Yes Yes Yes Yes Yes - Yes Yes Yes Yes L Note: Q1 = Representativeness of the exposed cohort, Q2 = Justified and satisfactory sample size, Q3 = Comparability between respondents and non-respondents, Q4 = Use of validated measurement tool, Q5 = Use of non-validated measurement tool that is defined, Q6 = Study controls for an important potentially confounding variable, Q7 = Study controls for other variables, Q8 = Used independent blind assessment or record linkage, Q9 = Used self-reported data, Q10 = Appropriate measurement of the association is presented and described; L = low risk of bias; M = moderate risk of bias; H = high risk of bias. 59 Table 2.6 Risk of bias assessment for qualitative studies using the GRADE-CERQual Scale. Author Year GRADE-CERQual resultsa Final Ayres129 2014 Methodological: Low Relevance: Low Coherence: Moderate Data adequacy: Low Low Boyd46 2017 Methodological: Low Relevance: Low Coherence: Moderate Data adequacy: High Moderate Brands125 2005 Methodological: Moderate Relevance: Low Coherence: Low Data adequacy: Low Low Guarino110 2009 Methodological: Low Relevance: Low Coherence: Moderate Data adequacy: Moderate Moderate Larney127 2017 Methodological: Low Relevance: Moderate Coherence: Low Data adequacy: High Low Note: a GRADE-CERQual = Grading of Recommendations, Assessment, Development and Evaluations-Confidence in the Evidence from Reviews of Qualitative Research. 60 Table 2.7 Summary of included studies examining MOUD access and associated factors among adolescents and young adults who use opioids. First author (Year) Study design Location Participants Sociodemographic Substance use characteristics MOUD type Inclusion/exclusion criteria Risk of Bias Alinksy (2020a)103 Cross-sectional USA N=13,537 treatment facilities Adolescents (age NR) All adolescent-specific SUD treatment facilities over the study period Buprenorphine, methadone, naltrexone Inclusion criteria: All SUD treatment facilities that participated in the 2017 National Survey of Substance Abuse Treatment Services; Exclusion criteria: NR; Low Alinksy (2020b)106 Retrospective cohort USA N=3,791 M (IQR): 18 (16 – 20) 58.9% Women; 65.7% white; OUD in 3 months before and 1 month after overdose Buprenorphine, methadone, naltrexone Inclusion criteria: 13-22 years; ³6 months continuous enrolment in the Truven-IBM Watson Health MarketScan Medicaid Database between 2009 and 2015; received primary or secondary diagnosis of opioid poisoning on emergency department or inpatient claims; Exclusion criteria: Disenrolled from insurance coverage; Low Angelotta (2016)107 Cross-sectional USA N=8,292 N=5,997 (73.3%) 18-29 years 100% Women; 85% white; Any primary opioid use at treatment admission Buprenorphine, methadone Inclusion criteria: ³12 years; pregnant women with an OUD admitted for treatment; primary substance use includes opioids; derived from the 2012 TEDS; Exclusion criteria: secondary or tertiary substance use includes opioids; missing data on MOUD; treatment occurred in Puerto Rico and Washington, DC; Moderate Ayres (2014)129 Qualitative UK N=30 N=5 young adults (Ages: 22, 27, 28, 29, 30) 2 Women; 3 Men; Any injection heroin use over the study period Methadone Inclusion criteria: Participated in ‘prescription in a day’ RCT through the Bristol Drug Project; retained in study for at least 3-months between October 2011 and September 2012; Exclusion criteria: NR Low Bachhuber (2017)108 Cross-sectional USA N=3,354 N=2,388 (71.2%) 18-29 years 100% Women; 84.9% white; Heroin or opioid analgesics at treatment admission Buprenorphine or methadone Inclusion criteria: 18-44 years; pregnant women; admitted to residential or outpatient treatment; had Medicaid insurance; data available in the 2013 and 2014 TEDS; Exclusion criteria: accessed detoxification services; Moderate Bagley (2020)118 Retrospective cohort USA N=15,281 N=4,268 (28%) 18-25 years 43.8% Women (18-21 years) 38% Women (22-25 years) Opioid use in the past year Buprenorphine, methadone, naltrexone Inclusion criteria: Experienced an opioid-related overdose between January 1, 2012 and December 31, 2014; had an ambulance encounter or through the emergency department, observation, or through a hospital encounter where an overdose was diagnosed; data derived from a Massachusetts Department of Health linked dataset; Exclusion criteria: Visits to Veterans Administration Hospitals; death within 30 days of overdose; Low Bateman (2014)130 Cross-sectional UK N=404 adolescents N=90 <16 years N=314 from 16-18 years Any opioid use over the study period Buprenorphine, lofexidine, methadone Inclusion criteria: Any prescribers attached to specialist SUD services in England between April 2006 and March 2007; Moderate 61 First author (Year) Study design Location Participants Sociodemographic Substance use characteristics MOUD type Inclusion/exclusion criteria Risk of Bias Exclusion criteria: Prescribers not attached to specialist SUD services; prescribers only in the criminal justice system; prescriptions written outside of study period; young people >18 years; Bell (1992)102 Prospective cohort Australia N=291 N=243 were <31 years 27.8% Women Any opioid use in the past 3 days or past 8 or more years Methadone Inclusion criteria: Assessed between March 1986 and June 1987; attended the first of two study interviews at a hospital-based methadone unit; Exclusion criteria: NR Moderate Bell (2021)119 Retrospective cohort USA N=318 Age NR; 60% Women; 84% white, 94% non-Hispanic OUD-related diagnostic Medicaid code over the study period Buprenorphine, buprenorphine-naloxone, naloxone, naltrexone Inclusion criteria: 10-19 years; OUD-related diagnostic code between July 2007 and January 2017; Exclusion criteria: NR; Low Boyd (2017)46 Qualitative Canada N=22 M (IQR): 26 (20-31) 8 Women, 14 Men; 19 white; 3 Indigenous Any injection drug use over the study period Methadone Inclusion criteria: Enrolled in the At-Risk Youth Study between May 2013 and September 2015; History of injection drug use; reported cessation of injection drug use for at least one 6-month period; could be actively injecting drugs; Exclusion criteria: NR Moderate Brands (2005)125 Qualitative Canada N=49 Women: M (SD): 18 (1) Men: M (SD): 17 (1) 24 Women; 25 Men; 58% white Men; 71% white Women Heroin use in the past year Methadone Inclusion criteria: 12-19 years; recruited from drop-in agencies between October 2000 and April 2002; past 12-month heroin use by any route; self-described involvement in “street-life”; Exclusion criteria: NR Low Chavez (2020)109 Retrospective cohort USA N=2,097 Age NR; 45.2% Women; 76.9% white OUD diagnosis over the study period Buprenorphine, naltrexone Inclusion criteria: OUD diagnosis between August 1, 2012 and May 31, 2016 based on Ohio Medicaid records; 12-18 years at time of diagnosis and did not turn 19 within 3-months of diagnosis; no pharmacy claim or procedure code for MOUD in year before OUD diagnosis; enrolled in Medicaid 9-12 months before OUD diagnosis; enrolled in Medicaid continuously for 3 months after OUD diagnosis; Exclusion criteria: NR Low Fagan (2008)131 Cross-sectional Ireland N=86 M (IQR): 16.8 (16-17) 54% Women Any opioid use at treatment admission Methadone Inclusion criteria: <19 years; enrolled in the YPP between January 2001 and October 2006; Exclusion criteria: NR Moderate 62 First author (Year) Study design Location Participants Sociodemographic Substance use characteristics MOUD type Inclusion/exclusion criteria Risk of Bias Feder (2017)22 Cross-sectional USA N=139,092 N = 3,086 (2.2%) from 15-17 years Heroin use: 49.3% Women; Other opioid use: 31.7% Women Any heroin or other opioid use at treatment admission Buprenorphine, methadone Inclusion criteria: Derived from the 2013 TEDS; treated for heroin, non-prescription use of methadone, or other opiate or synthetics; first treatment episode only; Exclusion criteria: Missing information on covariates; Data from Pennsylvania, Georgia, West Virginia, Wisconsin, Wyoming; Low Guarino (2009)110 Qualitative USA N=22 N=7 (31.8%) AYA M (SD): 24.29 (2.87) 86% Women; 100% white Any opioid use over the study period Methadone Inclusion criteria: 18-23 years; dependent on opioids; recruited through young adult methadone program in 2006; Exclusion criteria: NR Moderate Hadland (2017)81 Prospective cohort USA N=20,822 M (SD): 21 (2.5) 34.2% Women; 82.2% white OUD diagnosis over the study period Buprenorphine, naltrexone Inclusion criteria: 13-25 years; OUD diagnosis between January 1, 2001 and June 30, 2014; 6 months or more of continuous enrollment in insurance after OUD diagnosis; data derived from a large private USA health insurer that provided prescription drug coverage to all enrollees; Exclusion criteria: NR Low Hadland (2018a)112 Retrospective cohort USA N=4,837 M (IQR): 20 (19-21) 56.9% Women; 76.0% white OUD diagnosis over the study period Buprenorphine, methadone, naltrexone Inclusion criteria: 13-22 years; enrolled in the Truven-IBM Watson Health MarketScan Medicaid database between 2014 and 2015; primary or secondary OUD diagnosis in inpatient, emergency department, or outpatient claims; no prior OUD diagnosis or MOUD access in 60-days prior to OUD diagnosis; at least 3-months continuous enrolment in insurance after OUD diagnosis; Exclusion criteria: NR Low Hadland (2018b)111 Retrospective cohort USA N=6,864 Med (IQR): 20 (19-22) OUD diagnosis over the study period Buprenorphine, methadone, naltrexone Inclusion criteria: 13-22 years; enrolled in the Truven-IBM Watson Health MarketScan Medicaid database between 2014 and 2015; >11 months continuous enrolment in insurance; diagnosis of OUD; no MOUD receipt in month preceding OUD diagnosis; Exclusion criteria: NR Low Hadland (2020)104 Cross-sectional USA N=9,920 treatment facilities N=2,285 (23%) adolescent-tailored OUD treatment facilities OUD treatment facilities Buprenorphine, methadone, naltrexone Inclusion criteria: Treatment facilities that treat OUD and provide MOUD; from U.S. counties and county equivalents identified through the SAMHSA Behavioral Treatment Service Locator and the CDC as of October 2018; Exclusion criteria: Provided buprenorphine or methadone detoxification; Low Hand (2017)113 Cross-sectional USA N=8,656 N=6,111 (70.6%) <31 years 100% Women Primary opioid use at treatment admission Buprenorphine, methadone Inclusion criteria: Pregnant seeking admission to private or public OUD treatment; primary opioid use; derived from the 2013 TEDS; Low 63 First author (Year) Study design Location Participants Sociodemographic Substance use characteristics MOUD type Inclusion/exclusion criteria Risk of Bias Exclusion criteria: NR Knittel (2020)120 Retrospective cohort USA N=179 M (SD): 28.9 (4.5) 100% Women 91.6% white OUD diagnosis over the study period Buprenorphine, methadone, oxycodone taper or brief maintenance Inclusion criteria: Incarcerated at North Carolina Correctional Institute for Women between 2016 and 2018; Pregnant and identified as having OUD through prison prenatal clinic roster problem lists; Exclusion criteria: Incorrectly identified as being pregnant; First trimester pregnancy lost after arrival in prison; No medical records beyond pregnancy test; Low Krans (2016)114 Retrospective cohort USA N=791 M (SD): 27.3 (4.7) 100 % Women; 96.9% white OUD diagnosis over the study period Buprenorphine, methadone Inclusion criteria: Pregnant women with OUD; delivered an infant at University-affiliated hospital between 2009-2012; received MOUD; Exclusion criteria: NR Moderate Krans (2019)115 Prospective cohort USA N=12,587 M (SD): 27.7 (4.7) 100% Women; 87.8% white OUD diagnosis over the study period Buprenorphine, methadone Inclusion criteria: 15-44 years; enrolled in Medicaid; have a life birth between January 1, 2009 and September 30, 2015; OUD diagnosis during pregnancy; data derived from the Pennsylvania Department of Health and Human Services Medicaid Program; Exclusion criteria: Later pregnancy excluded if interpregnancy interval less than 24 weeks; Low Krebs (2021)13 Retrospective cohort Canada N=4,048 N=446 (11%) 12-18 years 64.4% Women N=3,602 (89%) 19-24 years 55.1% Men Ever accessed health services for OUD Buprenorphine-naloxone, injectable OAT, methadone, slow-release oral morphine Inclusion criteria: All individuals diagnosed with OUD between January 1, 1996 and September 30, 2018; no record of death and not lost to follow-up over the study period; Exclusion criteria: NR; Low Larney (2017)127 Qualitative Australia N=46 N=6 young adults (ages: 25, 26, 28, 28, 28, 28) 4 Women, 2 Men Opioid dependence documented upon incarceration Buprenorphine, methadone Inclusion criteria: Incarcerated between September 2012 and October 2013; continued MOUD from community, commenced MOUD in custody, or recently initiated MOUD (<28 days); voluntarily ceased MOUD in custody or reported opioid dependence but have not sought MOUD in custody; Exclusion criteria: NR Moderate Liebling (2016)116 Cross-sectional USA N=200 M (SD): 24.5 (3.24) 34.5% Women; 61.5% white Non-medical prescription opioid use in the past 30 days MOUD (not specified) Inclusion criteria: 18-29 years; residing in Rhode Island; enrolled in the Rhode Island Young Adult Prescription and Illicit Drug Study between January 2015 and February 2016; no current involvement in formal alcohol or substance treatment; able to complete interview in English; provide informed consent; must confirm non-medical use of prescription opioids in the past 30 days; Moderate 64 First author (Year) Study design Location Participants Sociodemographic Substance use characteristics MOUD type Inclusion/exclusion criteria Risk of Bias Exclusion criteria: NR Maremmani (2015)132 Cross-sectional Italy N=317 M (SD): 27.95 (7.7) 32.8% Women Heroin or prescription opioid use in the past 30 days OAT (not specified) Inclusion criteria: Participants accessing a SUD treatment units in Cossato and Bari over an 18-month period (study recruitment dates NR); Exclusion criteria: NR Moderate Mills (2004)128 Prospective cohort Australia N=210 M (SD): 21.5 (1.9) 40% Women Heroin use in the past 30 days Methadone Inclusion criteria: ≥18 years; no treatment for heroin use or incarceration in preceding month; provided contact details for follow-up; not previously enrolled in the Australian Treatment Outcome Study between February 2001 and August 2002; Exclusion criteria: NR Moderate Paino (2015)105 Cross-sectional USA N=307 adolescent treatment facilities NR All adolescent-specific SUD treatment facilities over the study period Acamprosate, buprenorphine, disulfiram, naltrexone Inclusion criteria: SUD treatment facilities participating in the National Treatment Centre Study between June 2009 and January 2012; provide minimum level of care at least equivalent to structured outpatient services defined by the American Society of Addiction Medicine; Exclusion criteria: Counsellors in private practice; transitional living facilities; court-ordered driver education classes; detoxification services; programs located in Veterans Health Administration facilities; prisons; methadone-only programs; Moderate Patrick (2020)121 Cross-sectional USA N=10,871 100% Women Simulated pregnant and nonpregnant women with OUD Buprenorphine, methadone Inclusion criteria: Prescribers in Florida, Kentucky, Massachusetts, Michigan, Missouri, North Carolina, Tennessee, Virginia, Washington, and West Virginia; contacted between March 7 to September 5, 2019; Exclusion criteria: NR; Moderate Schiff (2020)122 Retrospective cohort USA N=5,247 M (SD): 28.7 (5) 100% Women 86.7% white Clinical indication of OUD or MOUD use over the study period Buprenorphine, methadone Inclusion criteria: Pregnant women who had a delivery between October 1, 2011 and December 31, 2015; diagnosis of OUD from hospital discharge, an opioid overdose event, enrollment in a state-funded treatment program for OUD, receipt of buprenorphine or methadone treatment, or an insurance claim for neonatal abstinence syndrome; Exclusion criteria: Women with neonatal abstinence syndrome who received opioid prescription in 3 months before delivery or before 34 gestational weeks; OUD from diagnosis claim alone; Low Quigley (2012)117 Cross-section study USA N=77 M (SD): 25 (4.3) 100% Women OUD diagnosis over the study period Methadone Inclusion criteria: Pregnant women seeking methadone treatment in an inpatient psychiatry unit between June 2010 and April 2011; Exclusion criteria: NR High 65 First author (Year) Study design Location Participants Sociodemographic Substance use characteristics MOUD type Inclusion/exclusion criteria Risk of Bias Smyth (2012)96 Retrospective cohort study Ireland N=100 M (SD): 16.6 (0.9) 54% Women Any heroin or opioid use at treatment admission Buprenorphine, methadone Inclusion criteria: ≤18 years; heroin or opioid use; treated with MOUD; initiated treatment through the Young Persons Program between May 2000 and July 2008; Exclusion criteria: NR Low Stancliff (2012)124 Prospective cohort study USA N=153 N=16 M (SD): 23.4 (5.8) Heroin use at treatment admission Buprenorphine detoxification Inclusion criteria: Referred through syringe exchange programs between November 21, 2005 and July 28, 2008; Exclusion criteria: NR Low Stine (2009)133 Cross-sectional study Austria, Canada, and USA N=427 M (SD): 27.6 (5.9) 100% Women; 78.5% white Previous OUD diagnosis or OUD diagnosis at treatment admission Buprenorphine, methadone Inclusion criteria: 18-41 years; enrolled in the Maternal Opioid Treatment: Human Experimental RCT comparing methadone and buprenorphine that occurred between May 4, 2005 and October 31, 2008; current or historical OUD diagnosis and risk of relapse; provide opioid-positive urine sample; estimated gestational age limit of 13 weeks or 6 weeks if normal fetal heartbeat confirmed by sonogram; no vaginal bleeding in week prior to or at enrolment; Exclusion criteria: Medical condition that makes participation hazardous; acute severe psychiatric condition requiring treatment; imminent risk to self or others; pending legal action that could lead to withdrawal from study; evidence of regular benzodiazepine or alcohol use; multiple-fetus pregnancy; did not intend on delivering at local hospital; Low Winkelman (2020)123 Cross-sectional USA N=131,838 N=82,992 (63.0%) 12-29 years 100% Women Admitted to treatment for OUD Buprenorphine, methadone Inclusion criteria: Pregnant women admitted to treatment for OUD and identified through the TEDS between 1992 and 2017; Exclusion criteria: State of Florida due to incompatible reporting; admissions that are missing a referral source; treatment admission records that were missing data on study covariates; Low Yang (2011)126 Prospective cohort study Canada N=397 M (IQR): 24.5 (21.4-27.4) 53.4% Women; 100% Indigenous Daily injection or non-injection opioid use in the past 6 months Methadone Inclusion criteria: 14-30 years; enrolled in the Cedar Project between October 2003 and July 2007; lifetime or previous six-month self-reported injection or non-injection opioid use; provide written informed consent; Exclusion criteria: NR Low Note: Risk of bias or quality assessment was conducted using the modified Newcastle-Ottawa Scale for cohort and cross-sectional studies and the GRADE-CERQual tool for qualitative studies. Abbreviations: M, mean; Med, median; MOUD, medications for opioid use disorder; NR, none reported; OAT, opioid agonist treatment; OUD, opioid use disorder; SAMSHA, Substance Abuse and Mental Health Services; RCT, randomized controlled trial; SUD, substance use disorder; TEDS, Treatment Episode Dataset; USA, United States of America. 66 Table 2.8 Summary of study findings from included studies examining MOUD access and associated factors among adolescents and young adults who use opioids. First author (Year) Objective(s) Covariate(s)/Predictor(s) Outcome indicator(s) Proportion of AYA that accessed MOUD Factors associated with MOUD access Alinksy (2020a)103 Examine associations between adolescent-serving SUD treatment facility characteristics and the provision of MOUD Facility characteristics: non-profit status, acceptance of health insurance, cash-only treatment, outpatient treatment, residential treatment, inpatient treatment, license by national authority The provision of buprenorphine, methadone, or extended-release naltrexone N = 816 (23.1%) of SUD treatment facilities with adolescent programs provide buprenorphine, methadone, or extended-release naltrexone; 13.2% of cash-only facilities with adolescent-focused programs provide MOUD vs. 41.5% of cash-only facilities with adult-focused programs Positive associations: Non-profit vs. for-profit (OR: 1.38, 95% CI: 1.08 – 1.75), Insured vs. free/subsidized treatment (OR: NR), Offer inpatient services/licensed by national authority vs. not (OR: NR); Negative associations: South vs. Northeast (OR: 0.24, 95% CI: 0.19-0.30), West vs. Northeast (OR: 0.15, 95%: 0.12-0.19), Midwest vs. Northeast (OR: NR); Alinksy (2020b)106 The percentage and characteristics of AYA who receive MOUD within 30 days of an opioid-related overdose Age, Gender, Racial identity, Pregnancy status, Pain condition, Depression, Self-harm/suicidal ideation, Anxiety disorder, Attention-deficit/hyperactivity disorder, Type of SUD, Prior MOUD, Prior behavioral health service, Prior opioid prescription, Year of overdose Receipt of timely addiction treatment (including buprenorphine, methadone or naltrexone) within 30 days of opioid-related overdose N = 67 (1.9%) between 13-22 years received buprenorphine, methadone, or naltrexone within 30 days of opioid-related overdose Positive associations: OUD vs. no OUD diagnosis (AOR: 9.03, 95% CI: 3.95 – 20.7), Prior MOUD vs. none (AOR: 14.2, 95% CI: 7.29 – 27.8); Negative associations: NR; Angelotta (2016)107 Explore the relationship between use of OAT for pregnant women with OUD and other potential factors that affect OAT access State prenatal child abuse laws, Principal source of referral to treatment, Geographical region of USA, Medicaid coverage of MOUD Absence of methadone or buprenorphine in treatment plan of pregnant women with primary OUD N=2,641 (44.0%) between ages 12-29 received methadone or buprenorphine N = 7 (21.88%) 12-17 years N = 1,224 (42.15%) 18-24 years N = 1,410 (46.06%) 25-29 years Positive associations: NR Negative associations: SUD care provider referral vs. self-referral (OR: 2.21, 95% CI: 1.91-2.56), Other healthcare provider referral vs. self-referral (OR: 1.51, 95% CI: 1.31-1.74), Criminal justice referral vs. self-referral (OR:7.17, 95% CI: 6.08-8.43), Other community referral vs. self-referral (OR: 3.78, 95% CI: 3.22-4.44), Unknown referral source vs. self-referral (OR: 2.07, 95% CI: 1.45-2.95), South vs. Northeast (OR: 2.41, 95% CI: 2.10-2.76), West vs. Northeast (OR: 1.37, 95% CI: 1.19-1.58), MOUD Medicaid coverage vs. none (OR: 2.28, 95% CI: 1.97-2.64), State permits child abuse charges for SUD vs. not (OR: 1.43, 95% CI: 1.26-1.62); Ayres (2014)129 Understand the effectives of an acceptability of a same-day methadone prescription intervention NR Positive outcomes and motivation for using methadone NR Positive associations: Feeling like they are in a bad place and are looking for stabilization; Negative associations: Long wait times or physicians take too long to prescribe methadone, Gatekeeper barriers and having to go from one doctor to the next in search of prescription; Bachhuber (2017)108 Estimate the association between state Medicaid coverage of methadone and use State Medicaid coverage of methadone or buprenorphine, Age, Racial or ethnic identity, Planned use of methadone or buprenorphine 52.9% (51.2-54.6) in all treatment settings 30.7% (27.2-34.3) in residential treatment 36.3% (32.0-40.6) in intensive outpatient Positive associations: All settings: Medicaid vs. private/non-Medicaid/no insurance (AD: 21.2, 95% CI: 4.6-37.9), Residential: Medicaid vs. private/non-67 First author (Year) Objective(s) Covariate(s)/Predictor(s) Outcome indicator(s) Proportion of AYA that accessed MOUD Factors associated with MOUD access of OAT among pregnant women admitted for specialty OUD treatment Education, Heroin use, Treatment referral source, Residential, Intensive outpatient, Non-intensive outpatient treatment 63.5% (61.4-65.5) in non-intensive outpatient Medicaid/no insurance (AD: 16.1, 95% CI: 0.8-31.4), Intensive outpatient: Medicaid vs. private/non-Medicaid/no insurance (AD: 37.0, 95% CI: 8.1-66.0) Negative associations: NR; Bagley (2020)118 Estimate the time to MOUD treatment and rates of MOUD access in the 12 months after a non-fatal overdose Age, Gender, Homelessness, Involuntary treatment, Past-year: anxiety, depression, prescription benzodiazepine use, MOUD, detoxification, residential treatment Treatment with methadone, buprenorphine, or naltrexone following non-fatal overdose N=1209 (28%) 18-21 years N=193 (16%) received buprenorphine N=121 (10%) received naltrexone N=85 (7%) received methadone N=3,059 (36%) 22-25 years accessed MOUD: N=612 (20%) received buprenorphine N=367 (12%) received methadone N=306 (10%) received naltrexone Positive associations: 18-21 vs. 26-45 and naltrexone (AHR: 1.65, 95% CI: 1.36-2.00); 22-25 vs. 26-45 and naltrexone (AHR: 1.41, 95% CI: 1.23-1.61); Negative associations: 18-21 vs. 26-45 and methadone (AHR: 0.60, 95% CI: 0.45-0.70); Bateman (2014)130 Describe the nature of prescribing pharmacological treatment to AYA and identify differences in prescribing between younger and older adolescents Age, Prescriber who wrote the prescription Prescribed methadone, buprenorphine, or lofexidine N=33 (36.7%) <16 years N=172 (54.7%) 16-18 years Positive associations: 16-18 vs. <16 years (OR: 2.08, 95% CI: 1.03-4.16) at the bivariate level, not statistically significant after adjusting for the prescriber; Negative associations: NR; Bell (1992)102 Understanding factors associated with being rejected from MMT Drug use, Health and social functioning, Treatment for SUD, Illegal activities Being rejected from a methadone program N=196 (80.7%) ≤30 years N=15 (62.5%) ≤20 years N=81 (79%) 21-25 years N=100 (86%) 26-30 years Positive associations: Daily vs. <daily opioid use (AOR: 10, 95% CI: 4.5-20), Positive vs. negative urine opioid screen (AOR: 5, 95% CI: 1.8-14), ≥10 criminal convictions vs. <10 (AOR: 17, 95% CI: 3.5-100); Negative associations: NR; Bell (2021)119 Examining demographic factors associated with the receipt of buprenorphine Age, Racial or ethnic identity, Sex Buprenorphine receipt N=177 (55.7%) received any MOUD N=79 (44%) received buprenorphine-naloxone N= 66 (37%) received naltrexone N= 26 (15%) received naloxone N=6 (3%) received buprenorphine Positive associations: Older vs. younger age (per year older) (AOR: 3.29, 95% CI: 2.00-5.40); Negative associations: NR; Boyd (2017)46 Explore how street-youth characterize their transitions into period of injection cessation as well as perceived barriers to injection cessation, including experiences with MMT programs NR NR Majority accessed MMT (proportion NR) Positive associations: Wanting to cease injection drug use; Negative associations: Treatment costs; Brands (2005)125 68 First author (Year) Objective(s) Covariate(s)/Predictor(s) Outcome indicator(s) Proportion of AYA that accessed MOUD Factors associated with MOUD access Assess motivation street-involved youth’s motivation with respect to treatment Sociodemographic information, Specific drug use patterns, Characteristics of heroin use including symptoms of opioid dependence, Tolerance and withdrawal, Risk factors for Infections associated with heroin use, Efforts to quit or cut down Gender differences in reasons for seeking help and barriers to methadone N=18 (16%) accessed methadone Positive associations: Women more likely to access methadone in comparison to Men (29% vs. 4%, p<0.05); Negative associations: Women more like to experience program restrictions (38% vs. 0%, p<0.005) and stigma or fear (25% vs. 4%, p<0.05) as barriers to treatment in comparison to Men; Men more likely to report friends’ influence (32% vs. 4%, p<0.05) as a barrier to treatment; Chavez (2020)109 Examine the receipt of medications and health care within 3 months of an OUD diagnosis Age, Gender, Ethnicity, County of residence, Clinical characteristics, Mental health conditions, Other SUD, Opioid overdose, Pain-related diagnoses, Pharmacy claims data, Health care utilization Receipt of buprenorphine or naltrexone within 3 months of OUD diagnosis 4.6% (2.8 – 5.6) accessed any MOUD: 3.9% (3.1 – 4 .8) accessed buprenorphine 0.8% (0.5 – 1.2) accessed any oral or injectable naltrexone Positive associations: Any MOUD: 12-15 vs. 16-18 years: 1.2% vs. 5.9% (p<0.01); Any buprenorphine: 12-15 vs. 16-18 years: 0.7% vs. 5.1% (p<0.01); Negative associations: NR Fagan (2008)131 Describe the patterns of substance use and psychosocial problems of under-19 year old opiate-dependent teenagers presenting to a specialist adolescent opiate treatment service Age, Gender, Education, Residence, Family history of SUD, Relationship status, Main opiate used, Secondary substance use, Route of heroin use, Criminal behavior, Psychiatric history, Hepatitis-C status Gender differences in methadone prescription N=86 (100%) accessed methadone Positive associations: Women vs. Men: Currently in a relationship (76% vs. 25%, p<0.001), History of deliberate overdose (32% vs. 8%, 0=0.007); Men vs. Women: Sibling alcohol use (29% vs. 5%, p=0.007), Past criminal convictions (63% vs. 35%, p=0.02), Younger age of school leaving (13.9 years vs. 14.9 years, p=0.01); Negative associations: NR; Feder (2017)22 Provide information on the extent of MOUD use among adolescents treated for OUD Age, Gender, Racial or ethnic identity, Referral source, Homelessness, Number of substances reported at admission Receipt of methadone or buprenorphine N=18 (2.4%) of adolescents who reported heroin use N=9 (0.4%) of adolescents who reported other opioid use Positive associations: NR; Negative associations: Adolescents vs. adults who use heroin (AOR: 0.09, 95% CI: 0.05-0.14), Adolescents vs. adults who use other opioids (AOR: 0.05, 95% CI: 0.03-0.10); Guarino (2009)110 Gather qualitative data on AYAs’ perceptions of the components of effective treatment NR NR N=7 (100%) accessed methadone Positive associations: Feeling as though their life is “really bad” and they want treatment, Making information about treatment available to youth, Having failed at inpatient detoxification and residential treatment; Negative associations: Feeling forced or experiencing external pressure; Hadland (2017)81 Identify trends in and disparities in pharmacotherapy for youth Age, Gender, Racial or ethnic identity, Neighborhood education and poverty levels, Geographic region, Census region, Year of diagnosis Receiving buprenorphine or naltrexone within 6 months of OUD diagnosis N=5,580 (26.8%) accessed buprenorphine or naltrexone N=4,976 (23.9%) accessed buprenorphine N=604 (2.9%) accessed naltrexone Any MOUD: Positive associations: NR; Negative associations: 13-15 vs. 21-25 years (AOR: 0.03, 95% CI: 0.02-0.06), 16-17 vs. 21-25 years (AOR: 0.25, 95% CI: 0.21-0.29), 18-20 vs. 21-25 years (AOR: 69 First author (Year) Objective(s) Covariate(s)/Predictor(s) Outcome indicator(s) Proportion of AYA that accessed MOUD Factors associated with MOUD access 0.64, 95% CI: 0.60-0.69), Being a woman (AOR: 0.79, 95% CI: 0.73-0.84), Non-Hispanic Black racial identity (AOR: 0.58, 95% CI: 0.33-0.99), Hispanic vs. non-Hispanic ethnicity (AOR: 0.83, 95% CI: 0.71-0.97), Low-middle vs. low- poverty level (AOR: 0.90, 95% CI: 0.83-0.98); Buprenorphine vs. Naltrexone Positive associations: Non-metropolitan vs. metropolitan area (OR: 1.44, 95% CI: 1.19-1.75), Low/Low-middle vs. high educational level neighborhood (OR: 1.77, 95% CI: 1.29-2.43), High vs. low poverty level (OR: 1.82, 95% CI: 1.16-2.84), High-middle vs. low- poverty level (OR: 1.67, 95% CI: 1.27-2.20), Low-middle vs. low- poverty level (OR: 1.25, 95% CI: 1.01-1.53), Midwest vs. South (OR: 1.30, 95% CI: 1.04-1.62); Negative associations: Younger age [16-17 vs. 21-25 years (OR: 0.47, 95% CI: 0.32-0.68), 18-20 vs. 21-25 years (OR: 0.78, 95% CI: 0.65-0.94)], Being a woman (OR: 0.82; 95% CI: 0.69-0.99); Hadland (2018a)112 Identify the frequency that youths who presented for care for OUD received timely addiction treatment Age, Gender, Racial or ethnic identity, Medicaid status, Pregnancy status, Depression, Anxiety disorder, Attention-deficit/hyperactivity disorder, Alcohol use disorder, Other SUD, Acute pain condition, Chronic pain condition Receipt of methadone, buprenorphine, or naltrexone within 3 months of an OUD diagnosis N=1,139 (23.5%) accessed any MOUD N=936 (19.4%) accessed buprenorphine N=135 (2.8%) accessed naltrexone N=68 (1.4%) accessed MMT Positive associations: Adolescents vs. young adults and naltrexone (35.3% vs. 11.1%, p<0.001) Negative associations: NR; Hadland (2018b)111 Determine the percentage of Medicaid-enrolled youth with OUD who receive recommended MOUD and identify disparities in access Age, Gender, Racial or ethnic identity, Psychiatric comorbidity Receipt of buprenorphine, methadone, or naltrexone N=1,483 (21.6%) accessed any MOUD N=1,245 (18.1%) accessed buprenorphine N=157 (2.3%) accessed naltrexone N=81 (1.2%) accessed methadone Positive associations: Adolescents vs. young adults (p<0.001) and naltrexone, Young adults vs. adolescents and methadone (p<0.001) Negative associations: Age 13-15 vs. ≥21 (AOR: 0.09, 95% CI: 0.04-0.21), Age 16-17 vs. ≥21 (AOR: 0.17, 95% CI: 0.12-0.24), Age 18-20 vs. ≥21 (AOR: 0.76, 95% CI: 0.67-0.87), Men vs. Women (AOR: 0.75, 95% CI: 0.67-0.86), Black vs. Non-Hispanic white (AOR: 0.39, 95% CI: 0.28-0.55), Depression (AOR: 0.79, 95% CI: 0.66-0.96), Comorbid alcohol use disorder (AOR: 0.70, 95% CI: 0.51-0.97), Comorbid substance use disorder (AOR: 0.83, 95% CI: 0.70-0.98) 70 First author (Year) Objective(s) Covariate(s)/Predictor(s) Outcome indicator(s) Proportion of AYA that accessed MOUD Factors associated with MOUD access Hadland (2020)104 Determine the availability of OUD treatment facilities that provide medications for adolescents Age, Gender, Racial or ethnic identity, Employment, Poverty status, Insurance, US Census Bureau division, Rural/Urban, Medically underserved area, Opioid overdose rate per 100,000 Treatment facilities that provide MOUD and accept adolescents N=1,889 (60.1%) of US Counties had treatment facilities that provided MOUD N=1,062 (33.8%) of US Counties had adolescent-tailored programs N=371 (11.8%) of US Counties had adolescent programs that provided buprenorphine N=40 (1.3%) of US Counties had adolescent programs that provided methadone N=512 (16.3%) of US Counties had adolescent programs that provided naltrexone N=742 (23.6%) of US Counties had adolescent programs that permitted MOUD for outside prescribers/facilities Positive associations: Greater county-level population of 45-64 vs. 11-17 years (ARR: 1.04, 95% CI: 1.00-1.07); Higher vs. lower proportion in poverty (ARR: 1.02, 95% CI: 1.01-1.04); Middle Atlantic vs. New England (ARR: 1.52, 95% CI: 1.13-2.04); Mountain vs. New England (ARR: 1.43, 1.02-2.00); Medium vs. Large Central Metropolitan area (ARR: 1.32, 95% CI: 1.10-1.59); Small vs. Large Central Metropolitan area (ARR: 1.70, 95% CI: 1.44-2.00); Micropolitan vs. Large Central Metropolitan area (ARR: 2.09, 95% CI: 1.67-2.62); Noncore vs. Large Central Metropolitan area (ARR: 2.13, 95% CI: 1.68-2.71); Negative associations: Greater county-level population of 25-44 vs. 11-17 years (ARR: 0.96, 95% CI: 0.94-0.99); Hand (2017)113 Compare data related to self-reported substance used leading to treatment admission, characteristics of treatment received, and demographic characteristics between US Census regions Age, Racial or ethnic identity, Education, Employment, Insurance status, Marital status, Primary substance use, Injection drug use, Treatment history Differences in demographic characteristics by census region N=3,975 accessed MOUD N=1,519 (54.1%) in the Northeast USA N=921 (47.7%) in the Midwest USA N=876 (49.7%) in the West USA N=659 (30.6%) in the South USA Positive associations: Northeast vs. South census region (AOR: 2.84, 95% CI: 2.51-3.22), Midwest vs. South census region (AOR: 2.08, 95% CI: 1.82-2.37), West vs. South census region (AOR: 2.03, 95% CI: 1.76-2.33); Negative associations: NR; Knittel (2020)120 Quantify the extent that pregnant women in a Southeastern prison received OAT during incarceration Age, Racial or ethnic identity, Custody status, Admitted to health unit, Pregnancy trimester, Substance use history, OAT history and type, Delivery prior to release Receipt of MOUD MOUD versus non-standard treatment (no MOUD, oxycodone taper, brief oxycodone maintenance) N=51 (28.5%) received MOUD N=20 (11.2%) received buprenorphine N=31 (17.3%) received methadone N=41 (22.9%) received oxycodone taper or brief maintenance Positive associations: Second vs. first trimester (AOR: 5.42, 95% CI: 1.18-25.01); Third vs. second trimester (AOR: 8.30 (1.78-38.74); Yes vs. no OAT prior to incarceration (AOR: 25.15, 95% CI: 10.07-62.79); Negative associations: NR; Krans (2016)114 Characterize and compare patients who initiated methadone vs. buprenorphine during their pregnancy and identify patient characteristics predictive of buprenorphine use during pregnancy Age, Racial identity, Marital status, Employment, Education, Medicaid, Primiparous, Care provider information, Medical comorbidities, Substance use history and route, Treatment history, Social risk factors Receipt of buprenorphine vs. methadone N=711 (100%) accessed MOUD N=608 (76.9%) accessed methadone N=183 (23.1%) accessed buprenorphine Positive associations: Older age (AOR: 1.01, 95% CI: 1.02-1.11), Employed vs. unemployed (AOR: 1.87, 95% CI: 1.20-2.90), Pre-pregnancy MOUD vs. none (AOR: 2.68, 95% CI: 1.78-4.02); Negative associations: Benzodiazepine use vs. none (AOR: 0.48, 95% CI: 0.30-0.77), Children not in maternal custody vs. being in maternal custody (AOR: 0.63, 95% CI: 0.40-0.99), Partner with substance use vs. none (AOR: 0.37, 95% CI: 0.22-0.63); Krans (2019)115 Evaluate individual-level factors associated with MOUD use during pregnancy and temporal trends in methadone versus Age, Racial or ethnic identity, County of residence, Medica co-morbidities, Pregnancy-associated comorbidities, Receipt of methadone or buprenorphine N=7,034 (55.9%) accessed MOUD N=3,618 (28.7%) accessed methadone N=3,416 (27.1%) accessed buprenorphine Positive associations: Buprenorphine use increased from 15.8% (95% CI: 13.9-17.8) in 2009 to 30.9% (95% CI: 28.8-33) in 2015); 71 First author (Year) Objective(s) Covariate(s)/Predictor(s) Outcome indicator(s) Proportion of AYA that accessed MOUD Factors associated with MOUD access buprenorphine use across rural and geographic regions Substance use in pregnancy, MOUD utilization Negative associations: Methadone use decreased from 31.6% (95% CI: 29.3-33.9) in 2009 to 25.2% (95% CI: 23.3-27.1); Krebs (2021)13 Estimate the OUD cascade of care for all adolescents and young adults compared to older adults Gender, Income assistance, Rurality, OUD-related comorbidities Describe key factors associated with MOUD engagement N=163 (36.5%) 12-18 years received MOUD 60.1% received buprenorphine-naloxone 38% received methadone N=2,572 (71.4%) 19-24 received MOUD 48.3% received buprenorphine-naloxone 49.5% received methadone Positive associations: Older vs. younger age (71.4% vs. 36.5%, p-value: NR); Older vs. younger age and methadone access (49.5% vs. 38%, p-value: NR); Younger vs. older age and buprenorphine-naloxone access (60.1% vs. 48.3%, p-value: NR) Negative associations: NR; Larney (2017)127 Explore the intentions of opioid-dependent prisoners with regards to MOUD in custody and following release NR NR NR Positive associations: Fear of contracting Hepatitis C in a prison setting motivated MOUD use; Negative associations: NR; Liebling (2016)116 Assess patient-level, provider-level, health care system, and structural factors associated with SUD treatment access among young adults who report NMPOU Age, Gender, Racial or ethnic identity, Sexual orientation, Education, Employment, Monthly income, Geographic residence type, Overdose, Substance use type, Injection drug use, Mental illness, Prescribed opioids, Discrimination due to drug use, incarcerated or juvenile detention, Homelessness, Recruitment period Substance use treatment access N=48 (24%) accessed MOUD (not specified) Never attempted vs. successfully enrolled: Positive associations: Monthly income $501-$1,500 vs. <$501 (ARR: 3.93, 95% CI: 1.53-10.12), Non-white vs. white (ARR: 3.16, 95% CI:1.28-7.83); Negative associations: Hispanic or Latino vs. non-Hispanic (ARR: 0.30, 95% CI: 0.10-0.95), Drug-related discrimination by medical community vs. no (ARR: 0.25, 95% CI: 0.10-0.62), Ever incarcerated vs. no (ARR: 0.31, 95% CI: 0.14-0.66); Unsuccessfully attempted vs. successfully enrolled: Positive associations: Monthly income $501-$1,500 vs. <$501 (ARR: 5.36, 95% CI: 1.79-16.03), Ever overdosed by accident (ARR: 2.71, 95% CI: 1.06-6.91); Negative associations: NR; Maremmani (2015)132 To evaluate patients entering a Northern and Southern Italian out-patient OAT program Age, Gender, Treatment history, Early relapse, Employed, Primary substance use, Recent substance use Entering OAT program in Northern vs. Southern Italy N=317 (100%) accessed OAT (not specified) Northern vs. Southern Italy: Positive associations: Older vs. younger age (AOR: 4.97, 95% CI: 2.19-11.3), ≤1 month vs. >1 month since last treatment (AOR: 1.52, 95% CI: 1.53-13.8); Negative associations: Buprenorphine use vs. none (AOR: 0.041, 95% CI:0.006-0.284), Codeine use vs. non (AOR: 0.008, 95% CI: 0-0.197), Heroin use vs. none (AOR: 0.031, 95% CI: 0.005-0.203), Methadone use (AOR: 0.02, 95% CI:0.003-0.15), Oxycodone vs. none (AOR: 0.011, 95% CI: 0-0.486), Tramadol vs. none (AOR: 0.013, 95% CI: 0.001-0.276), Combined heroin & NMPOU (AOR: 0.025, 95% CI: 0.002-0.280); 72 First author (Year) Objective(s) Covariate(s)/Predictor(s) Outcome indicator(s) Proportion of AYA that accessed MOUD Factors associated with MOUD access Mills (2004)128 Examine the rate of progression from initial heroin use to first treatment episode among younger vs. older people who use heroin Age, Gender, Education, Living with parents, Main source of income, incarceration Rate of progression from initial heroin use to first treatment for heroin use N=78 (37%) accessed methadone Positive associations: Younger age of treatment initiation based on age of first regular heroin use (age 19.3 vs. 26.2, p<0.001), Years from regular heroin use to first treatment entry (2.4 vs. 5.1 years, p<0.001), Being a woman (β=1.35, 95% CI: 0.57-2.13); Negative associations: NR; Paino (2015)105 Examine the relationship between the proportion of adolescent clients in a treatment program and the availability of MOUD Proportion of adolescent clients, Treatment funding arrangement, Treatment accredited, Organization size, Client admission, Age, Inpatient services, 12-step orientation, Proportion of counselors with Graduate degrees, Proportion of counselors with alcohol/drug accreditation, Geography, Competition density Extent that a treatment centre provides acamprosate, tablet naltrexone, buprenorphine, injectable naltrexone or disulfiram N= 24 (17%) provided acamprosate N= 16 (11%) provided tablet naltrexone N= 16 (11%) provided buprenorphine N= 14 (10%) provided injectable naltrexone N= 13 (9%) provided disulfiram Positive associations: Privately vs. publicly funded (OR: 2.36, p<0.001), Accredited vs. not (OR: 2.14, p<0.05), Larger vs. smaller organization (OR: 2.07, p<0.001), Greater vs. smaller proportion of counselors with Graduate degrees (OR: 1.02, p<0.001); Negative associations: Greater vs. smaller proportion of adolescent clients (OR: 0.964, p<0.001), Clients admitted for treatment (OR: 0.765, p<0.10); Patrick (2020)121 Obtain estimates of differences in buprenorphine and methadone access for pregnant vs. nonpregnant women of reproductive age Age, Racial or ethnic identity, Insurance status, State Success rate for pregnant vs. nonpregnant callers N=2,312 (67.6%) received an appointment with buprenorphine clinician N=1,055 (61.4%) pregnant callers N=1,257 (73.9%) nonpregnant callers N=477 (13.9%) received an appointment at an opioid treatment program for methadone N=240 (88.6%) pregnant callers N=237 (89.4%) nonpregnant callers Positive associations: NR; Negative associations: Pregnant vs. nonpregnant (RR: 0.83, 95% CI: 0.79-0.87); Nonpregnant women with Medicaid vs. private insurance (40.3% vs. 49.2%, p<0.001); Quigley (2012)122 Understand the knowledge and attitudes related to methadone among this population Demographic characteristics, Substance use, Treatment knowledge and attitudes Motivating factors for seeking methadone N=77 (100%) accessed methadone Positive associations: Concern of how drug use was hurting their baby (96%, N=74); Negative associations: NR; Schiff (2020)117 Examine extent that maternal racial or ethnic identity is associated with the use of MOUD in the year before delivery Age, Education, Medicaid enrolment in month of delivery, Marital status, Rurality, Mental health, Health care utilization during pregnancy, Opioid-related variables, MOUD receipt Extent of MOUD use and type of MOUD used N=3,474 (66.2%) received any MOUD Buprenorphine: N=1,617 (35.5%) white women N=NA (0%) Hispanic women N=96 (20.8%) non-Hispanic Black women Methadone: N=1,265 (27.8%) white women N=59 (25.2%) Hispanic women N=110 (23.8%) non-Hispanic Black women Both: N=253 (5.6%) white women N=NA (0%) Hispanic women N=22 (4.8%) non-Hispanic Black women Any MOUD use in year before delivery: Positive associations: NR; Negative associations: Non-Hispanic Black vs. white ≤25 years (AOR: 0.23, 95% CI: 0.14-0.38); Hispanic vs. white ≤25 years (AOR: 0.29, 95% CI: 0.20-0.42); Non-Hispanic Black vs. white 26-34 years (AOR: 0.46, 95% CI: 0.32-0.67); Hispanic vs. white 26-34 years (AOR: 0.46, 95% CI: 0.35-0.60); Buprenorphine vs. methadone: Positive associations: NR; Negative associations: Non-Hispanic Black vs. white with no maternal depression or anxiety (AOR: 0.41, 95% 73 First author (Year) Objective(s) Covariate(s)/Predictor(s) Outcome indicator(s) Proportion of AYA that accessed MOUD Factors associated with MOUD access None: N=1,416 (31.1%) white women N=126 (53.9%) Hispanic women N=234 (50.7%) non-Hispanic Black women CI: 0.25-0.69), Hispanic vs. white with no maternal depression or anxiety (AOR: 0.59, 95% CI: 0.39-0.85); Buprenorphine vs. no MOUD access: Positive associations: NR; Negative associations: Non-Hispanic Black vs. white with depression or anxiety (AOR: 0.49, 95% CI: 0.28-0.87); Hispanic vs. white with depression or anxiety (AOR: 0.56, 95% CI: 0.39-0.85); Black vs. white with no depression or anxiety (AOR: 0.20, 95% CI: 0.12-0.33); Black vs. white with no depression or anxiety (AOR: 0.27, 95% CI: 0.20-0.38); Smyth (2012)96 Providing a descriptive analysis of the experience of heroin-dependent adolescents entering a substitution treatment program over an 8-year period Demographic characteristics, Education, Parental support, Familial substance use, Homelessness, Incarceration, Criminal activity, Substance use patterns, Infectious diseases, Treatment history, Route of discharge Characteristics of adolescents presenting for methadone by gender n=100 (100%) accessed methadone Positive associations: Men vs. Women: Younger age (13.8 vs. 14.9 years, p=0.002), Sibling opiate use (56% vs. 32%, p=0.02), Previous criminal convictions (59% vs. 29%, p=0.004), Ever incarcerated (41% vs. 14%, p=0.004), Discharged from prison (14% vs. 2%, p=0.05); Women vs. Men: Current relationship (64% vs. 16%, p<0.001), History of self-harm (41% vs. 18%, p=0.01); Negative associations: NR; Stancliff (2012)124 Demonstrate that buprenorphine could be successfully provided to people who use heroin from lower socioeconomic populations Gender, Ethnicity, Insurance status, Employment, Opioid type and route, Age applied for buprenorphine, Age of first opioid use, Previous methadone treatment involvement Requesting buprenorphine detoxification vs. maintenance N=16 (10.5%) requested buprenorphine detoxification Buprenorphine detoxification vs. maintenance Positive associations: Younger age when applying for buprenorphine (23.4 vs. 40.2 years, p<0.05), Younger age of first opioid use (18.8 vs. 21.3 years, p<0.05), white (87.5% vs. 27.7%, p<0.05), Injection drug use (100% vs. 49.6%, p<0.05); Negative associations: Latino (6.3% vs. 44.5%, p<0.05), Insured (12.5% vs. 80%, p<0.05), Employed (6.3% vs. 45.3%, p<0.05); Stine (2009)133 Evaluate the association between sociodemographic factors, substance use history, gestational age, and treatment history variables and consent for participation in a methadone RCT Age, Racial identity, Marital status, Gestational age, Education, Employment, Current methadone enrolment, Number of previous drug treatments, Cocaine use in past 30 days Consenting to participate in a RCT N=208 (48.7%) participated in RCT Positive associations: NR; Negative associations: Currently enrolled in methadone (AOR: 0.46, 95% CI: 0.26-0.79); Winkelman (2020)123 Examine trends in MOUD among pregnant women referred to treatment before and after Medicaid expansion Age, Racial or ethnic identity, Education, Employment, Census region, Treatment service setting, Treatment referral source Receipt of MOUD Adjusted receipt of MOUD from 1992-2017: Criminal justice referral: 26.3% (95% CI: 25.7-27.0, p<0.001) Positive associations: MOUD receipt increased from 1992 to 2017 for individual and other referral sources; Criminal justice referral in US State that participated in Medicaid expansion; 74 First author (Year) Objective(s) Covariate(s)/Predictor(s) Outcome indicator(s) Proportion of AYA that accessed MOUD Factors associated with MOUD access Individual referral: 59.1% (95% CI: 58.8-59.5, p<0.001) Other referral source: 51.3% (95% CI: 50.8-51.7, p<0.001) Negative associations: Criminal justice vs. individual referral in 2017 (ARR: 0.52, 95% CI: 0.48-0.55); Criminal justice vs. other referral in 2017 (ARR: 0.59, 95% CI: 0.55-0.64); Yang (2011)126 Identify sociodemographic characteristics, substance use patterns, traumatic life events, and other factors associated with methadone use among Indigenous AYA Age, Gender, Relationship status, Pregnancy, Child previously apprehended, Family Residential School history, Removed from custody of biological parents, Homelessness, Incarceration, Been to a reserve, Suicidality, Treatment history Lifetime or past six-month methadone use N=93 (23.4%) ever used methadone Positive associations: Older vs. younger age (AOR: 1.17, 95% CI: 1.08-1.28), Women vs. Men (AOR: 3.76, 95% CI: 2.00-7.07), HCV-positive vs. negative (AOR: 1.53-4.95), Daily injection drug use (AOR: 2.59, 95% CI: 1.46-4.61); Negative associations: Weekly or more vs <weekly alcohol use (AOR: 0.43, 95% CI: 0.21-0.87) Abbreviations: AD, Adjusted Difference; AHR, Adjusted Hazard Ratio; AOR, adjusted odds ratio; ARR, Adjusted Risk Ratio; CI, Confidence Interval; HCV, hepatitis C virus; MOUD, medications for opioid use disorder; NR, none reported; OAT, opioid agonist treatment; OR, odds ratio; OUD, opioid use disorder; P, p-value; RCT, randomized controlled trial; SUD, substance use disorder; TEDS, Treatment Episode Dataset; USA, United States of America. 75 Chapter 3: Time to opioid agonist treatment initiation and before and after substance use and other patterns among adolescents and young adults in Vancouver, Canada 3.1 Introduction On the context of the ongoing toxic drug crisis, OAT like MMT and buprenorphine-naloxone are recognized as critical tools to reducing toxic drug poisonings and other negative health outcomes. Within the study setting, this can be seen through the implementation of youth-specific clinical guidelines for the treatment of OUD, which recommend the provision of OAT to all AYA who report moderate to severe OUD. Despite these recommendations, research to date on the use of and outcomes associated with OAT use among AYA is limited. For example, a Cochrane review found only two randomized controlled trials examining the use of OAT among AYA,83 resulting in calls for more high-quality research into OAT engagement and outcomes among AYA.27, 85, 98 Given the lack of high-quality evidence examining OAT among AYA and the importance of understanding OAT initiation, retention and outcomes among AYA, this study sought to identify sociodemographic-, substance use-, health system-, and criminal justice-related factors associated with recent OAT among AYA who report recent weekly opioid use. Additionally, we sought to compare before and after substance use, difficulty accessing health services, incarceration, and homelessness patterns following OAT between AYA who: 1) initiated and were retained on OAT and 2) initiated and discontinued OAT, versus AYA who 3) reported opioid use but did not initiate OAT. 76 3.2 Methods Data for this analysis was derived from the ARYS, with study details and procedures previously described in section 1.8. 3.2.1 Study Sample To compare before and after substance use, difficulty accessing services, incarceration, and homelessness patterns using non-linear growth curve analyses, the sample was restricted to participants who reported recent weekly illicit opioid use but who were not concurrently enrolled in OAT (last six months). This permitted the before and after comparison of participants who reported recent weekly illicit opioid use but who may or may not have initiated OAT. Additionally, participants who stopped or decreased their frequency of illicit opioid use in the absence of OAT were retained in the analyses from their first report of weekly illicit opioid use as they could still be eligible for OAT. 3.2.2 Study Variables Exposure to OAT was assessed based on the question: “in the last 6 months, have you received any medications for the treatment of your alcohol or drug use?”. Participants could report multiple types of OAT within the last 6-month period, as they may have initiated one type of OAT and switched to a more preferred OAT afterwards; however, participants who reported non-medical 77 prescription opioid or OAT use (e.g., ‘diverted’ MMT) were not classified as having received OAT. Types of OAT included: Methadone/Methadose; buprenorphine-naloxone; slow-release oral morphine (SROM); injectable hydromorphone, diacetylmorphine, or other injectable opioids; as well as other substitution treatments (i.e., prescription opioids). The risk environment74 and patient-centered healthcare accessibility75 frameworks guided independent variable selection as described in section 1.8. This resulted in the consideration self-reported socio-demographic, substance use-related, health and social service utilization, and behavioural factors hypothesized to be associated with the outcome of interest. These included: age (per year older); sex (male vs. female); self-reported Indigenous identity, defined as First Nations,154 Inuit,155 or Métis peoples156 (Indigenous vs. white), which may act as a proxy for the impacts of anti-Indigenous racism, socioeconomic status, and intergenerational trauma; Other self-reported racial or ethnic identity, which included Black, Latinx, Middle Eastern, South Asian, and ‘other’ Asian (Other racial or ethnic identity vs. white); relationship status (single vs. other); education level (>high school vs. other); self-reported diagnosis of mental illness (yes vs. no); any injection drug use (yes vs. no); and non‐fatal overdose, defined as an overdose or acute reaction following drug use (yes vs. no).157 Past-six-month (hereafter referred to as ‘recent’) daily and weekly injection and non-injection substance use variables were derived by reading participants a list of substances and asking them to identify the types of substances used and their respective frequency of use over the previous six-month period. These included heroin or fentanyl use (yes vs. no), which were combined due to the increased presence of fentanyl within the heroin supply; non-medical prescription opioid use (NMPOU) (yes vs. no); cocaine use (yes vs. no); crack cocaine use (yes vs. no); and crystal methamphetamine use (yes vs. no). Due to the lower frequency 78 of reported daily NMPOU or heroin or fentanyl use, we combined the NMPOU and heroin or fentanyl use (yes vs. no) into a single “daily illicit opioid use” variable to examine the relationship between high-intensity opioid use and recent OAT. Additional factors were examined in the analyses including: incarceration, defined as being in detention, prison or jail overnight or longer (yes vs. no); homelessness, defined as sleeping on the street, having no fixed address, staying with friends or staying in a shelter or hostel (yes vs. no); employment (yes vs. no), defined as regular, temporary, or self-employment that is legal; difficulty accessing services, defined as needing but not being able to obtain health or social (yes vs. no); accessing a detoxification program (yes vs. no); accessing a recovery house (yes vs. no), defined as a communal living environment that supports participants’ recovery goals;158 accessing a treatment centre (yes vs. no), defined as a short-term, intensive program that provides treatment and recovery supports;158 accessing a counsellor (yes vs. no); and, accessing Narcotics Anonymous, Cocaine Anonymous, Alcoholics Anonymous, or Self-Management and Recovery Training (yes vs. no). All measures referred to exposures in the last six months, except for age, gender, and racial or ethnic identity. Collectively, these variables represent micro-, meso-, and macro-level risk factors that may influence OAT initiation,74 and seek to provide a better understanding into OAT approachability, appropriateness, and availability as described within the patient-centred healthcare accessibility framework.75 3.2.3 Statistical approach 79 3.2.3.1 Baseline comparisons To compare the baseline characteristics between participants who initiated and did not initiate OAT, Mann-Whitney U-test was used for continuous variables and Pearson's Chi-squared test was used for binary variables. 3.2.3.2 Cox regression analysis To identify factors associated with the time to the first OAT initiation event, we conducted a preliminary Cox proportional hazard regression. To be eligible, participants were required to have reported recent weekly illicit opioid use but no recent OAT (in the last six months) during a baseline or semi-annual follow-up visit, and then have attended a subsequent follow-up visit after a report of recent weekly illicit opioid use but no recent OAT. Participants who reported continuous OAT enrolment from their baseline interview were excluded from analyses; however, if participants discontinued OAT, they were re-included in the analysis if they reported recent weekly opioid use and attended a subsequent study visit. For this analysis, a bivariate Cox model examined the association between the explanatory variables of interest and time to OAT vs. no OAT (outcome), defined as the time between a participant’s first report of recent weekly illicit opioid use and a subsequent report of recent OAT (last six months). Given interviews were conducted bi-annually, time was calculated based on the number of days between a first and follow-up interview, whereas time to the event was calculated based on mid-time point between the first and follow-up interview. All substance use variables 80 were lagged to the previous observation period to avoid reverse causality. We checked the variance inflation factor to test for collinearity. Two Cox regression models were employed in this analysis, including one that adjusted for daily illicit opioid use and another that adjusted for separate categories of weekly illicit opioid use. To build a reduced multivariable Cox model, we retained all explanatory variables that met statistical significance at the bivariate level (p<0.1) and used a backward selection process dropping variables with the largest p-value, except age, sex, and self-reported Indigenous, racial or ethnic identity, which were retained in the final models. We continued this process until the multivariable model with the lowest Akaike Information Criterion (AIC), a measure of model fit, was identified.159, 160 This technique has been previously employed and described with the ARYS cohort.161, 162 3.2.3.3 Non-linear growth curve analysis To compare changes in substance use, difficulty accessing health services, incarceration, and homelessness before and after OAT, we established two case groups and one ‘no OAT’ control group. Each of these groups consisted of participants that provided three consecutive observations, or a ‘trio’ of observations (e.g., ‘before event’ – ‘event’ – ‘after event’), within a three-year period. This was done to account for any time participants were away because of treatment or for other reasons. Trios are representative of event-level data, meaning that participants could contribute multiple trios to both the case and control groups. 81 The two case groups consisted of AYA who 1) initiated and were retained in OAT, and 2) initiated and discontinued OAT, and a ‘control’ group of AYA who 3) did not initiate OAT. Each case event was then matched to two control events and McNemar’s test and non-linear growth curve analysis was used to examine before and after substance use, difficulty accessing services, incarceration, and homelessness between case and control trios. 3.2.3.3.1 Case groups definition: ‘Retained’ and ‘discontinued’ OAT For the OAT retained group, participants were required provide consecutive reports of: recent weekly illicit opioid use but no OAT within that last six months at time 1 (‘before event’), OAT in the last six months at time 2 (‘event’), and OAT in the last six months at time 3 (‘after event’), all within a three-year period. Participants could report different types of OAT due to transitioning from one to another. Similarly, contributing a trio of observations to the OAT discontinuation group required consecutive reports: of recent weekly illicit opioid use but no recent OAT within the last six months at time 1 (‘before event’), OAT in the last six months at time 2 (‘event’), and a no recent OAT at time 3 (‘after event’), all within a three-year period. 3.2.3.3.2 Control group definition: ‘No OAT’ As with the case groups, contributing a trio of events to the control group required consecutive reports of: recent weekly illicit opioid use but no recent OAT at time 1 (‘before event’), no recent OAT at time 2 (‘event’), and no recent OAT and at time 3 (‘after event’), all within a three-year 82 period. This allows for a comparison between participants who initiated OAT and controls who qualified for but did not initiate OAT. 3.2.3.4 Matching of cases to control trios For this analysis, each case was matched to approximately two controls by randomization and based on participant characteristics at time 1 (‘before event’). The matching criteria were sex, racial or ethnic identity (Indigenous, other racial or ethnic identity vs. white), age (within ± 5 years), recent injection drug use, years of injection drug use (within ± 3 years), and recent illicit opioid use (daily vs. weekly). We also matched for recent crack cocaine use (weekly vs. other) as we found a significant difference in recent weekly crack cocaine use between cases and controls. To avoid bias, we applied a bootstrapping technique163 to increase the stability of the case and control estimates.164-167 We repeated the matching procedure 50 times to create 50 samples and ran the McNemar and non-linear growth curve analyses 50 times and summarized the result as the mean of the results. 3.2.3.5 Within-group changes among case and control groups McNemar’s test compared within-group differences in substance use, difficulty accessing health services, incarceration, and homelessness patterns before and after OAT between 1) ‘OAT continuers’ vs. matched ‘no OAT’ controls, and 2) ‘OAT discontinuers’ vs. matched ‘no OAT’ controls. 83 3.2.3.6 Between-group changes between case and control groups We then proceeded with non-linear growth curve analyses to compare the between-group differences in the change in substance use, difficulty accessing health services, incarceration, and homelessness patterns from before to after OAT.168, 169 The resulting slope of the line represents the degree and direction of change (p<0.05) between each of the case groups and their matched controls, indicating whether the between-group differences were significant. For these analyses, all significance tests were two-sided at a significance level of p<0.05. R Foundation for Statistical Computing (Version 3.2.4; Vienna, Austria) was used to conduct all analyses.92 This technique to examine before and after patterns and behaviors has been employed in research among people who use drugs.164-167 3.3 Results Between September 2005 and June 2018, 676 participants reported recent weekly illicit opioid use; however, 101 (14.9%) participants were excluded from the analysis as they were continuously enrolled in OAT and their initiation period could not be derived, as were 121 (17.9%) participants who completed one study visit. A summary of the baseline characteristics of participants who reported recent weekly opioid use, stratified by recent OAT vs. no recent OAT, are presented in Table 3.1. 84 A total of 454 participants reported recent weekly opioid use, contributing 2,241 observations over a median follow-up of four study visits (IQR = 2-6). Of these, 217 (32.1%) participants reported initiating OAT at some point over follow-up, accounting for 1,115.1 person-time risk years and an incidence rate of 23 (95% CI: 20-26) per 100 person-years. Among participants who did initiate OAT, 175 (38.5%) initiated OAT once, 38 (8.4%) initiated OAT twice, and 4 (0.9%) initiated OAT three times. Table 3.2 presents the unadjusted and adjusted Cox regression of factors associated with time to recent OAT initiation. In the first adjusted Cox model, recent daily illicit opioid use [adjusted hazards ratio (AHR) = 2.74, 95% confidence interval (CI) = 1.85–4.05], injection drug use (AHR = 2.31, 95% CI = 1.52–3.52), accessing a treatment centre (AHR = 2.01, 95% CI = 1.23–3.27), and later follow-up period (AHR = 1.02, 95% CI = 1.00–1.05) were positively associated with recent OAT. In the second adjusted Cox model, recent weekly heroin or fentanyl use (AHR = 2.35, 95% CI = 1.53–3.62), injection drug use (AHR = 2.59, 95% CI = 1.72–3.90), accessing a treatment centre (AHR = 2.05, 95% CI = 1.28–3.27), and later follow-up period (AHR = 1.02, 95% CI = 1.00–1.05) were positively associated with recent OAT; however, there was no association between recent weekly NMPOU and OAT initiation.' A total of 336 participants were eligible for inclusion in the before and after analysis, contributing 1,528 observations. Of these, 100 participants contributed 108 trios to the ‘OAT continuers’ group, 48 participants contributed 52 trios to the ‘OAT discontinuers’ group, and 244 participants contribute 577 trios to the ‘no OAT control’ group. ‘OAT continuers’ (n=100) reported receiving MMT (n=91), buprenorphine-naloxone (n=10), and SROM (n=2), while ‘OAT discontinuers’ 85 (n=48) reported receiving MMT (n=40), buprenorphine-naloxone (n=9), and SROM (n=1) at least once. The within-group differences in substance use, difficulty accessing health services, incarceration, and homelessness patterns from the before and the after period are presented in Tables 3.3 and 3.4. In Table 3.3, participants retained in OAT demonstrated greater reductions than the control group in the prevalence of: any injection drug use (-12.1% vs. -11.7%), non-fatal overdose (-13.1% vs. -9.3%), daily illicit opioid use (-28.0% vs. -9.3%), weekly heroin or fentanyl use (-31.8% vs. -20.2%), weekly cocaine use (-6.5% vs. -4.5%), and homelessness (-22.4% vs. -8.6%); however, the opposite was observed for any weekly NMPOU (-20.6% vs. -21.6%), weekly crystal methamphetamine use (+0.9% vs. -3.0%), incarceration (+3.7% vs. -1.9%), and difficulty accessing health or social services (-2.8% vs. -6.9%). Table 3.4 presents the results from the before and after comparison between case events that involved OAT discontinuation in comparison to control events that did not involve any OAT. In this comparison, events that involved OAT discontinuation demonstrated greater reductions than controls in the prevalence of any non-fatal overdose (-13.7% vs. -6.3%), daily illicit opioid use (-17.6% vs. -12.2%), weekly heroin or fentanyl use (-33.4% vs. -24.9%), weekly crystal methamphetamine use (-15.6% vs. -1.8%), and homelessness (-25.5% vs. -6.5%). Alternatively, our comparison of events that involved OAT discontinuation to controls demonstrated smaller reductions in the prevalence of any injection drug use (-5.9% vs. -16.2%), weekly NMPOU (-3.9% vs. -20.2%), weekly cocaine use (-2.0% vs. -8.2%), incarceration (-2.0% vs. -4.0%), and difficulty accessing any health or social services (0% vs. -5.9%). 86 The results of the non-linear growth curve analyses of between-group differences are reported in Tables 3.5 and 3.6. This analysis suggests that participants who were retained in OAT demonstrated greater reductions than ‘no OAT’ controls in the prevalence of any daily illicit opioid use (slope: -1.83 vs. -0.63, p=0.015), although no other significant differences arose. Nevertheless, a non-statistically significant reduction in homelessness (p =0.070) and an increase in difficulty accessing services (p=0.078) was observed among AYA who were retained in OAT vs. ‘no OAT’ controls, while participants who discontinued OAT demonstrated non-statistically significant reductions in homelessness (p =0.085) and weekly NMPOU (p=0.061) when compared to ‘no OAT’ controls. 3.4 Discussion The finding that 43% of ARYS participants who reported weekly opioid use did not report accessing OAT is concerning. Given evidence that OAT access among adults increased from 73.2% in 2006 to 78.9% in 2016 in Vancouver, Canada, findings indicate that many AYA are not accessing potentially life-saving OAT.30 Adding to this, our findings of frequent OAT re-initiation events complement existing research among adults demonstrating that the cessation and re-initiation of OAT is similarly common among AYA.170 This may be explained by known barriers to treatment in the study setting, which include geographical barriers, being unable to secure treatment, being involuntarily discharged from treatment, high treatment costs, and long treatment wait times.43, 44 However, this may also be attributed to a reluctance towards OAT among AYA, as reported in a recent qualitative investigation in the study setting, where OAT is not viewed as 87 part of their long-term treatment and recovery goals.24 Results also indicate that being retained on OAT was associated with significant reductions in recent daily illicit opioid use, and that recent daily illicit opioid use, recent weekly heroin use, and injection drug use were positively associated with a shorter time to OAT. Additionally, recent SUD treatment centre access was positively associated with a shorter time to OAT, while accessing detoxification, a counsellor, and a recovery house approached statistical significance reinforcing calls for the incorporation of OAT into other health and treatment settings.171-174 Another notable finding was that being retained in OAT was associated with significant within-group reductions; however, the only between-group reduction observed was in daily illicit opioid use between participants retained in OAT vs. ‘no OAT’ controls. While reductions in daily illicit opioid use were observed among cases and controls, this may be attributed to the expansion of SUD treatments and programming over the duration of the study, such as the establishment of a low-barrier, youth-specific health service provider and outreach team.51 This may also explain the positive association between follow-up period and shorter time to OAT, given that the expansion of services may have increased AYAs’ access to OAT and other treatments within the study setting. This study reinforces evidence that OAT is effective at reducing high frequency opioid use among AYA18-20, 83, 95 and supports recommendations for the provision of OAT to AYA.26, 28, 175 However, the absence of significant reductions between cases and controls with respect to weekly heroin or fentanyl use, weekly NMPOU use, weekly stimulant use, homelessness, incarceration, and difficulty accessing health services is concerning. Firstly, the continued use of opioids while on 88 OAT aligns with a previous Cochrane review, which found that 46% of AYA reported continued opioid use while on MMT.29 Secondly, results demonstrating continued crystal methamphetamine use in this sample complement qualitative literature from the study setting that found that some adults continue using stimulants to counter MMT’s sedating effects, among other reasons.176 Hence, the absence of significant reductions in substance use, difficulty accessing health services, incarceration, and homelessness emphasize the need for treatment interventions for AYA who report polysubstance use and that meet AYAs’ recovery priority and goals. Potential solutions to improving OAT retention among AYA have been proposed85 and include implementing tailored approaches to OAT that acknowledge the differences between AYA and adults.70-72 Examples include working collaboratively with AYA to determine an adequate OAT dose,85, 177-179 as a higher OAT dose is positively associated with reductions in opioid and stimulant use;180, 181 expanding access to take-home dosing;85, 182, 183 supporting AYA with accessing safe and stable housing, employment and income assistance, and re-connecting with school and culture in a way that meet AYAs’ treatment goals;24, 85, 184, 185 and, working with AYA to include family, friends, or peers in treatment programming.186, 187 Nonetheless, future research that seeks to understand the relationship between OAT receipt and health and social support access may be beneficial to improving the continuity of care for AYA, in addition to adolescent-specific research on ways to better engage adolescents in OAT. Adding to this, future research comparing AYA who were retained in OAT for longer durations to AYA retained in OAT for shorter durations may provide more insight into the long-term use of OAT and associated outcomes. Lastly, this study excluded naltrexone due to recommendations against 89 its use in the study setting;26 however, the American Academy of Pediatrics28 recommends naltrexone for the treatment of OUD, warranting further investigation into its effectiveness on opioid use outcomes among AYA and in the context of the toxic drug crisis. There are several limitations with the ARYS cohort that are further described in section 7.4, including generalizability of findings, unmeasured confounding, and social desirability bias.165, 188, 189 Additionally, this analysis may be limited by unmeasured confounding, where a number of factors related to treatment delivery could not be accounted for (e.g., provision of other supports or treatments alongside OAT, dosage, quality of care received), which are known factors of treatment retention and substance use outcomes that may bias the results. Due to limitations in the study instrument, participants were asked about their OAT access over a six-month period and so treatment cessation over this period may not have been captured or participants may have transitioned between different OAT. This may have resulted in participants being included in the case groups despite having stopped and re-initiated treatment, leading to the inclusion of OAT discontinuers in the OAT retained group. Furthermore, a before and after comparison could not be conducted on variables that were used in matching (i.e., weekly crack cocaine use) and the use of event-level data does not allow for the examination of individual OAT trajectories. Additionally, a majority of participants reported polysubstance use, which may influence OAT retention and outcomes. Lastly, this study included participants who did not have a formal OUD diagnosis and who may therefore be less likely to be provided OAT. 3.5 Conclusions 90 Being retained on OAT was associated with significant reductions in daily illicit opioid use, which is promising and indicative that these treatments are beneficial among AYA in the study setting. Nevertheless, more than half of the participants did not initiate OAT over the study period and the absence of other significant reductions in substance use and other patterns among AYA who were retained in or discontinued OAT vs. controls that did not access OAT is discouraging. Findings highlight the importance of providing AYA access to a continuum of health and social services, harm reduction interventions, and a more diverse array of therapeutic options that improve substance use and health outcomes. 91 Table 3.1 Baseline characteristics of AYA who reported recent weekly opioid use stratified by initiation of OAT over the study period (September 2005 to June 2018) (n=454). Characteristic Total (%) (n = 454) Opioid agonist treatment p - value Yes (%) (n = 217) No (%) (n = 235)g Age (<19 vs. ≥19) 39 (8.6) 23 (10.6) 16 (6.8) 0.205 Sex (male vs. female) 307 (67.6) 145 (66.8) 162 (68.9) 0.630 Indigenous identity (vs. white) 117 (25.9) 72 (30.6) 45 (20.7) 0.021 Other racial or ethnic identity (vs. white)a 41 (9.1) 19 (8.1) 22 (10.1) 0.752 Relationship status (single)b 313 (68.9) 146 (67.3) 166 (70.6) 0.441 High school educationb 177 (39.0) 84 (38.7) 91 (38.7) 0.998 Mental illnessb 283 (62.3) 133 (61.3) 148 (63.0) 0.712 Injection drug useb 295 (65.0) 161 (74.2) 132 (56.2) <0.001 Non-fatal overdoseb 121 (26.7) 68 (31.3) 52 (22.1) 0.025 Daily illicit opioid useb, c 252 (55.5) 139 (64.1) 111 (47.2) <0.001 Weekly heroin or fentanyl useb 366 (80.6) 188 (86.6) 176 (74.9) 0.002 Weekly NMPO useb, d 147 (32.4) 59 (27.2) 87 (37.0) 0.026 Weekly cocaine useb 93 (20.5) 45 (20.7) 48 (20.4) 0.953 Weekly crack cocaine useb 128 (28.2) 63 (29.0) 64 (27.2) 0.578 Weekly CM useb, e 217 (47.8) 103 (47.5) 113 (48.1) 0.861 Incarcerationb 99 (21.8) 56 (25.8) 42 (17.9) 0.038 Homelessnessb 297 (65.4) 142 (65.4) 153 (65.1) 0.960 Employmentb 191 (42.1) 83 (38.2) 108 (46.0) 0.106 Difficulty accessing servicesb, f 409 (90.1) 193 (88.9) 214 (91.1) 0.449 Detoxificationb 75 (16.5) 40 (18.4) 35 (14.9) 0.312 Recovery houseb 31 (6.8) 14 (6.5) 17 (7.2) 0.625 Treatment centreb 23 (5.1) 13 (6.0) 10 (4.3) 0.481 Counsellorb 49 (10.8) 23 (10.6) 26 (11.1) 0.874 NA/CA/AA/SMARTb, g 51 (11.2) 27 (12.4) 24 (10.2) 0.454 Note: a Other racial or ethnic identity includes Black, Latinx, Middle Eastern, South Asian, and ‘other’ Asian; b refers to activities in the last six months; c refers to a combination of illicit opioids that includes heroin, fentanyl, and non-medical prescription opioids; d NMPO = non-medical prescription opioid; e CM = crystal methamphetamine; f refers to difficulty accessing health and social services; g NA/CA/AA/SMART = narcotics anonymous, cocaine anonymous, alcoholics anonymous, and self-management and recovery training; g two participants were excluded from the baseline descriptive analysis due to missing data for the outcome variable 92 Table 3.2 Cox Proportional Hazard regression analysis of factors associated with time to first opioid agonist treatment among AYA who reported recent weekly opioid use (n=454). Unadjusted model Adjusted Model 1i Adjusted Model 2j Characteristic Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Follow-up period (per six-months later) 1.04 (1.02 – 1.06) 1.02 (1.00 – 1.05)k 1.02 (1.00 – 1.05)k Age (<19 vs. ≥19) 0.72 (0.35 – 1.48) 1.01 (0.96 – 1.07) 1.03 (0.98 – 1.09) Sex (male vs. female) 1.06 (0.80 – 1.41) 1.05 (0.76 – 1.47) 1.03 (0.74 – 1.44) Indigeneity (Indigenous vs. white) 0.74 (0.53 – 1.04) 0.74 (0.50 – 1.11) 0.77 (0.51 – 1.15) Other racial or ethnic identity (Other vs. white)a 1.27 (0.82 – 1.98) 1.06 (0.58 – 1.94) 1.07 (0.59 – 1.94) Relationship status (single vs. other) 1.17 (0.88 – 1.55) Education (>high school vs. other) 1.23 (0.94 – 1.65) Mental illness (yes vs. no) 0.92 (0.69 – 1.23) Injection drug use (yes vs. no)b, c 2.76 (2.00 – 3.80)k 2.31 (1.52 – 3.52)k 2.59 (1.72 – 3.90)k Non-fatal overdose (yes vs. no)b, c 1.53 (1.14 – 2.07)k 1.03 (0.70 – 1.52) 1.06 (0.72 – 1.55) Daily illicit opioid use (yes vs. no)b, c, d 2.94 (2.14 – 4.04)k 2.74 (1.85 – 4.05)k --- Heroin/fentanyl use (≥weekly vs. <weekly)b, c 3.62 (2.49 – 5.27)k --- 2.35 (1.53 – 3.62) k NMPO use (≥weekly vs. <weekly)b, c, e 1.01 (0.71 – 1.42) --- Cocaine use (≥weekly vs. <weekly)b, c 1.19 (0.84 – 1.71) Crack cocaine use (≥weekly vs. <weekly)b, c 0.87 (0.63 – 1.21) CM use (≥weekly vs. <weekly)b, c, f 1.14 (0.86 – 1.50) Incarceration (yes vs. no)b 1.00 (0.71 – 1.41) Homelessness (yes vs. no)b 0.87 (0.66 – 1.15) Employment (yes vs. no)b 0.71 (0.53 – 0.95) 0.80 (0.56 – 1.15) 0.81 (0.56 – 1.15) Difficulty accessing services (yes vs. no)b, g 1.29 (0.89 – 1.87) Detoxification (yes vs. no)b 2.45 (1.69 – 3.55)k 1.49 (0.92 – 2.42) 1.56 (0.94 – 2.59) Recovery house (yes vs. no)b 2.03 (1.22 – 3.39)k 1.65 (0.91 – 3.00) 1.62 (0.91 – 2.91) Treatment centre (yes vs. no)b 2.61 (1.63 – 4.16)k 2.01 (1.23 – 3.27)k 2.05 (1.28 – 3.27)k Counsellor (yes vs. no)b 1.84 (1.21 – 2.81)k 1.54 (0.92 – 2.58) 1.56 (0.94 – 2.59) NA/CA/AA/SMART (yes vs. no)b, h 1.76 (1.19 – 2.59)k 1.19 (0.67 – 2.12) 3.11 (0.63 – 1.94) Note: a Other racial or ethnic identity includes Black, Latinx, Middle Eastern, South Asian, and 'other’ Asian; b refers to activities in the last six months; c refers to activities lagged to the previous, available follow-up; d refers to a combination of illicit opioids that includes heroin and non-medical prescription opioids; e NMPO = non-medical prescription opioids; f CM = crystal methamphetamine; g refers to difficulty accessing health and social services; h NA/CA/AA/SMART = narcotics anonymous, cocaine anonymous, alcoholics anonymous, and self-management and recovery training; i Adjusted model included a daily illicit opioid use co-variate; j Adjusted model included a weekly heroin or fentanyl use co-variate; k refers to variables that were statistically significant at p<0.05 93 Table 3.3 Substance use, difficulty accessing health services, incarceration, and homelessness patterns in the period before and after opioid agonist treatment (OAT) among participants who were retained in OAT (n=108) vs. controls who did not access OAT (n= 207). Variables OAT periodf p value Before n (%) After n (%) Injection drug usea Continuers 88 (82.2) 75 (70.1) 0.012 Controls 171 (82.6) 147 (70.9) <0.001 Non-fatal overdosea Continuers 34 (31.8) 20 (18.7) 0.015 Controls 60 (28.9) 41 (19.6) 0.042 Daily illicit opioid usea, b Continuers 84 (78.5) 54 (50.5) <0.001 Controls 142 (68.7) 123 (59.4) <0.001 Weekly heroin or fentanyl usea Continuers 92 (86.0) 58 (54.2) <0.001 Controls 172 (82.9) 130 (62.7) <0.001 Weekly NMPO usea, c Continuers 32 (29.9) 10 (9.3) <0.001 Controls 68 (33.0) 24 (11.4) <0.001 Weekly cocaine usea Continuers 18 (16.8) 11 (10.3) 0.146 Controls 23 (11.0) 13 (6.5) 0.170 Weekly CM usea, d Continuers 48 (44.9) 49 (45.8) 1.000 Controls 105 (50.8) 99 (47.8) 0.513 Incarcerationa Continuers 22 (20.6) 26 (24.3) 0.522 Controls 43 (21.0) 40 (19.1) 0.642 Homelessnessa Continuers 67 (62.6) 43 (40.2) <0.001 Controls 123 (59.5) 105 (50.9) 0.052 Difficult accessing servicesa, e Continuers 88 (82.2) 91 (85.0) 0.677 Controls 182 (88.0) 168 (81.1) 0.088 Note: a refers to activities in the previous 6 months; b refers to a combination of illicit opioids that includes heroin and non-medical prescription opioids; c NMPO = non-medical prescription opioids; d CM = crystal methamphetamine; e refers to difficulty accessing health and social services; f before and after values represent the mean number of cases and controls based on the mean numbers from 50 datasets, and each case was matched to approximately two controls depending on randomization by sex (male vs. female), racial or ethnic identity (Indigenous, other racial or ethnic identity vs. white), recent injection drug use (yes vs. no), age (±5 years), years injecting drugs (±3 years), and recent weekly crack use (yes vs. no) 94 Table 3.4 Substance use, difficulty accessing health services, incarceration, and homelessness patterns in the period before and after opioid agonist treatment (OAT) among participants not retained in OAT (n=52) vs. controls who did not access OAT (n=95). Variables OAT Periodf p value Before n (%) After n (%) Injection drug usea Discontinuers 44 (86.3) 41 (80.4) 0.450 Controls 83 (87.4) 68 (71.2) 0.004 Non-fatal overdosea Discontinuers 15 (29.4) 8 (15.7) 0.070 Controls 25 (25.9) 19 (19.6) 0.389 Daily illicit opioid usea, b Discontinuers 43 (84.3) 34 (66.7) 0.052 Controls 64 (67.3) 52 (55.1) 0.088 Weekly heroin or fentanyl usea Discontinuers 47 (92.2) 30 (58.8) <0.001 Controls 83 (86.9) 59 (62.0) 0.001 Weekly NMPO usea Discontinuers 8 (15.7) 6 (11.8) 0.617 Controls 26 (27.7) 7 (7.5) 0.001 Weekly cocaine usea Discontinuers 6 (11.8) 5 (9.8) 1.000 Controls 15 (15.9) 7 (7.7) 0.201 Weekly CM usea, d Discontinuers 27 (52.9) 19 (37.3) 0.080 Controls 45 (47.5) 43 (45.7) 0.720 Incarcerationa Discontinuers 11 (21.6) 10 (19.6) 1.000 Controls 21 (22.2) 17 (18.2) 0.621 Homelessnessa Discontinuers 30 (58.8) 17 (33.3) 0.006 Controls 57 (60.1) 51 (53.6) 0.342 Difficulty accessing servicesa, e Discontinuers 41 (80.4) 41 (80.4) 0.724 Controls 85 (89.1) 79 (83.2) 0.296 Note: a refers to activities in the previous 6 months; b refers to a combination of illicit opioids that includes heroin and non-medical prescription opioids; c NMPO = non-medical prescription opioids; d CM = crystal methamphetamine; e refers to difficulty accessing health and social services; f before and after values represent the mean number of cases and controls based on the mean numbers from 50 datasets, and each case was matched to approximately two controls depending on randomization by sex (male vs. female), racial or ethnic identity (Indigenous, other racial or ethnic identity vs. white), recent injection drug use (yes vs. no), age (±5 years), years injecting drugs (±3 years), and recent weekly crack use (yes vs. no) 95 Table 3.5 Non-linear growth curve analyses of substance use, difficulty accessing health services, incarceration, and homelessness patterns between cases retained on OAT (n=108) vs. controls who did not access OAT (n=207). Variables Slope (95% CIf) p value Injection drug usea Continuers -1.49 (-3.55, 0.58) 0.729 Controls -1.63 (-1.72, -1.54) Non-fatal overdosea Continuers -1.01 (-2.47, 0.46) 0.534 Controls -0.70 (-0.75, -0.65) Daily illicit opioid usea, b Continuers -1.83 (-3.23, -0.43) 0.015 Controls -0.63 (-0.68, -0.58) Weekly heroin or fentanyl usea Continuers -2.27 (-3.84, -0.70) 0.182 Controls -1.57 (-1.62, -1.52) Weekly NMPO usea, c Continuers -2.23 (-4.16, -0.30) 0.747 Controls -2.18 (-2.25, -2.11) Weekly cocaine usea Continuers -0.80 (-2.88, 1.27) 0.791 Controls -0.76 (-0.83, -0.69) Weekly CM usea, d Continuers 0.02 (-1.38, 1.42) 0.600 Controls -0.22 (-0.27, -0.17) Incarcerationa Continuers 0.33 (-1.24, 1.90) 0.409 Controls -0.12 (-0.18, -0.06) Homelessnessa Continuers -1.48 (-2.89, -0.07) 0.070 Controls -0.62 (-0.67, -0.57) Difficulty accessing servicesa, e Continuers 0.28 (-1.43, 1.99) 0.087 Controls -0.72 (-0.78, -0.66) Note: a refers to activities in the previous 6 months; b refers to a combination of illicit opioids that includes heroin and non-medical prescription opioids; c NMPO = non-medical prescription opioids; d CM = crystal methamphetamine; e refers to difficulty accessing health and social services; f CI = Confidence Interval 96 Table 3.6 Non-linear growth curve analyses of substance use, difficulty accessing health services, incarceration, and homelessness patterns between cases retained on OAT (n=52) vs. controls who did not access OAT (n=95). Variables Slope (95% CIf) p value b Injection drug usea Discontinuers -0.89 (-4.10, 2.32) 0.234 Controls -2.11 (-2.23, -1.99) Non-fatal overdosea Discontinuers -1.46 (-4.01, 1.08) 0.345 Controls -0.61 (-0.72, -0.50) Daily illicit opioid usea, b Discontinuers -1.41 (-3.53, 0.71) 0.409 Controls -0.80 (-0.87, -0.73) Weekly heroin or fentanyl usea Discontinuers -2.66 (-5.14, -0.19) 0.328 Controls -1.83 (-1.94, -1.72) Weekly NMPO usea, c Discontinuers -0.70 (-4.59, 3.20) 0.061 Controls -3.05 (-3.42, -2.68) Weekly cocaine usea Discontinuers -0.32 (-3.44, 2.80) 0.439 Controls -1.19 (-1.36, -1.02) Weekly CM usea, d Discontinuers -1.14 (-3.26, 0.97) 0.165 Controls -0.12 (-0.19, -0.05) Incarcerationa Discontinuers -0.14 (-2.26, 1.97) 0.697 Controls -0.29 (-0.39, -0.19) Homelessnessa Discontinuers -1.74 (-3.83, 0.35) 0.085 Controls -0.45 (-0.55, -0.35) Difficulty accessing servicesa, e Discontinuers 0.38 (-2.41, 3.17) 0.192 Controls -0.85 (-0.98, -0.72) Note: a refers to activities in the previous 6 months; b refers to a combination of illicit opioids that includes heroin and non-medical prescription opioids; c NMPO = non-medical prescription opioids; d CM = crystal methamphetamine; e refers to difficulty accessing health and social services; f CI = Confidence Interval 97 Chapter 4: Buprenorphine-naloxone willingness among adolescents and young adults in Vancouver, Canada 4.1 Introduction Within the study setting, buprenorphine-naloxone – that is also referred to as SuboxoneÒ – is recommended as a first line treatment option for AYA with moderate to severe OUD.26, 28 Additionally, all licensed physicians and nurse practitioners within the study setting are permitted to prescribe buprenorphine-naloxone for the treatment of OUD without requiring an exemption or additional training.190 As a partial opioid agonist, initiating buprenorphine-naloxone may lead to withdrawal symptoms among those who are actively using opioids and 12 to 48 hours of abstinence from opioids is often required prior to treatment induction.26, 34, 190, 191 Despite this, buprenorphine-naloxone has an improved safety profile in comparison to MMT and take-home dosing is more likely to be permitted, which provides flexibility and increased independence to those on treatment.26, 34 Alternatively, MMT, which is more restrictive as daily witnessed dispensation is often required, is recommended as a second line treatment in the study setting,26, 34 especially for AYA who have difficulty being retained on buprenorphine-naloxone. This includes Methadose™, which is a concentrated formulation of MMT that was introduced in British Columbia in 2014.55, 192 Given the added burden of MMT and Methadose™, buprenorphine-naloxone has been recommended as 98 a first line treatment for AYA and also in the de-intensification of MMT and other OAT programming.34, 193 To date, research has found that adolescents are receiving partial opioid agonists, like buprenorphine-naloxone, at higher proportions than full opioid agonists, like MMT, when compared to older populations, and that AYA are less likely to received OAT in comparison to adult populations.194 This is also true within the study setting, where recent evidence demonstrates that AYA are being prescribed buprenorphine-naloxone at higher proportions than their adult counterparts.195 Although previous literature has suggested that differences in access between AYA and adults may be attributable to healthcare providers’ reluctance towards prescribing OAT to AYA,138-140 recent qualitative evidence from the study setting has found low levels of interest in OAT among AYA, including buprenorphine-naloxone,24 which aligns with research examining buprenorphine-naloxone willingness among adults in the study setting.196 Nevertheless, this may be explained by the listing of buprenorphine-naloxone as a first line treatment in British Columbia within existing OUD treatment guidelines for AYA.26 In considering the importance of treatment acceptability through the patient-centred accessibility framework, and the micro-, meso-, and macro-level factors that may be influencing AYAs’ treatment decision-making, this study sought to examine factors associated with buprenorphine-naloxone interest. This included both initial interest in using buprenorphine-naloxone, as well as factors associated with becoming interested or enrolling in buprenorphine-naloxone over time. By gauging AYAs’ interest in using buprenorphine-naloxone, the intent of this analysis is to better characterize the potential reach of buprenorphine-naloxone, to identify ways to improve the 99 provision of buprenorphine-naloxone, and better engage AYA in treatment programming with the goal of enhancing the health and wellbeing of AYA who use opiates. 4.2 Methods Data for this analysis was derived from the ARYS, with study details and procedures previously described in section 1.8. 4.2.1 Study Sample To examine factors associated with participants’ interest in using buprenorphine-naloxone, participants who responded to the question of “would you like to go on Suboxone?” at baseline or over follow-up were eligible for inclusion in this analysis. Participants who responded either affirmatively or negatively to the question were included in the analysis, while participants who indicated that they were “not using opiates” or “already on buprenorphine-naloxone” were excluded. Due to the high proportion of drug toxicity deaths among people who report illegal stimulant use, this analysis was inclusive of participants who reported any opioid use as existing clinical guidelines indicate that OAT may be beneficial to AYA who primarily use stimulants but who also report occasional opioid use and are at a risk of overdose.26, 34 For this analysis, the study period was from between December 2014 and June 2018, which is when the question regarding participants’ interest in using buprenorphine-naloxone was included on the study questionnaire. 100 Participants who were initially disinterested in buprenorphine-naloxone were asked to select one or more reasons for why they were disinterested in use buprenorphine-naloxone. These included: “Satisfied with Methadose™ program”, “Don’t want to go into withdrawal”, “Unable to find a doctor to prescribe Suboxone”, “Would like to, but cost is a barrier”, “Don’t know what Suboxone is”, “Need more information about Suboxone”, “Not interested in opioid maintenance program”, and “Other” (open-ended). Additionally, participants who indicated that they were “Satisfied with Methadose™ program”, or who provided an open-ended response that they were satisfied with another OAT, were retained in the analysis given that clinical guidelines recommend considering the de-intensification of OAT programming by transitioning people to buprenorphine-naloxone.34 Furthermore, participants who initially were disinterested in using buprenorphine-naloxone and who provided a subsequent study follow-up interview during the study period were included in the secondary analysis of factors associated with time to becoming interested in using buprenorphine-naloxone or actual enrolment in buprenorphine-naloxone. Participants that indicated that they were no longer using opioids at follow-up were excluded from the analysis examining factors associated with the time to a positive change in buprenorphine-naloxone interest, and a flow-chart outlining the sample derivation, including inclusion and exclusion criteria, is presented in Figure 4.1. 4.2.2 Study Variables The outcome of interest in the primary analysis was an initial interest in using buprenorphine-naloxone while the outcome in the secondary analysis was a positive change in buprenorphine-naloxone interest or subsequent enrolment over study follow-up. Self-reported sociodemographic, substance use, behavioral, and health and social service utilization variables hypothesized to be 101 associated with the outcomes of interest in the primary and secondary analyses were considered and guided by the risk environment74 and patient-centered healthcare accessibility75 frameworks. These included: age (per year older); study follow-up period, defined as the time period when participants conducted a study follow-up interview (per additional six month period); sex (female vs. male); self-reported Indigenous identity, defined as First Nations,154 Inuit.155 or Métis peoples156 (Indigenous vs. white), which may act as a proxy for the impacts of anti-Indigenous racism, socioeconomic status, and intergenerational trauma; Other self-reported racial or ethnic identity, defined as an affirmative response to being Black, South Asian, Chinese, Other Asian, Latinx, and Middle Eastern (Other vs. white); education level (>high school vs. other); years of drug use (per year longer); ever any injection drug use (yes vs. no); non‐fatal overdose, defined as an overdose or acute reaction following drug use (yes vs. no);157 recent weekly heroin or fentanyl use (yes vs. no); recent weekly non-medical prescription opioid use (NMPOU), defined as acquiring prescription opioids and using them for reasons other than prescribed (yes vs. no); recent weekly cocaine use (yes vs. no); recent weekly crack cocaine use (yes vs. no); and recent weekly crystal methamphetamine use (yes vs. no). Other variables included: recent incarceration, defined as being in detention, prison or jail overnight or longer in the past six months (yes vs. no); recent homelessness, defined as sleeping on the street, having no fixed address, staying with friends or staying in a shelter or hostel (yes vs. no); recent difficulty accessing services, defined as needing health or social services but not being able to obtain them (yes vs. no); ever accessing MMT (yes vs. no); recent MMT access (yes vs. no); accessing a detoxification program (yes vs. no); accessing a recovery house, defined as a communal living environment that supports participants’ recovery goals (yes vs. no);158 accessing a substance use treatment centre, defined as a short-term, intensive program that provides treatment and recovery supports (yes vs. no);158 accessing a counsellor (yes 102 vs. no); accessing Narcotics Anonymous, Cocaine Anonymous, Alcoholics Anonymous, or Self-Management and Recovery Training (NA/CA/AA/SMART) (yes vs. no); accessing residential treatment, defined as longer-term, live-in treatment settings where medical or other treatment are provided (yes vs. no);43 accessing outpatient treatment, defined as accessing community health clinics that provide OAT (yes vs. no);197 and, drug court involvement (yes vs. no). All substance use variables were lagged to the previous follow-up to address potential reverse causation. This technique has been used and described within the ARYS cohort previously.161, 162 The selected variables represent micro-, meso-, and macro-level risk factors that may influence buprenorphine-naloxone interest,74 and also provide an opportunity to understand buprenorphine-naloxone acceptability and appropriateness as explained patient-centred healthcare accessibility framework.75 4.2.3 Statistical Analyses 4.2.3.1 Baseline comparisons Baseline characteristics of participants who reported initial buprenorphine-naloxone interest were compared to participants who were initially disinterested in using buprenorphine-naloxone. For this, Mann-Whitney U-test to make comparisons for continuous variables and Pearson’s χ2 test was used to compare variables with binary outcomes. Reasons for an initial disinterest in using buprenorphine-naloxone were also collected and participants were able to provide multiple explanations for their disinterest. 103 4.2.3.2 Logistic regression analysis A multivariable logistic regression analysis was then employed to identify factors associated with initial buprenorphine-naloxone disinterest, which was assessed based on participants’ first response to the question regarding buprenorphine-naloxone interest. For this analysis, we began by examining the bivariate associations between our outcome of interest – an initial disinterest in using buprenorphine-naloxone – and the explanatory variables of interest, which allowed for the identification of potential confounders. Variables that were significant at p<0.10 were then included in the full model, which was then subjected to a backward selection model. This involved reducing the model by removing explanatory variables with the largest p-value until the model with the lowest AIC was identified, which is a measure of model fit. This technique has been employed within ARYS and has been described previously.198-200 All significance tests were two-sided at a significance level of p<0.05 for these analyses and were conducted using SAS software version 9.4 (SAS, Cary, NC). 4.2.3.3 Cox regression analysis Participants who were initially disinterested in using buprenorphine-naloxone and attended at least one subsequent follow-up interview to assess for changes in interest over time were included in the secondary analysis. To identify factors associated with time to a positive change in buprenorphine-naloxone interest or actual enrolment, a multivariable Cox proportional hazard model was employed. A reduced model was identified using a backwards selection process, whereby all variables with statistical significance of p<0.10 at the bivariate level were included in a full model. Variables with the largest p-value were removed stepwise and repeated until a 104 reduced model with the lowest AIC value was reached.159, 160 The reduced model was then assessed using variance inflation factors, but no collinearity between variables was observed. 4.3 Results Between December 2014 and June 2018, a total of 685 participants completed at least one study questionnaire. Of these, n=180 (26.3%) participants reported not currently using opioids, n=16 (2.3%) were already on buprenorphine-naloxone, and an additional 42 (6.1%) participants were missing data on the outcome variable and excluded from the analysis. Of the remaining n=447 (65.3%) participants, n=60 (13.4%) reported an interest in using buprenorphine-naloxone, while n=387 (86.8%) reported being disinterested in using buprenorphine-naloxone. Among those disinterested in using buprenorphine-naloxone at baseline, 106 (27.4%) were recently enrolled on MMT, while 47 (11.7%) observations involved being disinterested in using buprenorphine-naloxone due to satisfaction with other OAT, including methadone/Methadose™, injectable diacetylmorphine, hydromorphone, and morphine. The characteristics of this sample, measured at their first study visit during the study period, stratified by initial interest in using buprenorphine-naloxone, are presented in Table 4.1. Bivariate and multivariable results for a logistic regression model to identify factors associated with an initial interest in using buprenorphine-naloxone are presented in Table 4.2. Multivariable results indicate that self-reported Indigenous identity (vs. white) (adjusted odds ratio [AOR]=0.45, 95% confidence interval [CI]: 0.21–0.94) and other racial or ethnic identity (vs. white) (AOR=0.11, 95% CI: 0.01–0.80) were negatively associated with initial willingness to use 105 buprenorphine-naloxone, while self-reported recent weekly heroin or fentanyl use (AOR=4.05, 95% CI: 1.81–9.07) was positively associated. Additionally, 387 (86.6%) participants who were initially disinterested in using buprenorphine-naloxone provided 402 reasons for their initial disinterest and 532 observations for their disinterest over follow-up (as participants could list multiple reasons). Reasons for initial disinterest in buprenorphine-naloxone as well as reasons for disinterest over follow-up are listed in Table 4.3. Of the 387 participants who were initially disinterested in using buprenorphine-naloxone, 83 (21.4%) participants were excluded because they were not seen for a subsequent follow-up interview during the study period, 44 (11.4%) participants were excluded because they reported not using opioids over follow-up, and 12 (3.1%) participants were excluded due to missing outcome variable data. The remaining 248 (64.1%) participants seen over follow-up between December 2014 and June 2018, contributing 645 observations over a median study follow-up of two study visits (Interquartile Range [IQR] = 1–4). Over follow-up, 85 (34.3%) participants were identified as reporting a positive change in interest in using buprenorphine-naloxone; specifically, 68 (27.4%) participants reported buprenorphine-naloxone interest and 17 (6.9%) reported already being on buprenorphine-naloxone, accounting for 322.5 person-time risk years and an incidence rate of 0.29 (95% CI: 0.23-0.34). Additionally, 105 (42.3%) AYA reported recent engagement in MMT, while 111 (20.9%) observations for being disinterested in using buprenorphine-naloxone included being satisfied with other OAT. The results of the bivariate and multivariable Cox regression analysis of factors associated with time to a positive change in buprenorphine-naloxone disinterest or actual enrolment are presented 106 in Table 4.4. In the multivariable model, ever accessing MMT (adjusted hazards ratio [AHR]=3.47, 95% CI: 1.54–7.83), weekly heroin or fentanyl use (AHR=2.23, 95% CI: 1.08–4.61), and having a high school education (AHR=1.69, 95% CI: 1.03–2.77) were positively associated with time to a positive change in buprenorphine-naloxone interest over follow-up. However, later study follow-up period (AHR=0.84, 95% CI: 0.73-0.97) was found to be negatively associated with time to a positive change in buprenorphine-naloxone interest or actual enrolment. 4.4 Discussion Although this study identified a low initial interest in using buprenorphine-naloxone, there was an increase in the number of participants who reported being interested or enrolling in buprenorphine-naloxone over study follow-up. There was also a large proportion of the sample that were engaged with MMT and thus may not have been interested or benefited from buprenorphine-naloxone. Overall, our findings indicate a low level of interest in using buprenorphine-naloxone among AYA despite evidence from the study setting that AYA receive partial opioid agonists, like buprenorphine-naloxone, at higher proportion in comparison to older populations.13 Findings are, however, consistent with previously documented lower levels of engagement with OAT among AYA compared to older populations.22, 109, 111, 201 Recent research among AYA in Vancouver, Canada indicates that many AYA do not envision OAT as being part of their long-term treatment journey.24 This is particularly important considering our finding that a significant proportion of AYA reported a lack of interest in any OAT (initial: n=161, 40%; follow-up: n=211, 39.7%), underlining the importance of offering AYA 107 opportunities to access a broad range of meaningful and purposeful harm reduction, health and social service, and treatment supports. Despite the low level of interest in using buprenorphine-naloxone, findings demonstrated that AYA who engage in regular heroin or fentanyl use were more interested in using buprenorphine-naloxone. This suggests that some AYA are interested in trying buprenorphine-naloxone even though it may be less effective in the context of high frequency use of potent opioid analogues,202 or that these participants are more likely to be offered buprenorphine-naloxone given they are ‘medically eligible’ for treatment. Our finding that AYA who self-reported Indigenous, racial or ethnic identity were less likely to report an interest in using buprenorphine-naloxone is concerning given the known effectiveness of buprenorphine-naloxone in reducing use of toxic street opioid use and related harms. Given recent findings of widespread anti-Indigenous racism within British Columbia’s health care systems, the lower interest in buprenorphine-naloxone may be attributed to discrimination or prejudice that many Indigenous, racial or other ethnic identities experience when attempting to access healthcare.203, 204 This is further supported by participants’ reasons for being unwilling to use buprenorphine-naloxone, where 23 (5.7%) initial responses and 39 (7.3%) responses over follow-up included mention of a previous negative health care experience as a reason for why participants were disinterested in buprenorphine-naloxone. To remedy this, there have been suggestions for the expansion of Indigenous cultural safety training, as well as anti-racism training, throughout the health care system.144, 205 This includes addressing healthcare providers’ biases towards Indigenous peoples and other racial or ethnic identities, as well as incorporating culturally-based practices and traditional medicine within treatment settings and programs, which previous research among Indigenous AYA has indicated is an important treatment component.144 108 Given the need to refrain from opioid use prior to buprenorphine-naloxone induction, fear of experiencing withdrawal symptoms (initial: n=49, 12.2%; follow-up: n=96, 18.0%) was another common reason for initial buprenorphine-naloxone disinterest. This is because buprenorphine-naloxone causes precipitated withdrawal if opioids were recently used36 and so patients must remain abstinent from opioids for 12 to 48 hours before initiating buprenorphine-naloxone,26, 34, 190, 191 which acts as a treatment deterrent. To address this, an alternative method to treatment induction known as ‘the Bernese method’ has demonstrated promising results,36, 37, 206 including in this study setting,38 which has been increasingly used by physicians and nurse practitioners since the completion of this study. This approach involves gradually titrating patients onto buprenorphine-naloxone while patients continue to use prescribed or illicit opioids, in turn avoiding the need for detoxification prior to treatment initiation.36-38, 206 Considering the number of AYA who reported experiencing withdrawal as a reason for being disinterested in using buprenorphine-naloxone, expanding access to this micro-dosing induction may be an effective approach to engage AYA who fear precipitated withdrawal. Although we found a positive association between having a high school education and time to buprenorphine-naloxone willingness, many participants reported that they did not know what buprenorphine-naloxone was (initial: n=45, 13.4%; follow-up: n=19, 3.6%), or that they required more information about buprenorphine-naloxone (initial: n=19, 4.7%; follow-up: n=28, 5.3%). While the proportion of participants who reported not knowing what buprenorphine-naloxone was decreased over follow-up, findings point to potential gaps in communicating advances or improvements in treatment approaches to AYA who use opioids, such as through the Bernese 109 method, and the need for identifying novel and impactful ways to reach this population. One evidence-based approach to improving awareness of advances in research and treatment is working with peers with lived and living experience of substance use to understand appropriate messaging and ways to effectively disseminate information through their respective networks.207, 208 To date, there is limited research examining the use of peer networks to disseminate information about improvements and advances in treatments and so future research into how peer networks can be mobilized for knowledge dissemination may be beneficial, including through social media platforms. Consistent with previous literature that some AYA want detoxification programs and do not consider OAT as part of their treatment journey,24 this analysis found that a small number of participants were disinterested in using buprenorphine-naloxone as they preferred detoxification (initial: n=14, 3.5%; follow-up: n=7, 1.3%). However, there are concerns that detoxification might increase the risk of harm arising from a reduced tolerance for illegal opioids upon discharge, which increases overdose risk.69, 209 One potential solution is providing buprenorphine-naloxone to patients within detoxification settings,210 therefore decreasing the likelihood of relapse and overdose upon discharge from detoxification. This approach has been employed within the study setting and has demonstrated positive results.211 Similar to previous literature from the study setting,196 this analysis found a positive association between ever accessing MMT and time to buprenorphine-naloxone interest or enrolment. This suggests that AYA who had previously attempted and discontinued MMT may benefit from buprenorphine-naloxone. Previous research has hypothesized that the restrictiveness of MMT, 110 whereby daily witnessed dispensation is required, may act as a treatment deterrent.81 As buprenorphine-naloxone has an improved safety profile, take-home dosing is permitted, which may be more favorable to AYA who prefer this flexibility.87, 212, 213 Hence, while buprenorphine-naloxone is listed as a first line treatment and MMT as a second line treatment within the study setting,26 based on our current study findings, the option of buprenorphine-naloxone should not be overlooked for AYA who are currently on or previously attempted MMT.214, 215 Conversely, several participants reported disinterest in buprenorphine-naloxone due to being satisfied with other OAT (initial: n=47, 11.7%; follow-up: n=111, 20.9%), highlighting the importance of ensuring that AYA who are stabilized on OAT are not transitioned off or on to buprenorphine-naloxone without their consultation and consent. Lastly, a concerning finding was the negative association between later chronological study follow-up period and interest in using or actually enrolling in buprenorphine-naloxone. This finding arises despite policy efforts to improve access to buprenorphine-naloxone, such as listing of buprenorphine-naloxone as a first-line treatment for OUD.26 There are several potential explanations for this, including the increased awareness through peer networks of the potential for buprenorphine-naloxone to cause precipitated withdrawals for those who are actively using opioids. This may also be explained by the increasing presence of highly potent synthetic opioids within the illegal drug supply, which evidence suggests may be hampering buprenorphine-naloxone initiation and outcomes due to the difficulty transitioning from these highly potent opioids.216 Alternatively, logistical challenges associated with treatment may also present barriers to AYA remaining engaged in treatment, and so providing access to a broad range of OAT that align with AYAs’ treatment needs and goals may be beneficial. This could include prescribing 111 extended-release buprenorphine,217, 218 which is a monthly-administered injection that eliminates the need for oral buprenorphine-naloxone and frequent pharmacy or clinic visits. Nevertheless, future research into the treatment experiences and outcomes of AYA who use fentanyl and are accessing buprenorphine-naloxone may help identify ways to better engage and retain this population in buprenorphine-naloxone. There are several limitations with the ARYS cohort that are further described in section 7.4, including generalizability of findings, unmeasured confounding, and social desirability bias.165, 188, 189 Additionally, changes to the illicit drug supply since the completion of this study also limit the generalizability of the study findings, where the increasing presence of opioid analogues and benzodiazepines have challenged response efforts to the toxic drug crisis and treatment effectiveness;216 hence, future research into the use of buprenorphine-naloxone in the context of an increasingly toxic and changing drug supply would be valuable. Additionally, the study sample for this analysis included AYA who reported any opioid use, which raises concerns that AYA with less intense opioid use who may not require buprenorphine-naloxone were included in the analysis. However, clinical guidelines from British Columbia recommend the use of OAT among AYA with a stimulant use disorder who also use opioids, given that stimulants were involved in a significant number of drug toxicity deaths.26 Similarly, the sample included participants who had or were receiving MMT/Methadose™ and who may have been less likely to be interested in using buprenorphine-naloxone; nevertheless, existing guidelines suggest that transitioning to buprenorphine-naloxone may beneficial for those who are stable on MMT due to the added flexibility,34 and therefore these participants were retained in the analysis. Another limitation was that participants were removed from the analysis if they indicated they were no longer using 112 opioids, regardless of whether they reinitiated opioid use. This analysis was also unable to account for gender-based differences as the study instrument did not collect information on participants’ gender, and so future research on gender-based differences in buprenorphine-naloxone willingness may be valuable. Lastly, although substance use related variables were lagged to the previously available follow-up, treatment-related and other variables were not lagged and therefore there the temporal relationship between these variables and interested in using buprenorphine-naloxone could not be inferred. 4.5 Conclusions The low levels of buprenorphine-naloxone interest observed in this study suggests that many AYA are not interested in buprenorphine-naloxone treatment. Despite this, participants provided several reasons for being disinterested in using buprenorphine-naloxone, highlighting the importance of improving awareness of what buprenorphine-naloxone is through peer and other networks; reducing barriers to treatment induction and expanding access to micro-dosing induction regimens; and improving access to culturally safe treatment services. Given the high risk of mortality for AYA who use drugs in the current study setting, these findings emphasize the importance of providing AYA with access to a continuum of harm reduction interventions, treatments, health and social supports, and better understanding ways to improve buprenorphine-naloxone uptake and retention among AYA who may benefit from this treatment.113 Figure 4.1 Flow-chart of disinterest in using buprenorphine-naloxone or enrolling in buprenorphine-naloxone among adolescents and young adults in Vancouver, Canada between December 2014 and June 2018. Notes: a Eligible participants were included in a logistic regression of factors associated with initial buprenorphine-naloxone interest vs. an initial disinterest to use buprenorphine naloxone; b Eligible participants were included in a Cox proportional hazard model of factors associated with time to buprenorphine-naloxone interest or already being on buprenorphine-naloxone vs. continued disinterest in using buprenorphine-naloxone; c Among those initially disinterest in using buprenorphine-naloxone, 106 (27.4%) participants reported recent MMT enrolment, and 47 (11.7%) unique reasons for buprenorphine-naloxone disinterest included being satisfied with other OAT; d Among those disinterested in using buprenorphine-naloxone over follow-up, 77 (47.2%) participants reported recent MMT enrolment and 111 (20.9%) unique reasons for buprenorphine-naloxone disinterest included being satisfied with other OAT.114 Table 4.1 Baseline characteristics of adolescents and young adults in Vancouver, Canada stratified by an interest in using buprenorphine-naloxone when first asked between December 2014 and June 2018 (n=447). Characteristic Total (%) (n = 447) Buprenorphine-naloxone interest p - value Yes (%) (n = 60) No (%) (n = 387) Age (med, IQR) 24 (22 – 27) 24 (21 – 28) 24 (22 – 27) 0.567h Study follow-up period 20 (18 – 22) 20 (18 -21) 20 (18 – 22) 0.300h Sex (female) 81 (32.7) 15 (34.1) 66 (32.4) 0.240 Indigenous identity (vs. white) 125 (28.0) 10 (16.7) 115 (29.7) 0.012 Other racial or ethnic identity (vs. white)a 45 (10.1) 1 (1.7) 44 (11.4) 0.027 High school education 188 (42.1) 24 (40.0) 164 (42.4) 0.717 Years drug use (med, IQR) 8.5 (6 – 12) 9.3 (6 – 13) 8.3 (5 – 12) 0.286h Injection drug useb 284 (63.5) 43 (71.7) 241 (62.3) 0.160 Non-fatal overdoseb 127 (28.4) 19 (31.7) 108 (27.9) 0.548 Weekly heroin or fentanyl useb 273 (61.1) 51 (85.0) 222 (57.4) <0.001 Weekly NMPO useb, c 71 (15.9) 12 (20.0) 59 (15.2) 0.349 Weekly cocaine useb 45 (10.1) 6 (10.0) 39 (10.1) 0.985 Weekly crack useb 47 (10.5) 5 (8.3) 42 (10.9) 0.554 Weekly CM useb, d 255 (57.0) 38 (63.3) 217 (56.1) 0.290 Incarcerationb 79 (17.7) 7 (11.7) 72 (18.6) 0.185 Homelessnessb 247 (55.3) 29 (48.3) 218 (56.3) 0.221 Difficulty accessing servicesb, e 173 (38.7) 21 (35.0) 152 (39.3) 0.527 Ever MMTd 179 (40.0) 28 (46.7) 151 (39.0) 0.261 MMTb, f 127 (28.4) 21 (35.0) 106 (27.4) 0.224 Detoxificationb 78 (17.4) 14 (23.3) 64 (16.5) 0.197 Recovery houseb 25 (5.6) 4 (6.7) 21 (5.4) 0.766i Treatment centreb 22 (4.9) 6 (10.0) 16 (4.1) 0.068 Counsellorb 63 (14.1) 11 (18.3) 52 (13.4) 0.315 NA/CA/AA/SMARTb, g 60 (13.4) 13 (21.7) 47 (12.1) 0.045 Residential treatmentb 1 (0.2) 0 (0) 1 (0.3) 1.000i Outpatient treatmentb 3 (0.7) 0 (0) 3 (0.8) 1.000i Drug courtb 1 (0.2) 0 (0) 1 (0.3) 1.000i Notes: a Other self-reported racial or ethnic identity includes Black, Latinx, Middle Eastern, South Asian, and 'other’ Asian; b refers to activities in the last six months; c NMPO = non-medical prescription opioids; d CM = crystal methamphetamine; e refers to difficulty accessing health and social services; f MMT = methadone maintenance treatment or Methadone™; g NA/CA/AA/SMART = narcotics anonymous, cocaine anonymous, alcoholics anonymous, and self-management and recovery training; h P-value is generated using Mann-Whitney U-test; i P-value is generated using Fisher’s Exact Test because of small cell count 115 Table 4.2 Bivariate and multivariable logistic regression of factors associated with an initial interest in using buprenorphine-naloxone among AYA between December 2014 and June 2018 (n=447). Unadjusted Adjusted Characteristic Odds Ratio (95% CI) p value Odds Ratio (95% CI) p value Age (per year older) 1.03 (0.96 – 1.10) 0.391 1.04 (0.97 – 1.11) 0.332 Study follow-up period 0.93 (0.81 – 1.06) 0.278 Sex (female vs. male) 1.40 (0.79 – 2.43) 0.242 0.65 (0.36 – 1.17) 0.151 Indigenous identity (Indigenous vs. white) 0.40 (0.20 – 0.82) 0.012 0.45 (0.21 – 0.94) 0.034 Other racial or ethnic identity (vs. white)a 0.10 (0.01 – 0.78) 0.027 0.11 (0.01 – 0.80) 0.030 High school education 0.90 (0.51 – 1.56) 0.717 Years drug use (per year longer) 1.03 (0.97 – 1.09) 0.313 Injection drug useb 1.53 (0.86 – 2.85) 0.162 Non-fatal overdoseb 1.20 (0.65 – 2.13) 0.548 Weekly heroin or fentanyl useb 4.21 (2.11 – 9.37) <0.001 4.17 (1.97 – 8.80) <0.001 Weekly NMPO useb, c 1.39 (0.67 – 2.70) 0.350 Weekly cocaine useb 0.99 (0.36 – 2.30) 0.985 Weekly crack useb 0.75 (0.25 – 1.81) 0.555 Weekly CM useb, d 1.35 (0.78 – 2.41) 0.292 Incarcerationb 0.57 (0.23 – 1.24) 0.190 Homelessnessb 0.71 (0.41 – 1.23) 0.223 Difficulty accessing servicesb, e 0.83 (0.46 – 1.46) 0.527 Ever MMTe 1.37 (0.79 – 2.36) 0.262 MMTb, f 1.43 (0.79 – 2.52) 0.226 Detoxificationb 1.54 (0.77 – 2.90) 0.200 Recovery houseb 1.17 (0.33 – 3.25) 0.784 Treatment centreb 2.46 (0.84 – 6.35) 0.076 Counsellorb 1.44 (0.68 – 2.86) 0.317 NA/CA/AA/SMARTb, g 2.00 (0.97 – 3.88) 0.048 1.96 (0.93 – 4.11) 0.077 Notes: a Other self-reported racial or ethnic identity includes Black, Latinx, Middle Eastern, South Asian, and 'other’ Asian; b refers to activities in the last six months; c NMPO = non-medical prescription opioids; d CM = crystal methamphetamine; e refers to difficulty accessing health and social services; f MMT = methadone maintenance treatment or Methadone™; g NA/CA/AA/SMART = narcotics anonymous, cocaine anonymous, alcoholics anonymous, and self-management and recovery training; 116 Table 4.3 Reasons for an initial disinterest in buprenorphine-naloxone (n=387, 402 observations) and over follow-up (n=163, 532 observations) among AYA between December 2014 and June 2018. Reasons for not buprenorphine-naloxone disinterest Initial (n, %) Follow-up (n, %) Not interested in OAT program 161 (40.0) 211 (39.7) Don’t know what buprenorphine-naloxone is 54 (13.4) 19 (3.6) Don’t want to go into withdrawal 49 (12.2) 96 (18.0) Satisfied with Methadose™ or other OAT program 47 (11.7) 111 (20.9) Previous negative treatment experience 23 (5.7) 39 (7.3) Need more information about buprenorphine-naloxone 19 (4.7) 28 (5.3) Prefer detoxification 14 (3.5) 7 (1.3) Would like to continue opioid use 13 (3.2) 11 (2.1) Inconvenience of pills or daily medications 10 (2.5) 6 (1.1) Didn’t work for peers or family 4 (1.0) 2 (0.4) Not effective for pain management 3 (0.7) 0 (0) Mistrust in health care system and medication 2 (0.5) 0 (0) Would like to, but cost is a barrier 2 (0.5) 2 (0.4) Only addresses physical cravings 1 (0.2) 0 (0) 117 Table 4.4 Bivariate and multivariable Cox proportional hazard model of factors associated with time to a change in interest in using or actual buprenorphine-naloxone enrolment among street-involved AYA between December 2014 and June 2018 (n=248). Unadjusted Adjusted Characteristic Odds Ratio (95% CI) p value Odds Ratio (95% CI) p value Age (per year older) 1.01 (0.96 – 1.06) 0.652 0.97 (0.91 – 1.04) 0.372 Study follow-up period 0.90 (0.81 – 1.00) 0.052 0.85 (0.73 – 0.98) 0.030 Sex (female) 0.88 (0.56 – 1.37) 0.562 1.64 (0.92 – 2.92) 0.093 Indigenous identity (Indigenous vs. white) 1.16 (0.72 – 1.86) 0.550 1.33 (0.71 – 2.48) 0.377 Other racial or ethnic identity (vs. white)a 0.74 (0.35 – 1.59) 0.442 0.94 (0.44 – 2.01) 0.867 High school education 1.50 (1.00 – 2.25) 0.053 1.69 (1.03 – 2.77) 0.039 Years drug use (per year longer) 1.00 (0.96 – 1.05) 1.000 Injection drug useb, c 1.47 (0.88 – 2.46) 0.137 Non-fatal overdoseb, c 1.12 (0.71 – 1.75) 0.624 Weekly heroin or fentanyl useb, c 1.85 (1.09 – 3.15) 0.024 2.23 (1.08 – 4.61) 0.031 Weekly NMPO useb, c, d 0.96 (0.46 – 2.02) 0.924 Weekly cocaine useb, c 0.70 (0.29 – 1.65) 0.408 Weekly crack useb, c 1.17 (0.60 – 2.29) 0.648 Weekly CM useb, c, e 1.54 (0.99 – 2.39) 0.054 1.51 (0.90 – 2.52) 0.119 Incarcerationb 0.87 (0.51 – 1.50) 0.619 Homelessnessb 1.56 (1.05 – 2.33) 0.028 1.44 (0.88 – 2.34) 0.142 Difficulty accessing servicesb, f 1.36 (0.87 – 2.12) 0.179 Ever MMTg 1.99 (1.22 – 3.27) 0.006 3.47 (1.54 – 7.83) 0.003 MMTb, g 1.26 (0.82 – 1.95) 0.290 Detoxificationb 2.15 (1.23 – 3.76) 0.008 Recovery houseb 2.06 (0.84 – 5.07) 0.116 Treatment centreb 1.73 (0.66 – 4.50) 0.264 Counsellorb 1.45 (0.74 – 2.83) 0.274 NA/CA/AA/SMARTb, h 1.51 (0.77 – 2.96) 0.226 Notes: a Other self-reported racial or ethnic identity includes Black, Latinx, Middle Eastern, South Asian, and 'other’ Asian; b refers to activities in the last six months; c refer to activities lagged to the previous, available follow-up; d NMPO = non-medical prescription opioids; e CM = crystal methamphetamine; f refers to difficulty accessing health and social services; g MMT = methadone maintenance treatment or Methadone™; h NA/CA/AA/SMART = narcotics anonymous, cocaine anonymous, alcoholics anonymous, and self-management and recovery training; 118 Chapter 5: Methadone maintenance treatment discontinuation among adolescents and young adults in Vancouver, Canada 5.1 Introduction The toxic drug crisis has led to thousands of preventable deaths across North America.2 This is particularly true for people with OUD, who are at a heightened risk of experiencing a toxic drug poisoning.219-221 Methadone maintenance treatment (MMT) has proven effective in treating OUD and reducing associated harms.222, 223 Hence, existing clinical guidelines in North America and in British Columbia, where this study is situated, recommend the prescription of MMT to people who report the regular use of illicit opioids, including adolescents and young adults (AYA).26, 28 Existing evidence indicates that being retained in MMT is central to realizing positive treatment outcomes;224, 225 however, examinations of MMT discontinuation are primarily restricted to adults,226 while research among AYA primarily focuses on buprenorphine-naloxone retention. For example, one study demonstrated that AYA are less likely to be retained in buprenorphine-naloxone in comparison to adult populations.88, 89 Additionally, retrospective chart review of AYA at an outpatient pediatric MOUD clinic in the Northeast USA found that female sex, and a negative urine screen for tetrahydrocannabinol and opioid use and positive urine screen for buprenorphine-naloxone after initiating buprenorphine-naloxone were associated with being retained on buprenorphine-naloxone at follow-up.225 A randomized controlled trial was also conducted among AYA in the USA, where buprenorphine-naloxone discontinuation was found to be positively 119 associated with baseline cocaine use, not being in an intimate relationship, having children, and having a single parent.227 To date, evidence among adult populations suggests people receiving MMT were more likely to be retained in treatment in comparison to other MOUD, while alluding to potential factors associated with MMT discontinuation. For example, findings from a 24-week randomized controlled trial among adults found that 74% of participants receiving MMT and 46% of participants receiving buprenorphine-naloxone were retained in the study by the end of the 24-week study period.228 Similarly, a randomized controlled trial among pregnant people between 6 and 30 weeks of gestation with OUD in the USA, Australia, and Canada that examined MOUD retention at the time of delivery reported higher retention in MMT (82%) when compared to buprenorphine (67%).229 This finding is supported by evidence of a higher preference for MMT among AYA who are interested in initiating OAT, which may be explained by perceptions that it is more effective at addressing mental illness and physical pain.24 Within the study setting, Vancouver, British Columbia, research among adults found self-reported Indigenous identity, recent incarceration, sex work, and injection heroin use were negatively associated with MMT use, while female sex, HIV-positive status, and crack cocaine smoking were positively associated.170 Additionally, one study examined the impacts of regulatory changes to the MMT formulation on substance use and other health outcomes among HIV-positive people, finding that a switch to a more concentrated Methadose™ formulation in January 2014 was associated with significant increases in heroin injection.230 One study from Vietnam found that HIV-positivity, higher education, challenges managing life skills, and disclosing one’s health 120 conditions to their partner were negatively associated with methadone adherence, while older age, living with pain, and mental illness were positively associated with MMT retention.231 Lastly, one qualitative study examining how AYA navigate MOUD treatment in Vancouver, Canada identified health policy barriers to MMT retention, which included burdensome, required daily witnessed dispensation; stringent missed dose and re-initiation policies; limited or inaccessible take-home dosing; and recommended dosage levels that were insufficient in the context of the potent illicit drug supply.232 Of the evidence examining MMT among AYA, there has been one retrospective chart review of AYA accessing MOUD in Sydney, Australia. This study found that participants who received MMT were retained for an average of 354 days versus 58 days in buprenorphine-naloxone,233 suggesting that some AYA are better retained in MMT compared to buprenorphine-naloxone. In the context of the toxic drug crisis,234 this knowledge gap highlights the need for additional research into ways to prevent MMT discontinuation among AYA. Given existing guidelines support the use of MMT for AYA in the study setting26 our research sought to understand ways to improve MMT retention among AYA. This involved identifying reasons for and factors associated with time to MMT discontinuation among AYA who reported initiating MMT over the study period. Additionally, this study sought to examine factors associated with potentially ‘actionable’ MMT discontinuation, which are reasons for MMT discontinuation that can be addressed through policy or guideline changes. 121 5.2 Methods Data for this analysis was derived from the ARYS, with study details and procedures previously described in section 1.8. 5.2.1 Study Sample For this study, the analysis was restricted to the period between December 2005 and June 2018, which is the period that data was available, and the sample was restricted to participants who reported any weekly or daily illicit opioid use in the last six months at any point over the study period. Existing clinical guidelines recommend the use of MOUD, including MMT, for all AYA who use opioids regularly given the increased presence of toxic, synthetic opioids within the illicit drug supply.26 Participants who responded affirmatively to the question “in the last 6 months, have you been in any kind of alcohol or drug treatment (including methadone/Methadose™ or Suboxone®)?” and subsequently reported accessing MMT were eligible for inclusion in the analytic sample. Participants who, at their baseline interview, reported MMT enrolment in the last six months were excluded from the analysis due to the inability to deduce when these participants commenced MMT; however, participants were re-included in the sample if they re-initiated MMT at any point over the study period. Additionally, participants were removed from the analysis if they reported a MMT discontinuation event; however, participants were re-included in the analysis if they subsequently re-initiated MMT and they could therefore contribute more than one initiation event. Participants were right-censored – whereby a participant leaves the study prior to the outcome being observed or the study ends prior to their experiencing the outcome of interest – if 122 they were lost to follow-up or if they reported recent MMT at the end of the study period. More specifically, we observed an 83.4% censoring rate in the primary analysis, which was positively associated with female sex but negatively associated with older age, and a 93.6% censoring rate in the sub-analysis, though the sample size was small and no statistically significant differences were observed. Given the intentional use of censoring and that we do not suspect the study conditions to impact participants’ decisions to initiate MMT, we assessed that censoring is likely to be non-informative. Participants who provided an affirmative response to receiving MMT in the past six months at some point over the study follow-up period were asked the follow-up question of “are you currently on MMT?”. Participants who responded affirmatively were considered retained, while participants who responded negatively were deemed to have discontinued MMT. Participants who reported that they were not currently on MMT were then asked to provide one or more reasons for ceasing MMT from a list or could provide an open-ended response; however, participants who discontinued MMT between study periods, and responded negatively to the question about recently being on MMT at a subsequent study follow-up visit, were not asked if they were currently on MMT and therefore did not have the opportunity to provide their reasons for MMT discontinuation. Participants who reported that they had discontinued MMT due to treatment completion (e.g., physician-initiated tapering, switching to another MOUD) were excluded from the analysis, and the remaining reasons for MMT discontinuation were tabulated. 123 5.2.2 Study Variables The primary outcome of interest was time to any MMT discontinuation while the secondary outcome was time to MMT discontinuation that could possibly be addressed through policy or guideline changes, which included: missing a dose or being taken off by a healthcare provider; having difficulty accessing a pharmacy; and experiencing cost or affordability barriers. Dependent variable selection was guided by the Risk Environment74 and Patient-Centered Accessibility75 conceptual frameworks, and also drew from prior literature examining MMT discontinuation among AYA and adult populations. A number of variables hypothesized to be associated with the outcomes of interest were considered, and include: age (per year older); age of first ‘hard’ drug use (per year older); sex (male vs. female); self-reported Indigenous identity, defined as First Nations,154 Inuit,155 or Métis peoples156 (Indigenous vs. white), which may act as a proxy for the impacts of anti-Indigenous racism, socioeconomic status, and intergenerational trauma; Other self-reported racial or ethnic identities, defined as an affirmative response to being Black, South Asian, Chinese, Other Asian, Latinx, Middle Eastern, or other (Other vs. white); moderate to severe depression (yes vs. no), measured using the Centre for Epidemiological Studies Depression scale;235 child welfare involvement (yes vs. no); and moderate to severe levels of the following five categories of childhood adverse events – sexual abuse (yes vs. no), physical abuse (yes vs. no), emotional abuse (yes vs. no), physical neglect (yes vs. no), and emotional neglect (yes vs. no) – measured using the Childhood Trauma Questionnaire.236 Other variables include: MMT initiation period, defined as having initiated MMT before or after the introduction of Methadose™ in the study setting (≥2014 vs. ≤2013);56 recently living in the Downtown Eastside (DTES) (in the last six months) (yes vs. no), which is an inner-city neighborhood of Vancouver with high levels 124 of poverty and illicit drug use; any injection drug use (yes vs. no); any and recent injection drug use (yes vs. no); non-fatal overdose, defined as an overdose or acute reaction following drug use (yes vs. no) in the last six months;157 recent daily illicit opioid use (yes vs. no), a combined variable that includes daily injection and non-injection heroin, fentanyl, or non-medical prescription opioid use (NMPOU); recent weekly heroin or fentanyl use (yes vs. no); recent weekly NMPOU (yes vs. no); recent weekly cocaine use (yes vs. no); recent weekly crack cocaine use (yes vs. no); and recent weekly crystal methamphetamine use (yes vs. no). Additional factors included: recent employment (yes vs. no), defined as legal self-employment, regular or temporary work; recent homelessness, defined as sleeping on the street, having no fixed address, staying with friends or staying in a shelter or hostel (yes vs. no); recent incarceration, defined as being in detention, prison or jail overnight or longer in the past six months (yes vs. no); recent non-pharmacological addiction treatment access, defined as accessing a treatment centre, recovery house, counselor, Narcotics Anonymous, Cocaine Anonymous, Alcoholics Anonymous, Self-Management and Recovery Training, or any other non-pharmacological treatments (yes vs. no); recent difficulty accessing addiction treatment services (yes vs. no); and, recent difficulty accessing health and social services (yes vs. no). 5.2.3 Statistical analyses 5.2.3.1 Baseline comparisons 125 A baseline analysis comparing participants who were retained in MMT to those who discontinued MMT was conducted. Pearson’s χ2 test was employed to compare binary variables and the Mann-Whitney U-test was used to make comparisons for continuous variables. 5.2.3.2 Extended Cox regression analysis A multivariable extended Cox regression model with time-dependent variables was used among participants who reported initiating MMT at any point over the study period. A multivariable extended Cox regression model with time-dependent variables was used among participants who reported initiating MMT at any point over the study period. Given that participants could report multiple MMT initiation and re-initiation events, an extended Cox model allows the analysis to proceed without requiring that the proportional hazard assumption be met.237 An initial examination of the bivariate associations between the explanatory variables and our outcome of interest was conducted, and then a full model was built that consisted of all variables that were significant at p<0.10. A backwards model selection approach was used whereby explanatory variables with the largest p-values were removed until a reduced model with the lowest Akaike Information Criterion (AIC) was identified. The variance inflation factor was calculated to determine collinearity between variables, which was not present. Previous ARYS studies have described and utilized this approach.198-200 A multivariable extended Cox regression sub-analysis was also conducted to identify factors associated with time to potentially ‘actionable’ MMT discontinuation events. This was defined as 126 MMT discontinuation that could be addressed through policy or clinical guideline changes, and the sub-analysis was restricted to participants who reported discontinuing MMT due to missing a dose or being taken off by a healthcare provider, having difficulty accessing a pharmacy, or experiencing cost or affordability barriers. The same model-building approach was employed as previously described and involved a backwards model selection approach until a reduced model with the lowest AIC was identified. all significance tests were two-sided at a significance level of p<0.05, and statistical analyses were conducted using SAS software version 9.4 (SAS, Cary, NC). 5.3 Results Among 696 participants who reported any weekly opioid use within the past six months, 308 (44.3%) participants reported recent MMT during the study period. Participants who had initiated MMT prior to their baseline interview (n=94, 30.5%), were missing data on their MMT status (n=43, 14.0%), or who discontinued MMT due to treatment completion (i.e., tapering) (n= 11, 3.6%) were excluded from the analysis. Of the remaining 160 participants who initiated MMT at some point over the study period, 102 (63.8%) reported discontinuing MMT and contributed 119 unique MMT discontinuation events. The baseline descriptive statistics comparing participants who were retained in MMT to participants who discontinued MMT are provided in Table 5.1. Of the MMT discontinuation events, a total of n=33 (27.7%) included an assessment of the reason for discontinuation, while n=86 (72.3%) events occurred between study follow-up periods and participants’ reasons for MMT discontinuation were not captured. The primary reasons for MMT discontinuation were missing doses or being taken off by healthcare provider (n=9), not wanting 127 to take it anymore (n=8) and having difficulty accessing the pharmacy (n=5), with additional reasons listed in Table 5.2. Multivariable extended Cox regression was then employed among participants who reported initiating MMT at some point over the study period and who conducted a subsequent follow-up interview (n=137). As demonstrated in Table 5.3, results demonstrate that time to MMT discontinuation was positively associated with recent weekly crystal methamphetamine use (Adjusted Hazard Ratio (AHR): 1.67, 95% Confidence Interval [CI]: 1.19–2.35). Conversely, older age of first ‘hard’ drug use (AHR: 0.95, 95% CI: 0.90-1.00) and female sex (AHR=0.66, 95% CI: 1.01–2.28) were negatively associated with MMT discontinuation, after adjusting for age (per year older) (AHR: 0.95, 95% CI: 0.90–1.00), MMT initiation period (≥2014 vs. ≤2013) (AHR=1.10, 95% CI: 0.74–1.64), self-reported Indigenous identity (Indigenous vs. white) (AHR=1.29, 95% CI: 0.88–1.89). Results from the sub-analysis of factors associated with time to ‘actionable’ MMT discontinuation are presented in Table 5.4. Findings indicate that time to ‘actionable’ MMT discontinuation was positively associated with recent regular crystal methamphetamine use (AHR: 3.79, 95% CI: 1.46–9.81) and recent regular heroin or fentanyl use (AHR=3.37, 95% CI: 1.21–9.38). However, older age (AHR=0.87, 95% CI: 0.76–0.99) was negatively associated with time to ‘actionable’ MMT discontinuation, after adjusting for MMT initiation period (≥2014 vs. ≤2013) (AHR=1.84, 95% CI: 0.63–5.35), non-pharmacological treatment access (AHR=1.81, 95% CI: 0.72–4.56), self-reported racial or ethnic identity (other vs. white) (AHR=1.77, 95% CI: 0.54–5.72), self-reported 128 Indigenous identity (Indigenous vs. white) (AHR=0.93, 95% CI: 0.31–2.76), and ever any injection drug use (AHR=0.39, 95% CI: 0.11–1.38). 5.4 Discussion Our findings demonstrate that over two-thirds of AYA in the study sample who initiated MMT subsequently discontinued treatment. Given evidence that AYA are retained in MMT for longer durations than other MOUD,112, 233 the low levels of MMT retention observed in the study setting are concerning. This may be explained by AYAs’ views on OAT as a short-term intervention to support their immediate transition off of illicit opioids, as reported in recent qualitative research in the study setting.24 Although a majority of participants were not asked for their reason for discontinuing MMT, the reasons for MMT discontinuation described by a sub-sample of participants provide some insight into ways that treatment services may be improved to better meet the needs of AYA. For example, the most common reasons for MMT discontinuation – such as missing doses, being taken off by a care provider, or having difficulty accessing a pharmacy – highlight potential policy and clinical changes that have potential to prevent discontinuation. In the study setting, clinical guidelines stipulate that missing three consecutive doses of MMT that requires patients to re-initiate MMT at a lower dose.34 Although this is appropriate for individuals who have been abstaining or reducing their overall consumption of opioids, for AYA who missed MMT doses because they were consuming illicit street opioids – that are characterized in the study setting by highly potent, 129 synthetic opioids – re-initiating MMT at a lower dose is likely insufficient to meet their physical dependence and may contribute to MMT discontinuation. The high levels of treatment discontinuation also point to the need for research into ways to improve MMT retention, including through improvements to existing clinical guidelines. Our finding that missing a dose or being removed by a healthcare provider was the most commonly reported reasons for MMT discontinuation reinforces previous findings that AYA view the required daily witnessed dispensation of MMT as overburdening and constraining.24 To address this, there have been suggestions that take-home dosing be expanded for AYA when able to be done safely;24 however, existing clinical guidelines limit take-home dosing. Given that existing guidelines around missed doses and re-induction were designed at a time when highly potent synthetic opioids were not widespread within the illicit drug supply, it is important that these guidelines are reviewed in the current context – and in light of interim RMG that improved access to take-home dosing and daily OAT delivery services to promote social distancing in the study setting66, 238 – to improve MMT retention among AYA. In addition to the reasons for MMT discontinuation provided, the analyses of factors associated with MMT discontinuation highlight additional ways to improve retention among AYA. Firstly, our finding that female AYA were less likely to discontinue MMT in comparison to male AYA suggests sex- and gender-based differences in treatment retention. This is complemented by evidence that adult women, and especially pregnant people,239 are retained in MMT for longer durations than men.240 Given trauma-informed perinatal programming, which prescribes MMT, is accessible within the study setting,150, 241-243 the negative association between female sex and MMT 130 discontinuation may reflect the availability of these supports. Alternatively, evidence has found that peer networks significantly influence male AYAs’ substance use treatment decision-making compared to female AYA,125 reiterating the importance of engaging with peer networks to identify ways to improve MMT retention.144, 244-246 Nevertheless, an AYA-specific gender-based analysis on MMT retention may highlight ways to address gender-based gaps in MMT retention among AYA. Another important finding was the association between recent crystal methamphetamine use and time to ‘actionable’ MMT discontinuation. This finding may be due to the increased use of stimulants in order to counteract the negative side effects of MMT (i.e., lethargy, tiredeness, etc.), due to participants’ seeking pleasure, or because of the high levels of polysubstance use reported among AYA in comparison to adult populations.72 Study findings support exploration of novel treatment approaches to address simultaneous opioid and stimulant use among AYA. A potential intervention that has demonstrated some promising results among adults who report polysubstance use is the dual prescription of MOUD alongside prescription stimulants. To date, preliminary research has found that when adequately dosed, the provision of stimulants alongside MOUD reduces both illicit opioid and stimulant use.151-153, 247 Given the potential benefits of prescribing both prescription opioids and stimulants to AYA, future research investigating the use of both types of medications and their impact on the health of AYA may be beneficial. The positive association between recent weekly fentanyl or heroin use and MMT discontinuation also provides some insight into ways to potentially improve the retention of AYAs’ in treatment. Firstly, this may be due to AYA receiving an insufficient MMT dose and so increasing their dosage 131 may support reductions in illicit opioid use. Alternatively, AYA who continue to use illicit opioids alongside MMT may benefit from being offered alternative types of OAT, such as slow-release oral morphine or injectable OAT, to reduce their reliance on the illicit drug supply. This is an important step to effectively address physical dependency and reduce overdose risk,248-250 especially in the context of an increasingly toxic drug supply. Lastly, the non-statistically significant, positive association between non-pharmacological treatment access and ‘actionable’ MMT discontinuation is notable and raises concerns that some AYA may be discouraged from continuing MMT when accessing other treatment services. Adding to this, our findings suggest that younger participants are more likely to report ‘actionable’ MMT discontinuation. This similarly raises concerns of a specific bias or stigma against prescribing MOUD to adolescents versus young adults, which is reinforced by evidence that adolescent-tailored treatment facilities are significantly less likely to provide MOUD to AYA in comparison to adult facilities.103, 194, 251 Study results signal the importance of further research into stigma towards MMT and other MOUD within non-pharmacological treatment settings, and especially among adolescent populations. Additionally, there may be benefits to implementing protections to ensure access to MOUD for all AYA to address stigma-related barriers to treatment access and continuation. There are several limitations with the ARYS cohort that have been described previously, including generalizability, unmeasured confounding, and social desirability bias.165, 188, 189 This analysis is additionally limited by the study questionnaire, which did not capture participants’ reasons for MMT discontinuation if they discontinued MMT between study follow-up periods. Hence, certain 132 reasons for MMT discontinuation, such as being imprisoned, are expected to be underrepresented in the reasons provided and in the statistical analyses. Conversely, participants could have discontinued MMT between study follow-up periods due to treatment completion (i.e., tapered off of MMT), which could have led to the inclusion of ‘treatment completers’ within the analytic sample and minimized or conflated the observed associations, or they could have discontinued and re-initiated MMT in the previous six-months but still have been considered retained in MMT as the questionnaire did not discern this. Another limitation is that some participants may have received both methadone and Methadose™ due to changes MMT provision during the study period and we were therefore unable to account for dosage in this analysis. The sub-analysis is also limited by the small sample size and findings should be interpreted with caution, but this analysis meets sample size requirements252-254 and provides exploratory insight into ways to address ‘actionable’ MMT discontinuation. Lastly, the study period for these analyses was restricted to the period before the adoption of clinical guidelines for the treatment of OUD among AYA in the study setting, and so future research investigating the impacts of those clinical guidelines on MMT retention would be valuable. 5.5 Conclusions Consistent with previous research among adults and AYA, this study demonstrated high levels of MMT discontinuation among the study sample, suggesting MMT may be a limited response in the context of a toxic drug crisis. While study findings point to potential opportunities to optimize MMT programming through measures such as providing access to a broader range of MOUD and treatment services and exploring the potential benefits of providing prescription stimulants to AYA 133 who report polysubstance use, a key implication is that MMT is not sufficient for many AYA. Innovative interventions and ones that center harm reduction remain critical to protecting the health of AYA. 134 Table 5.1 Baseline descriptive statistics of adolescents and young adults (AYA) who reported initiating methadone maintenance treatment (MMT) or Methadose stratified by ever reporting MMT discontinuation between December 2005 and June 2018 (n=160). Characteristic Total (%) (n = 160) Discontinued MMT p - value Yes (%) (n = 102) No (%) (n = 58) Age (med, IQR) 24 (22 – 27) 24 (22 – 26) 25 (22 – 27) 0.448j Age first drug use (med, IQR) 14 (12 – 15) 13 (12 – 15) 14 (12 – 15) 0.208j MMT Initiation Period (≥2014 vs. ≤2013) 67 (41.9) 33 (32.4) 34 (58.6) 0.001 Sex (female) 58 (36.3) 32 (31.4) 26 (44.8) 0.089 Indigenous identity (vs. white) 38 (23.8) 26 (25.5) 12 (20.7) 0.410 Other racial or ethnic identity (vs. white)a 11 (6.9) 8 (7.8) 3 (5.2) 0.596j High school education 55 (34.4) 29 (28.4) 26 (44.8) 0.036 Depressionb 65 (40.6) 37 (36.3) 28 (48.3) 0.137 Child welfare involvement 84 (52.5) 60 (58.8) 24 (41.4) 0.034 Sexual abusec 33 (20.6) 21 (20.6) 12 (20.7) 0.914 Physical abusec 47 (29.4) 33 (32.4) 14 (24.1) 0.337 Emotional abusec 74 (46.3) 51 (50.0) 23 (39.7) 0.239 Physical neglectc 51 (31.9) 34 (33.3) 17 (29.3) 0.772 Emotional neglectc 79 (49.4) 50 (49.0) 29 (50.0) 0.765 Living in the DTESd, e 76 (47.5) 54 (52.9) 22 (37.9) 0.068 Injection drug use 142 (88.8) 88 (86.3) 54 (93.1) 0.297j Injection drug used 120 (75.0) 80 (78.4) 40 (69.0) 0.184 Non-fatal overdosed 22 (13.8) 13 (12.7) 9 (15.5) 0.624 Daily illicit opioid used 92 (57.5) 62 (60.8) 30 (51.7) 0.265 Weekly heroin or fentanyl used 100 (62.5) 63 (61.8) 37 (63.8) 0.799 Weekly NMPO used, f 20 (12.5) 14 (13.7) 6 (10.3) 0.534 Weekly cocaine used 16 (10.0) 13 (12.7) 3 (5.2) 0.172k Weekly crack used 40 (25.0) 29 (28.4) 11 (19.0) 0.184 Weekly CM used, g 58 (36.3) 41 (40.2) 17 (29.3) 0.169 Employmentd 44 (27.5) 22 (21.6) 22 (37.9) 0.026 Homelessnessd 74 (46.3) 48 (47.1) 26 (44.8) 0.786 Incarcerationd 29 (18.1) 19 (18.6) 10 (17.2) 0.827 Non-pharmacological treatmentd 55 (34.4) 36 (35.3) 19 (32.8) 0.745 Difficulty accessing treatmentd, h 16 (10.0) 13 (12.7) 3 (5.2) 0.174k Difficulty accessing servicesd, i 34 (21.3) 22 (21.6) 12 (20.7) 0.959 Note: a Other self-reported racial or ethnic identity includes Black, Latinx, and Middle Eastern; b refers to moderate or severe depression as measured by the Centre for Epidemiological Studies Depression Scale (CES-D); c refers to child welfare involvement, moderate or severe childhood sexual abuse, physical abuse or neglect, and emotional abuse or neglect as measured by the subscales of the Childhood Trauma Questionnaire; d refers to activities in the last six months; e DTES = Downtown Eastside; f NMPO = non-medication prescription opioids; g CM = crystal methamphetamine; h refers to difficulty accessing treatments for substance use disorders; i refers to difficulty accessing health and social services; j p-value is generated using Mann-Whitney U-test; k p-value is generated using Fisher’s Exact Test because of small cell count 135 Table 5.2 Reasons for MMT discontinuation among a prospective cohort of street-involved AYA who initiated and discontinued MMT at some point between December 2005 and June 2018 in Vancouver, Canada (n=119). Reason for not MMT discontinuation Total (n) Missed doses or taken off by healthcare provider 9 Did not want to take it anymore 8 Difficulty accessing pharmacy 5 Side effects 5 Was not effective or could not find preferred dose 4 Too restrictive 1 Cost or affordability 1 Note: A total of 86 unique MMT discontinuation events occurred between study follow-up visits where participants were not asked to provide a reason for MMT discontinuation 136 Table 5.3 Bivariate and multivariable extended Cox proportional hazard model of factors associated with time to MMT discontinuation among street-involved AYA who reported initiating MMT between December 2005 and June 2018 (n=137). Unadjusted Adjusted Characteristic Odds Ratio (95% CI) p value Odds Ratio (95% CI) p value Age (per year older) 0.96 (0.91 – 1.01) 0.095 0.95 (0.90 – 1.00) 0.057 Age first drug use (per year older) 0.94 (0.90 – 0.99) 0.015 0.95 (0.90 – 1.00) 0.044 MMT Initiation Period (≥2014 vs. ≤2013) 1.13 (0.77 – 1.67) 0.095 1.10 (0.74 – 1.64) 0.626 Sex (female) 0.72 (0.60 – 1.06) 0.095 0.66 (0.44 – 0.99) 0.047 Indigenous identity (vs. white) 1.33 (0.92 – 1.93) 0.135 1.29 (0.88 – 1.89) 0.199 Other racial or ethnic identity (vs. white)a 1.88 (1.04 – 3.39) 0.036 1.80 (1.00 – 3.24) 0.051 High school education 0.70 (0.48 – 1.04) 0.075 Depressionb 0.67 (0.48 – 0.94) 0.021 Child welfare involvement 1.27 (0.91 – 1.77) 0.158 Sexual abusec 1.04 (0.65 – 1.65) 0.883 Physical abusec 1.28 (0.90 – 1.82) 0.168 Emotional abusec 0.90 (0.64 – 1.27) 0.539 Physical neglectc 1.40 (0.96 – 2.05) 0.078 Emotional neglectc 0.89 (0.63 – 1.26) 0.511 Living in the DTESd, e, f 1.18 (0.83 – 1.69) 0.348 Injection drug use 0.79 (0.56 – 1.10) 0.162 Injection drug used, e 1.01 (0.73 – 1.40) 0.939 Non-fatal overdosed, e 1.17 (0.71 – 1.93) 0.545 Daily illicit opioid used, e 1.08 (0.76 – 1.55) 0.665 Weekly heroin or fentanyl used, e 1.19 (0.83 – 1.69) 0.342 Weekly NMPO used, e, g 0.67 (0.34 – 1.34) 0.259 Weekly cocaine used, e 0.99 (0.61 – 1.59) 0.958 Weekly crack used, e 0.82 (0.54 – 1.25) 0.355 Weekly CM used, e, h 1.47 (1.04 – 2.07) 0.031 1.67 (1.19 – 2.35) 0.003 Employmentd, e 0.99 (0.63 – 1.54) 0.959 Homelessnessd, e 0.83 (0.57 – 1.21) 0.324 Incarcerationd, e 1.26 (0.78 – 2.03) 0.341 Non-pharmacological treatmentd, e 1.03 (0.71 – 1.50) 0.872 Difficulty accessing treatmentd, e, i 1.02 (0.52 – 2.00) 0.946 Difficulty accessing servicesd, e, j 1.04 (0.67 – 1.60) 0.871 Note: a Other self-reported racial or ethnic identity include Black, Latinx, and Middle Eastern; b Refers to moderate or severe depression as measure by the Centre for Epidemiological Studies Depression Scale (CES-D); c refers to child welfare involvement, moderate or severe childhood sexual abuse, physical abuse or neglect, and emotional abuse or neglect as measured by the subscales of the Childhood Trauma Questionnaire; d refers to activities in the last six months; e refers to variables that were lagged to the previous study visit; f DTES = Downtown Eastside; g NMPO = non-medical prescription opioids; h CM = crystal methamphetamine; i refers to difficulty accessing treatment for substance use disorders; j refers to difficulty accessing health and social services 137 Table 5.4 Bivariate and multivariable extended Cox proportional hazard model of factors associated with time to MMT discontinuation that could be addressed through policy change among AYA who reported initiating MMT between December 2005 and June 2018 (n=62). Unadjusted Adjusted Characteristic Odds Ratio (95% CI) p value Odds Ratio (95% CI) p value Age (per year older) 0.89 (0.80 – 0.99) 0.038 0.87 (0.76 – 0.99) 0.031 Age first drug use (per year older) 0.82 (0.71 – 0.95) 0.010 MMT Initiation Period (≥2014 vs. ≤2013) 2.31 (0.88 – 6.09) 0.090 1.84 (0.63 – 5.35) 0.262 Sex (female) 0.73 (0.30 – 1.79) 0.490 0.57 (0.22 – 1.59) 0.241 Indigenous identity (vs. white) 1.30 (0.56 – 3.32) 0.548 0.93 (0.31 – 2.76) 0.897 Other racial or ethnic identity (vs. white)a 2.21 (0.76 – 6.40) 0.145 1.77 (0.54 – 5.72) 0.343 High school education 0.78 (0.33 – 1.82) 0.567 Depressionb 0.86 (0.38 – 1.97) 0.721 Child welfare involvement 1.65 (0.74 – 3.67) 0.219 Sexual abusec 0.67 (0.21 – 2.11) 0.494 Physical abusec 1.87 (0.87 – 4.02) 0.109 Emotional abusec 0.94 (0.39 – 2.27) 0.898 Physical neglectc 2.57 (1.15 – 5.77) 0.022* Emotional neglectc 1.33 (0.58 – 3.08) 0.499 Living in the DTESd, e, f 0.83 (0.38 – 1.82) 0.636 Injection drug use 0.37 (0.15 – 0.91) 0.031 0.39 (0.11 – 1.38) 0.145 Injection drug used, e 1.86 (0.69 – 5.04) 0.220 Non-fatal overdosed, e 1.80 (0.68 – 4.72) 0.234 Daily illicit opioid used, e 2.11 (0.87 – 5.11) 0.097 Weekly heroin or fentanyl used, e 4.14 (1.56 – 11.0) 0.004 3.37 (1.21 – 9.38) 0.020 Weekly NMPO used, e, g 1.80 (0.49 – 6.57) 0.376 Weekly cocaine used, e 0.52 (0.07 – 3.84) 0.522 Weekly crack used, e 0.21 (0.03 – 1.48) 0.117 Weekly CM used, e, h 3.47 (1.50 – 8.05) 0.004 4.61 (1.78 – 11.9) 0.002 Employmentd 0.93 (0.37 – 2.32) 0.871 Homelessnessd 1.89 (0.87 – 4.14) 0.110 Incarcerationd 2.15 (0.76 – 6.06) 0.148 Non-pharmacological treatmentd, i 1.99 (0.91 – 4.36) 0.085 1.81 (0.72 – 4.56) 0.205 Difficulty accessing treatmentd, i 0.71 (0.09 – 5.76) 0.752 Difficulty accessing servicesa, j 0.87 (0.32 – 2.38) 0.781 Note: a Other self-reported racial or ethnic identity include Black, Latinx, and Middle Eastern; b Refers to moderate or severe depression as measure by the Centre for Epidemiological Studies Depression Scale (CES-D); c refers to child welfare involvement, moderate or severe childhood sexual abuse, physical abuse or neglect, and emotional abuse or neglect as measured by the subscales of the Childhood Trauma Questionnaire; d refers to activities in the last six months; e refers to variables that were lagged to the previous study visit; ; f DTES = Downtown Eastside; g NMPO = non-medical prescription opioids; h CM = crystal methamphetamine; i refers to difficulty accessing treatment for substance use disorders; j Refers to difficulty accessing health and social services 138 Chapter 6: Adolescent and young adults’ experiences navigating the OAT continuum in Vancouver, Canada 6.1 Introduction Despite existing recommendations and the demonstrated effectiveness of OAT,26, 28 some evidence suggests that AYA in the USA and Canada are significantly less likely to access OAT in comparison to adult populations.194 More specifically, a recent systematic review demonstrated that, firstly, AYA are less likely to receive OAT than adult populations, and, secondly, are more likely to be prescribed partial opioid agonists such as buprenorphine-naloxone rather than full agonists such as methadone and slow-release oral morphine.194 The latter is noteworthy given the important differences between partial and full opioid agonists, which have been shown to influence AYAs’ treatment decision-making and access to OAT.24 Nevertheless, recent evidence raises concerns that many AYA are not accessing or may even be avoiding these therapies in our setting.13, 24, 25, 194 For example, research has demonstrated that a lower proportion of AYA are accessing or being prescribed OAT in comparison to adults,13 and qualitative evidence suggests some AYA are highly ambivalent towards OAT and in particular buprenorphine-naloxone.24, 25 One qualitative study showed that AYA who did access OAT often viewed its longer-term use as incompatible with their goal of achieving complete abstinence from licit and illicit opioids.24 They often only accessed OAT as a short-term intervention to mediate withdrawal symptoms during in-patient treatment and detoxification and while in hospital.24 139 Both the risk environment74 and patient-centered healthcare accessibility75 frameworks point to potential social, structural, and environmental risk factors operating at micro-, meso-, and macro-levels, including healthcare system-related barriers, that may influence AYAs’ perspectives on and willingness and ability to engage with OAT. For example, one study conducted among adults found that stigma towards OAT at the macro-level results in meso-level policies that exclude people on OAT from accessing treatment and recovery services.255 Specifically, participants described being excluded from sober living and Narcotics Anonymous programs because they were deemed to be “actively using” drugs and therefore ineligible for these programs.255 Adding to this, entrenched poverty, homelessness, and marginalization among AYA experiencing street-involvement create upstream barriers that make it difficult for them to effectively access healthcare services and engage with OAT.256 Drawing on the risk environment and patient-centered accessibility frameworks, this study builds on this previous work to more closely examine how AYA contemplated, engaged, disengaged, and in some cases avoided OAT over time. Our purpose is to identify policy-related factors that can be addressed to improve OAT experiences and outcomes among AYA. We provide new insights into how OAT programming can be optimized to meet AYAs’ needs and goals. 6.2 Methods Most participants were recruited from the At-Risk Youth Study (ARYS), an open, prospective cohort of street-involved AYA in Vancouver.257 To be eligible to enrol in ARYS, AYA need to be between ages 14 and 26 at the time of recruitment, report any illicit drug use during the past 30 140 days, and be accessing health or social services for AYA experiencing unstable housing and homelessness. Additionally, some participants who were not enrolled in the ARYS study were recruited from various local drug treatment settings (e.g., youth-dedicated detoxification and treatment centers, safe houses). Recruitment occurred on a rolling basis over the duration of the study period. 6.2.1 Study Sample For this qualitative study, all participants had used heroin/fentanyl intensively (2 or more times per week by injection, inhalation, and/or ingestion) and undergone some form of drug treatment (e.g., OAT, in-patient detoxification and recovery programs, out-patient Twelve Step programs) in the previous 6 months at the time of their first interview. While some AYA still referred to using “heroin,” or stated more generally that they used “down” (a slang term for illicit opioids), it is generally recognized that illicit opioids obtained in Vancouver’s street-based drug markets now consist primarily of or are heavily adulterated with illicitly-manufactured fentanyl (it is for this reason that we use the term “heroin/fentanyl”).5, 62 All AYA had encountered some form of OAT over the course of their treatment trajectories, whether in the sense that it had been explicitly offered to them by a care provider or they had simply heard about it while attending in- and out-patient treatment. The majority of participants had initiated and discontinued OAT multiple times across the study period. 6.2.2 Study Procedures 141 A semi-structured interview guide developed by a medical anthropologist (DF) was used during interviews to elicit explanations of AYAs’ engagement with OAT across time and healthcare settings in Greater Vancouver. This interview guide was developed in collaboration with a Youth Advisory Council (YAC), a group of 8 AYA with lived and living experience of street-involvement, substance use, and mental health concerns. YAC members were actively involved in the creation of the interview guide and advised the research team on relevant lines of inquiry regarding OAT engagement among AYA, but they were not involved in the analysis and interpretation of the data in the case of this manuscript (see Giang et al., 2020 for a related paper that includes YAC member co-authors). The interview guide was divided into nine topic areas, including current living situation and drug use trajectories, accessing drug treatment and other kinds of substance use services, and experiences with OAT. For the OAT topic area, questions centered on participants’ experiences with different forms of OAT. Questions included: Who was involved in the decision to begin OAT? Have you ever switched from one type of OAT to another? What were the challenges of getting on this form of OAT? What were the benefits? After you went on it, how did things change? We also asked AYA about how daily adherence to OAT impacted other areas of their lives, including relationships with family, caregivers, friends, romantic partners, and healthcare professionals. Follow-up interviews focused on how things may or may not have changed for AYA since their previous interview(s) and delved deeper into AYAs’ understandings of their drug use and treatment trajectories. 142 Interviews began in 2018, and participants were then invited to complete follow-up interviews at 6-month intervals. While we attempted to follow up with each participant approximately every 6 months, this was not always possible due to the circumstances of young people’s lives (e.g., chronic unstable housing and homelessness). Alternatively, when the conditions of AYAs’ lives stabilized for periods of time, they sometimes expressed interest in more regular follow-up interviews (e.g., every 3 months). Participants who were seen for follow-up interviews contributed between two to six interviews over the study period. Co-authors DF and MT conducted in-person and telephone interviews in accordance with COVID-19 safety protocols, which took approximately 60 to 90 minutes to complete. Written informed consent was collected from participants prior to the commencement of their first interview and participants were reimbursed with a $30 CAD honorarium for each interview. Once completed, interviews were transcribed verbatim, deidentified, and reviewed to ensure that the transcripts corresponded with interview recordings. Transcripts were then uploaded to NVivo 12 software93 where all data pertaining to OAT (i.e., buprenorphine-naloxone, methadone, slow-release oral morphine) was coded and retrieved for thematic analysis. This study received ethical approval from the University of British Columbia Research Ethics Board (H17-01726; H18-03529). 6.2.3 Thematic Analysis Once OAT-specific content was identified and extracted, a preliminary codebook was developed by AP in consultation with MT and DF. This began with an inductive thematic analysis,258 whereby we identified overarching themes as they related to the risk environment and patient-centered 143 accessibility frameworks. We then subsequently refined these through the identification and inclusion of more detailed codes to provide a more nuanced understanding of AYAs’ OAT experiences and trajectories. This thematic analysis was an iterative process that involved multiple discussions between the research team on the interpretation of the findings and their implications in the context of an increasingly toxic, unregulated drug supply. Pseudonyms are used in the place of participants’ names to protect their confidentiality. 6.3 Results One hundred and seven semi-structured, in-depth interviews were conducted with 56 AYA in Vancouver between January 2018 and August 2020, with 30 AYA participating in one or more follow-up interviews. Participants ranged in age from 14 to 25 years and included 36 men, 18 women, and two non-binary participants. A majority identified as white (n=42) followed by Indigenous (n=13), Asian-Canadian (n=5), and African-Canadian (n=3), with some participants providing multiple responses. An additional two participants chose not to disclose their racial or ethnic identity. Thematic analysis of interviews highlighted how AYA contemplated, engaged, disengaged, and in some cases avoided OAT over time. Findings demonstrate social and policy factors that influence AYAs’ perceptions of, experiences with, and willingness to engage with OAT, including those contributing to frequent re-attempts at OAT. Results point to areas where existing treatment guidelines and services can be improved to meet the diverse needs of AYA in and beyond our setting. 144 6.3.1 OAT contemplation and initiation As they contemplated trying it, many AYA expressed negative perceptions of OAT, that, in some instances, resulted in avoidance. Joanne, a 14-year-old white woman, shared her hesitations around substituting illicit opioids with methadone, which she viewed as being as highly addictive as fentanyl and potentially causing the same cravings for opioids: “I know for a fact that if I had something like methadone – because it still gives you kind of a high – I’ll want to take more. And then I’m back in that cycle, and me being here [in residential treatment] will just be a waste of time because [methadone is] going to make me want to use again.” Some participants detailed the influence of friends on delaying or avoiding seeking OAT. Nicky, a 20-year-old non-binary person of mixed Indigenous Ancestry, was initially hesitant to try methadone at the outset of the study. They discussed in their first interview how witnessing the negative side effects of methadone experienced by a friend was especially influential when they were initially contemplating it: “I have a friend […] in her mid-thirties and she’s been on methadone for the past 15 years. And she can barely think straight. She’s so fucking out of it all the time, just, like, spaced out and she was never like that before she got onto methadone.” 145 In addition to concerns about addictiveness, ongoing cravings, and side effects, participants described how friends’ negative experiences with tapering off OAT shaped their perspectives. Tina, a 23-year-old woman, decided to cease methadone due to the burden of daily witnessed dispensation and having to re-initiate methadone at a lower dose when she missed three doses in a row. But her friend’s experiences also powerfully informed this decision: “[My] best friend was on, like, 80 mL [of methadone] and spent two months up north getting off of it and almost died. […] It gives me nightmares thinking about it.” While negative perceptions of OAT could lead some participants to avoid OAT altogether across the study period, for others the result was a delay in seeking OAT, or particular forms of OAT. A number of participants moved between different kinds of OAT as they attempted to figure out what form might work best for them in relation to their treatment and recovery goals. For example, while Nicky was initially hesitant to try methadone, over the course of the study period they navigated multiple forms of OAT. After trying Kadian for a period of time and finding that it did not sufficiently mediate cravings, Nicky tried methadone despite their initial hesitations, and had some success with it. Over the course of the study period, Tina eventually returned to methadone despite identifying a number of negative aspects of this treatment. Some participants reported unwelcome pressure from family members to go on OAT, while others reported that their families attempted to dissuade them from OAT. For example, Cory, a 21-year-old white man, explained how several members of his family expressed to him that they “didn’t like who [he was] on methadone.” A number of AYA reported their parents’ direct involvement in their treatment decision-making. Julia, a 17-year old white woman, had been on methadone in 146 the past at the outset of the study but told us that she had discontinued use because she lived far away from her methadone clinic and ultimately decided not to renew her prescription. Upon ceasing methadone, she experienced significant pressure from her father to initiate buprenorphine-naloxone: “My dad was like, ‘You gotta get on Suboxone©.’ But I don’t like the idea of Suboxone©. He just thought that if I was on Suboxone© that I was not gonna do drugs at all anymore ‘cause I wouldn’t be able to get high [due to the ‘blocking’ effect of partial opioid agonists].” In addition to experiencing pressure from family members surrounding OAT decision-making, participants also commonly reported feeling pressured or even coerced by healthcare providers when contemplating OAT, including what kind to try. Specifically, participants felt that providers were pushing them to try buprenorphine-naloxone rather than methadone, even when they indicated that they had previously tried and preferred methadone. As Julia recounted during her initial interview, she had experienced significant challenges finding a healthcare professional to prescribe her methadone instead of buprenorphine-naloxone: “I went to go see a doctor and the doctor was like, ‘No, we’re not gonna put you on methadone because you’re young.’ People have died from methadone, I guess? And they don’t want to, like, overdose me, which I understand completely but I also felt that they should have understood that I didn’t feel comfortable with Suboxone©.” 147 Being pressured into taking buprenorphine-naloxone and denied methadone was an extremely frustrating experience for many participants. Tina shared that, during a period of time when she was considering initiating OAT, at one clinic visit she was repeatedly offered buprenorphine-naloxone instead of the full range of OAT. This led her to leave the clinic “without anything because [she] was so frustrated and didn’t want to have that conversation with the doctor.” Alternatively, participants who were able to access their preferred form of OAT – usually methadone – described the positive impacts that this had on their trajectories. For example, Angel, a 16-year-old white woman who had previously tried but then discontinued buprenorphine-naloxone, described her satisfaction when she was finally able to access a form of OAT that worked for her: “I was on Suboxone© before, but I hated it. I just didn’t like the taste. Currently, I have been on methadone for about seven months and it’s unbelievable how much it’s helped me.” In some cases, the provision of OAT as part of what was offered at wrap-around service “hubs” for AYA was itself perceived as coercive. Trevor, a 20-year-old Indigenous man, noted at his initial interview that he had accessed a hub looking for food but quickly felt that providers there were pressuring him to go on OAT: “I went there because they had food and they’re like, ‘You have to be a client here [to get food].’ They’re like, ‘Do you do down [heroin/fentanyl]?’ And I’m like, ‘Yeah.’ And then, like, ‘Do you wanna get off of it?’ I’m like, ‘Yeah.’ And they’re like, ‘Sign this form.’ And 148 I got food and then they’re like, ‘Wait, you have more [forms to fill out].’ And the next thing I know I was in a doctor’s office, and I was like, ‘Whoa, what happened?’ And yeah, that’s how [getting on OAT] kinda started. It’s manipulative.” Trevor eventually accessed Kadian at another clinic. However, a sense of being pressured to take OAT and being excluded from treatment decision-making led several participants to disengage from care for extended periods of time. 6.3.2 OAT maintenance and retention For participants who went on OAT, staying on it was complicated by the everyday demands of navigating the broader risk environment. In the context of daily struggles to meet basic needs, participants questioned the value of OAT and its potential to impact their lives. During a follow up interview with Nicky that occurred during a period of time when they had recently discontinued methadone, they reflected on how the required daily witnessed dispensation of methadone was unrealistic and burdensome when navigating the complexities of street-involvement, poverty, and other health challenges: “You know it’s like, well, what’s the point in trying it at the end of the day? Like, especially when you’re not stable. I’ve got, you know, other doctor’s appointments. I’m homeless so I’ve gotta figure out food in a day. I’ve got to figure out fucking shelter. I’ve gotta figure out how to help my partner, […] you know?” 149 AYA also pointed out that, in the context of a drug supply that is heavily adulterated with highly potent fentanyl and related analogues, even high doses of OAT might “barely touch” (as Nicky put it) or manage their cravings and withdrawal symptoms. As Nicky elaborated, the inability of OAT to adequately mediate cravings and withdrawal symptoms – especially initially, while patients are being titrated to a higher dose – encourages treatment disengagement: “People just – eventually they give up because they’re like, fuck this shit, why would I try [OAT] if all that’s gonna happen is I’m gonna get nothing, you know, to even help me?” Some participants shared how existing guidelines around missed doses, whereby those who have missed three or more consecutive days of OAT are required to re-initiate OAT at a lower dose, discouraged retention. As Marcus, a 21-year-old man of mixed Indigenous Ancestry, explained, it took him approximately two months to achieve a longer period of retention on methadone due to repeatedly missing doses: “[When I started OAT] it took about two months, and they were pretty rough. […] I had a mess-up when I got out of the hospital [and my OAT was cut-off]. Say you’re at, like, 90 or 100 [millilitres] or whatever, well, you miss three days and they start you back at 30, at the beginning dose again. And then you’re really screwed – which I’ve had that happen to me already. Twice.” Other AYA indicated that their experiences around missed doses resulted in treatment disengagement and eventual relapse. As Robby, a 24-year-old white man, recollected: 150 “It was already, like, five days since I’d had my Kadian, so they couldn’t – once you miss your dose for, like, more than three days, they have to restart you back at the lowest dose possible and then slowly raise you up again. So I was on, like, 600 mg of Kadian and I asked to go back on it and they were like, ‘Well, we can start you at 30,’ or whatever and that was, like – to me that wouldn’t even put a dent in my [cravings and withdrawal symptoms]. So it was, like, really upsetting and I barely made it home. And then I ended up relapsing ‘cause I was – I just felt, like, so terrible I had to.” The requirement of daily witnessed dosing at a pharmacy weighed heavily on some participants. This was especially true for those who had secured employment while on OAT, only to find that their treatment regimen conflicted with their work schedule or requirements. Missed doses because of scheduling conflicts could lead to relapse. Julia explained why she had discontinued methadone yet again during a follow up interview: “I have trouble keeping a job because I work from this time to that time, and I need to take my methadone from this time to this time. I need to be able to get to the pharmacy and take [my methadone]. And then, like, when I was on the way to my job, [the pharmacy] wasn’t open, and sometimes they’d make me work later and by the time I got back, it was closed. So, I’d be withdrawing, and I’d have to go get drugs. It was just, like – I couldn’t keep a job because of it.” 151 Another participant who was employed shared their challenges with getting enough “carries” (take home doses of OAT) so that they could travel for work for extended periods of time. Adam, a 24-year-old man, described his preference for Kadian over buprenorphine-naloxone and methadone during his initial interview. At a follow-up interview, he described how the length of a work trip exceeded his maximum allowable duration for Kadian carries and he experienced difficulties receiving an emergency refill. Having experienced numerous difficulties with missing doses of Kadian previously that required re-initiating at a lower dose, he was very concerned about losing access as his work trip was extended beyond the anticipated end date. In this case, the implementation of interim RMG across British Columbia, which eased restrictions around the provision of take-home doses, was a positive development: “I went out to [a rural community] and I got carries for the whole time that I was there. I was actually really lucky because I tried to call my pharmacy to get more carries, and they were like, ‘No.’ But then I tried calling all the pharmacies around there and the one pharmacy – the only reason that they were even able to give me my Kadian was because of COVID. So, if it wasn’t for COVID, I never would have been able to get my meds and I would have had to leave the job site and miss out on, like, another $1000 worth of work.” Finally, a number of participants cited aging out of youth services and the transition to adult services as a moment when disengagement from OAT became more likely. Participants worried about building relationships and trust with new prescribers so that they would be provided with adequate, and in some cases take-home, doses. Tricia, a 25-year-old woman, described her hesitancy to access an adult clinic in order to procure Suboxone© carries: 152 “I’m scared to death to get my Suboxone© from, um, [an adult clinic] in Surrey. When I was 18, 19, 20, whatever, I went to an adult Suboxone©/methadone clinic. And I told myself, ‘I’m never coming back here.’ Like, I got treated [like] I was the young one and it’s just like, I saw things I did not need to see in Surrey at that clinic. And now I’m going to have to go back to adult services and I’m just – they’re just a lot stricter, you know what I mean? Like, I’m worried now that I’m gonna have to go back to witnessed doses, when I’ve been on carries for years.” 6.3.3 Tapering off and OAT discontinuation Consistent with previous research,24 many participants viewed OAT as a short-term intervention to mediate cravings and withdrawal symptoms and expressed a desire to discontinue use shortly after discharge from detoxification, residential treatment, and hospital settings. As described above, several participants experienced pressure and even coercion from prescribers to go and stay on OAT, and in particular buprenorphine-naloxone. However, there were also cases where providers and programs encouraged AYA to taper off of OAT after relatively short periods of time, despite guidelines that strongly caution against this approach. As Kenny, a 21-year-old white man, explained: “Basically, when I got intaked [sic] at a treatment centre they were like, ‘We want to see you in, like, the next month or two tapering off of [buprenorphine-naloxone],’ right? And, like, I didn’t really care at that point. Because I didn’t really have a whole lot of 153 experience. I was just like, ‘Okay, if you guys think that me tapering off this is a good idea, let’s do that,’ right? I was like, yeah, you know what? I don’t want to be on Suboxone©, right? Like, I’m in a treatment centre with support. Like, I don’t feel unsafe at all without this Suboxone© thing in my life. I don’t feel the need for it at all, right? While Kenny described wanting to taper off OAT at that treatment center – or at least not resisting the idea – in hindsight he connected tapering to a subsequent relapse and overdose. During another interview, he shared that he had re-initiated OAT in the hopes that it could protect him from having that happen again. Kenny and other AYA described how confusing it could be to navigate conflicting approaches to OAT across providers and programs. While some providers and programs advocate strongly for the longer-term use of OAT, others suggest short-term use and tapering. To complicate things further, AYA themselves have shifting ideas about whether OAT is a longer- or shorter-term treatment option. Many participants described wanting to quickly taper off OAT, and then experiencing a relapse following a taper. They identified tapering off OAT too quickly as a contributing factor. As Tricia reflected regarding the first time that she tried to taper off buprenorphine-naloxone when she was an adolescent: “I think my first taper went really quickly and I wasn’t ready back then. I was still in, like, [residential] treatment and stuff and they were, like, tapering me down. That was way back, [when I was] younger – like, teenager days. So, that didn’t work out. I think it lasted, like, a month and then I ended up using.” 154 Eventually, Tricia got back on buprenorphine-naloxone and was able to maintain a period of abstinence from illicit opioids. Motivated by her desire to begin a family, Tricia consulted with her doctor and made the decision to initiate another taper. This time, her plan was to taper over a longer period: “[I said to my doctor] ‘I’m doing so well right now, so let’s just do it slowly.’ I told [my doctor] that I want to stay on 6 mg for months before I go down to, like, 4 mg. So, this is gonna be quite a bit of a process. It might even take a year or two, who knows, but I just wanted to get it started ‘cause I haven’t tried to taper in years. He’s like, ‘Are you sure that’s gonna be okay?’ And it is a lot different. At nighttime I’m okay, but when I wake up, I feel like I need [buprenorphine-naloxone] right away. Which is fine.” Like Tricia, many participants expressed uncertainty about how and when to taper off OAT, even as they expressed a strong desire to do so. 6.4 Discussion Our findings point to important micro-, meso-, and macro-level environmental factors that influence AYAs’ engagement with OAT across time, demonstrating how patient-centered accessibility is significantly influenced by the risk environment that individuals are enmeshed. While many AYA who were hesitant to initiate OAT subsequently initiated or re-initiated treatment, our findings demonstrate how micro-level interactions with family members, peers, and healthcare providers can powerfully influence these trajectories, including extended periods of 155 avoidance. At the macro- and meso-levels, entrenched poverty and burdensome clinical guidelines created difficulties for staying on OAT, as well as challenges when attempting to taper off of OAT. Several AYA had to navigate conflicting recommendations regarding when and how to taper off of OAT. The risk environment that AYA are navigating must be accounted for in the designing of clinical guidelines and programs, including what kinds of OAT to prescribe and requirements surrounding their use (e.g., initiation dose level, dose restart level, witnessed dispensation, tapering). While we identified several challenges to navigating OAT, participants’ experiences also provide insight into how to improve OAT programming for AYA. Specifically, findings suggest that OAT engagement and retention would be improved by expanding access to the full range of OAT while simultaneously addressing real or perceived coercion into OAT, and in particular buprenorphine-naloxone; updating clinical guidelines to incorporate the interim RMG introduced during the COVID-19 pandemic; addressing treatment gaps arising from missed doses and take-home dosing, particularly for methadone; supporting AYA who are aging out of youth-dedicated services; and providing a clear pathway to OAT tapering for AYA when that is something that they indicate they want. AYA often enter the healthcare system with clear treatment goals and preferences, which can be shaped by family members and other caregivers, friends, and romantic partners. To date, there is some evidence highlighting the potential benefits of including family members in treatment programming and planning, and the positive impact of one’s social network on treatment willingness and engagement.259, 260 Involving caregivers may be particularly effective when AYA 156 are actively involved in decision-making around who is involved and how, and when the definition of caregivers extends beyond biological and adoptive family members to include chosen family members.261, 262 However, we must account for how family members and other caregivers may push AYA towards treatment programming that does not align with the latter’s interests and priorities and could even undermine their safety. For example, stigma towards OAT and preference for abstinence-based treatment approaches among family members may push AYA towards tapering off of or discontinuing OAT when they do not necessarily want to do so, increasing their risk of drug poisoning upon relapse.263 While this is not directly demonstrated in our findings, family and caregiver involvement in treatment decision-making should be secondary to fostering AYAs’ self-determination and safety in relation to their treatment and care. Our findings regarding the role of friends in shaping treatment trajectories is consistent with other similar research in Canadian settings,125, 144 which demonstrates that peers can discourage AYA from following up with prescribers and refilling OAT prescriptions. Although friends may discourage OAT initiation and adherence, our findings also demonstrate that social networks are crucial sources of information about OAT. Peer networks have previously been credited with reducing injection-related harms among people who use drugs and warrant further attention in the context of shaping AYAs’ understandings of OAT.146 For AYA who initiated OAT, the challenges of navigating the everyday emergencies of poverty, homelessness, and unstable housing alongside the demands of OAT programming led many to conclude that it was too burdensome, particularly if dosage levels were inadequate. Study participants identified the clinical guidelines regarding repeated missed OAT doses, which dictate 157 re-starting OAT at a lower dose, and the requirement of witnessed dispensation as major barriers to retention. This was especially true for AYA who were employed, for whom the stringent requirements of OAT programming could force them to decide between staying on OAT and maintaining employment. Health care providers should work closely and expediently with AYA to identify OAT dosage levels that works well for them during treatment initiation,85, 177-179 including after missed doses. Additionally, findings highlight the need for a continuum of health and social supports for AYA, which include providing access to safe, stable, supportive housing and employment and income-related supports.24, 85, 184, 185 In the absence of these supports, OAT can seem irrelevant to AYAs’ daily priorities and needs. With regards to buprenorphine-naloxone specifically, the required precipitated withdrawal prior to treatment initiation is a significant barrier for many AYA that has been reported in previous qualitative research from the study setting.24, 25 However, one approach that could help AYA reach an optimal dose of this treatment, including after repeated missed doses, is the use of micro-dosing induction. Micro-dosing induction does not require abstinence from opioids while titrating patients up to an adequate buprenorphine-naloxone dose, thus preventing precipitated withdrawal.193 Micro-dosing induction does require a longer duration of monitored administration to prevent withdrawal symptoms, and therefore residential detoxification and treatment settings may be suitable environments for the initiation of buprenorphine-naloxone via micro-dosing induction. Rapid methadone induction, and the co-prescription of oral morphine or hydromorphone tablets alongside initial doses of methadone, have also been used in our study setting with some success.264 This approach better supports patients in reaching an optimal methadone dose within a shorter 158 period of time, and provides patients with more comfort (i.e., reduced cravings and withdrawal symptoms) during methadone induction. The co-prescription of oral morphine or hydromorphone tablets alongside initial doses of methadone is a component of the provincial interim RMG that sought to promote physical distancing and reduce overdose risk during the COVID-19 pandemic in our setting.66, 238 Revising existing youth clinical guidelines to incorporate this component of interim RMG is warranted. Revising youth OUD guidelines to align with the most recent evidence may also help reduce the repercussions of missed doses. Crosstown Clinic – that provides injectable diacetylmorphine in Vancouver’s Downtown Eastside – has recently trialed and adopted a more flexible, patient-centred approach to addressing missed OAT doses, increasing the missed dose allowance from 3 to 10 days.265 Learning from the experiences of Crosstown Clinic, potential opportunities to improve OAT retention among AYA include increasing the missed dose allowance; including preprint orders on patients’ electronic medical records to ensure continuity of OAT when prescribers are not available; allowing nurses to dispense OAT; improving access to daily OAT delivery services; and dispensing up to half of the original dose that a patient had previously been receiving before missed doses.265 Prescribers can employ a range of diagnostic criteria – from rapid urine drug testing to accounting for patients’ self-reported illicit drug use patterns, frequency, and expenditures – in order to optimize dosage levels upon treatment initiation or re-initiation.66, 238, 265 Addressing barriers to take-home OAT doses, including the provision of prescription refills, must also be addressed. As one participant described, these barriers were lessened during the COVID-159 19 pandemic due to the introduction of the RMG,66, 238, 266 which allowed healthcare providers to prescribe longer durations of take-home OAT doses. However, RMG are temporary and there is no assurance that this flexibility will persist after the pandemic. Given recent evidence that take-home dosing for OAT during the COVID-19 pandemic has been safe and practical,183 there is a need to review and revise existing youth guidelines in order improve access to take-home dosing and daily OAT delivery services, thereby further reducing the impacts of missed doses on treatment continuation. Lastly, the challenges experienced by AYA when attempting to taper off of OAT highlight the importance of empowering AYA in relation to treatment decision-making and adopting a patient-centered approach.267 When AYA initially inquire or are approached about OAT, prescribers should at that time communicate relevant information regarding the process of tapering off of OAT, including the benefits longer-term tapering and the risks of short-term tapers. Previous research has suggested that it may be useful to talk to AYA about OAT using shorter timelines initially, as the idea of being on OAT for an extended period of time can dissuade some AYA from trying it at all.24 For AYA who communicate an intention to rapidly taper themselves off OAT against medical advice, it is important that prescribers clearly communicate the potential harms of doing so while also assuring AYA that they are willing to work with them on a longer-term taper and will support their re-initiation onto OAT at a later time. This scenario further emphasizes the importance of integrating the interim RMG into youth OUD clinical guidelines,66, 238, 266 because it is critical to facilitate access to prescribed safer alternatives to the increasingly toxic, unregulated drug supply among AYA who taper themselves off of OAT and subsequently begin using illicit opioids intensively again. 160 There are several limitations to this qualitative study. Our findings describe OAT engagement among AYA in a somewhat unique substance use treatment and policy landscape. Moreover, our findings are most representative of AYA experiencing entrenched poverty and unstable housing and homelessness, and who report intensive daily opioid use. Therefore, AYAs’ experiences in other places are likely to differ in some regards. Additionally, this article does not include the perspectives of healthcare providers, nor participants’ family members, caregivers, friends, and romantic partners. It therefore does not fully explore how these other social actors shaped AYAs’ OAT trajectories. Lastly, this research is limited in that AYA were not engaged in the interpretation and presentation of findings; however, co-authors MT and DF were engaged with the YAC involved in designing the interview guide for this research on a weekly basis, which informed their contributions to this analysis. 6.5 Conclusions In conclusion, it is critical that AYA be empowered with more control over treatment decision-making and trajectories. They should have access to the full range of OAT, including but not limited to buprenorphine-naloxone. Providers must work collaboratively with AYA to develop treatment plans and timelines that can be quickly adapted as AYAs’ circumstances, needs, and desires change. Given that many AYA view OAT as a shorter-term treatment option, it is critical that they are provided with a clear pathway to an OAT taper, as well as a range of additional treatment, health, and social services when they decide to taper off OAT. For healthcare providers, this requires viewing OAT as one of many tools available to support AYA in realizing their 161 treatment, recovery, and broader life goals. Such an approach will allow healthcare providers to develop the kinds of trust-based therapeutic relationships that can be lifesaving in the context of the increasingly toxic, unregulated drug supply. 162 Chapter 7: Conclusions 7.1 Summary of findings and contributions of this dissertation By investigating the OAT experiences and outcomes among street-involved AYA, this dissertation sought to identify barriers and challenges to OAT, in addition to understanding how to optimize OAT among street-involved AYA. The findings of each chapter, in addition to the policy implications of these findings, are summarized hereafter. Chapter 2 reports the results of a systematic review of academic databases and grey literature that identified peer-reviewed studies evaluating the availability, prescription receipt, or the initiation of MOUD. The 37 included studies accounted for 179,785 AYA and examined access to MMT (N=30), buprenorphine (N=26), and naltrexone (N=10). Findings reinforce concerns that AYA were less likely to access MOUD and suggest that adolescents are more likely to receive naltrexone or buprenorphine in comparison to young adults. This may be due to their increased safety profile and beliefs that they are less likely to be diverted to the illicit drug market. In addition to age-based differences in MOUD access, my review also identified criminal justice involvement, geographic and population-density, racial or ethnic identity-based, socioeconomic and educational, and sex-based factors associated with MOUD access. Potential opportunities to improve access to MOUD among AYA include improving the range of MOUD available, reducing stigma towards AYA who use drugs, and training prescribers to provide patient-centred, culturally safe, and trauma-informed care. 163 Chapter 3 sought to examine OAT initiation, as well as the before and after substance use and other patterns, among AYA. This involved examining sociodemographic-, substance use-, healthcare-, social service-, and criminal justice-related factors associated with time to OAT initiation, as well as the before and after substance use, service utilization, homelessness, and criminal justice patterns between AYA who did and did not initiate OAT. Findings demonstrated that participants retained in OAT demonstrates significant reductions in daily illicit opioid use when compared to matched controls who did not access OAT. However, no other statistically significant improvements in before and after patterns were observed between AYA who accessed OAT and matched controls who did not access OAT, underscoring the importance of providing additional resources and supports – including housing, education, employment, among others – alongside OAT and other treatments to improve AYAs’ experiences and outcomes. Chapter 4 examined initial interest in using buprenorphine-naloxone and factors associated with becoming interested over time. A total of 60 (13.4%) AYA reported initial buprenorphine-naloxone interest, while 85 (19.0%) AYA who were initially disinterested in buprenorphine-naloxone reported buprenorphine-naloxone interest or enrolment over follow-up. Initial buprenorphine-naloxone willingness was found to be positively associated with weekly heroin or fentanyl use; however, AYA who self-reported Indigenous identity, or other racial or ethnic identities, were less likely to report initial buprenorphine-naloxone interest. In Cox regression analysis, later study follow-up period was found to be negatively associated with time to buprenorphine-naloxone interest or enrolment, while ever accessing MMT, recent weekly heroin or fentanyl use, and having a high school education were positively associated with buprenorphine-naloxone interest. Study finding highlight the importance of increasing awareness about 164 buprenorphine-naloxone; expanding micro-dosing induction services; and ensuring that buprenorphine-naloxone and associated treatment services are culturally safe. Chapter 5 investigated factors associated with time to MMT discontinuation among AYA who initiated MMT over the study period, while a sub-analysis examined factors associated with time to ‘actionable’ MMT discontinuation that could be addressed through policy or guideline changes. Findings demonstrated that weekly crystal methamphetamine was positively associated with any MMT discontinuation, while female AYA and older age of first ‘hard’ drug use were negatively associated with any MMT discontinuation. In sub-analysis, recent weekly heroin or fentanyl use and weekly crystal methamphetamine use were positively associated with time to ‘actionable’ MMT discontinuation, while older age was negatively associated with time to ‘actionable’ MMT discontinuation. Findings demonstrated that MMT discontinuation is common among new AYA MMT initiators, which is concerning in the context of the toxic drug crisis. Study findings support the need to revise MMT programming and reduce barriers to retention including providing access to a broader range of MMT, harm reduction, and treatment services; exploring the co-prescription of stimulants alongside MMT; and revising clinical guidelines to provide more flexibility around missed doses and take-home dosing. Chapter 6 explored the perspectives and experiences of AYA as they navigated OAT services in the study setting. More specifically, this study sought to understand periods of OAT engagement, disengagement, and avoidance to elucidate ways to reduce the barriers and challenges experienced by AYA and improve clinical guidelines. Findings demonstrated that AYA experienced pressure from providers and family members to initiate buprenorphine-naloxone, despite their desire to 165 explore other treatment options and approaches. Additionally, AYA contemplating OAT expressed fears about its addictiveness and their inability to cease OAT in the future. Once AYA initiated OAT, staying on it was complicated by daily witnessed dosing requirements and strict rules around repeated missed doses; however, many AYA envisioned tapering off OAT in the not-too-distant future. Nevertheless, findings underscore the importance of working collaboratively with AYA to develop treatment plans and timelines that meet their unique needs and goals. Additionally, evidence from this dissertation suggests that OAT engagement and retention could be improved by expanding access to the full range of OAT. This also includes updating clinical guidelines to incorporate interim RMG introduced during the COVID-19 pandemic, which sought to promote physical distancing and reduce toxic drug poisonings and deaths by providing safer alternatives to the illicit drug supply. Addressing treatment gaps arising from missed doses and take-home dosing, providing a clear pathway to OAT tapering for AYA, and ensuring that AYA have access to a range of resources and supports alongside OAT – including housing, education, employment, among other supports – may improve AYAs’ perspectives on and experiences with OAT. 7.2 Overall contribution to the literature on OAT among AYA This dissertation addresses important knowledge gaps around AYAs’ access to, engagement in, and discontinuation of OAT within the study setting. Given the ongoing impacts of the toxic drug crisis, where AYA account for approximately 19% of toxic drug fatalities,9 these results are timely and seek to address concerning and problematic treatment gaps that may be contributing to 166 preventable harms. This included the examination of OAT access among AYA, which was elucidated through the systematic review of factors associated with MOUD access (Chapter 2) that identified a series of demographic and socio-structural factors associated with MOUD access. More specifically, findings from this systematic review added to suggestions that AYA were less likely to access or receive MOUD in comparison to adult populations, and that adolescents were more likely to be prescribed partial opioid agonist and opioid antagonist treatments that have a ceiling effect and typically block the effects of illicit, exogenous opioids.26 Another unique contribution of this dissertation is the examination of the before and after substance use and socio-structural patterns between AYA who initiated OAT and AYA who did not (Chapter 3), which contributes to calls for higher quality evidence examining MOUD access and associated outcomes among AYA.27, 85, 98 By employing a quasi-experimental study design, this analysis sought to address existing knowledge gaps and provided insight into the effectiveness of OAT in the study setting, demonstrating reductions in daily illicit opioid use among AYA who were retained in OAT in comparison to AYA who did not access OAT. This finding is demonstrative of the utility of OAT in reducing frequent substance use and in turn AYAs’ reliance on the illicit drug supply; however, the absence of positive changes in other substance use patterns or socio-structural factors suggest that OAT alone may be insufficient in addressing AYAs’ overall needs. This emphasizes the importance of ensuring AYA have access to a continuum of harm reduction and treatment supports, and that other socioeconomic supports – such as housing, education, employment, among others – are readily accessible. 167 Previous literature has speculated that the observed discrepancies in MOUD access between AYA and adult populations may be due to prescribers’ reluctance to provide these treatments to AYA due to concerns they may be ‘enabling’ substance use or that they are ineffective at supporting AYA in their treatment goals.138-140 However, findings from the analysis examining interest in buprenorphine-naloxone (Chapter 4) add to existing literature by suggesting an interplay between AYAs’ experiences accessing healthcare as well as practical challenge to initiating treatment. For example, the negative association between self-reported Indigenous identity, other racial or ethnic identities, and initial buprenorphine-naloxone interest suggests that experiences of racism or discrimination play an important role in OAT interest and access.204 This is elucidated by the In Plain Sight Report, which found rampant anti-Indigenous racism throughout British Columbia’s health care system that has negatively impacted trust and willingness to engage in health care services.204 Hence, high levels of discrimination against Indigenous peoples, as well as AYA who self-report other racial or ethnic identities, may have contributed to an aversion towards healthcare and an avoidance of OAT altogether. Adding to this, it has been posited that a strong emphasis on the prescription of buprenorphine-naloxone upon its introduction in British Columbia, and especially to AYA, may have contributed to the lower treatment willingness observed among Indigenous AYA and AYA who self-reported other racial or ethnic identities in this dissertation.25 In the context of the ongoing impacts of colonization and the complicity of medical and research institutions in colonial violence,268-272 the push to prescribe buprenorphine-naloxone can become yet another instance of the intertwining of care and control in relation to Indigenous AYA.25 This interpretation is reinforced by recent qualitative research from three cities across British Columbia, including Vancouver, where 168 Indigenous AYA shared that they felt overmedicalized within existing treatment services that did little to help them improve their mental, emotional, and spiritual health.47 Hence, Indigenous-specific and culturally safe approaches to substance use treatment, including in the provision of OAT, are needed to ensure that Indigenous AYA feel safe when accessing treatments for opioid use. To address this, efforts to reduce the sense of surveillance and monitoring (e.g., reducing people to their files) – which is often associated with colonial institutions (e.g., the child welfare system) – may signal safety to Indigenous AYA and improve their trust in and willingness to access and engage in OAT and other treatment, health care and social services.47 This dissertation also sought to understand factors associated with MMT discontinuation among AYA (Chapter 5), which is a significant knowledge gap given most research on OAT retention among AYA is specific to buprenorphine-naloxone. The association between crystal methamphetamine use and MMT discontinuation among AYA aligns with previous qualitative evidence that AYA may be using crystal methamphetamine to taper off of both licit (e.g., MMT) and illicit (e.g., heroin and fentanyl) opioids,24 as well as research demonstrating that AYA are more likely to report polysubstance use in comparison to adult populations.72 Findings reinforce the importance of employing patient-centered, trauma-informed approaches in treatment programming in order to reduce the potential for MMT discontinuation. This could include ensuring that AYA have access socioeconomic supports – such as housing, education, employment, among others – as well as ensuring that AYA have access to a broad range of OAT and can access or transition to the OAT they prefer. Discussing tapering approaches and protocols with AYA at the onset of their treatment initiation is also important, and AYA should have final decision-making authority over their treatment plan and programming. 169 Additionally, the association between MMT discontinuation and crystal methamphetamine use suggests that co-prescribing stimulants alongside OAT, which is supported within existing treatment guidelines in the study setting,26 may address potential concurrent, untreated stimulant use disorder. This may be particularly true for AYA with OUD who have undiagnosed Attention Deficit Hyperactivity Disorder, who are seeking the euphoric effects of stimulants to counteract the effects of OAT, or who had previously reported polysubstance use. Another contribution from this dissertation is the exploratory examination of ‘actionable’ MMT discontinuation that could be addressed through policy or guideline changes, which found an emerging relationship between MMT discontinuation and non-pharmacological treatment access. This illustrates the need for further research into the association between non-pharmacological treatment access and OAT discontinuation more broadly, as well as examining the potential for protections to ensure that AYA are not prematurely removed from OAT. Qualitative results from this dissertation also support previous findings on the importance of providing additional health, housing and social supports alongside OAT given that many AYA struggled to remain engaged in OAT while navigating street-involvement (Chapter 6). Some AYA were dissuaded or unable to access OAT due to strict clinical guidelines and OAT program requirements, such as required daily witnessed dispensation, limits on take-home doses, and prohibitive re-initiation protocols for AYA who missed OAT doses. In the context of the everyday emergencies of poverty, homelessness, and unstable housing, AYA found navigating these OAT program requirements difficult, which contributed to distrust in the effectiveness of existing treatments. This is supported by a scoping review that identified what constitutes youth-centered 170 mental health and substance use treatment programming,273 emphasizing the importance of providing a wide range of supports and resources to AYA to engage them more effectively in care. Additionally, there are several reported barriers to OAT engagement that were identified that require attention. For example, AYA seeking to initiate buprenorphine-naloxone are typically required to remain abstinent from all opioids prior to initiating buprenorphine-naloxone, and so micro-dosing induction has the potential to reduce induction-related barriers to buprenorphine-naloxone. For MMT, recommended initiation doses within existing clinical guidelines were deemed too low and ineffective for some AYA, especially in the presence of fentanyl and other highly potent opioid analogues. This also applies in instances where AYA missed consecutive doses and are required to re-initiate OAT at a lower dose, which may explain the high levels of MMT discontinuation observed in Chapter 5. Lastly, findings of undue pressure – and their impacts on OAT initiation, retention, and tapering – emphasize the importance of respecting and fostering AYAs’ self-determination and autonomy in their treatment decision-making. 7.3 Policy implications and recommendations There are several policy implications from this dissertation that suggest ways that OAT programming can be improved to meet the needs of AYA. Findings complement previous research outlining the challenges and barriers that many AYA experience when attempting to access, engage in, and taper off of OAT, and are demonstrative of ways that health policy may impact OAT engagement and AYAs’ health and well-being. Specific recommendations on ways to improve OAT programming are outlined in the discussion sections of Chapters 2-6, pointing to 171 the need to identify and implement innovative approaches to reducing barriers to OAT engagement. Potential solutions incorporating RMG within existing clinical guidelines, as well as investing in a broad range of harm reduction and treatment supports alongside OAT that acknowledge the unique treatment needs and goals of AYA. Firstly, quantitative findings demonstrate a need to consider the impact of the increasingly toxic drug supply on AYAs’ OAT experiences. For example, findings from this dissertation on the negative association between later follow-up period and buprenorphine-naloxone interest or enrolment suggest there is waning interest in buprenorphine-naloxone among AYA. This complements a recent population-level study from British Columbia that found that between January 1, 2008 and September 2018, those under the age of 40 were significantly less likely to successfully complete buprenorphine-naloxone induction in comparison to those age 40 years and older despite evidence that the odds of completing buprenorphine-naloxone induction increased during this period.274 Considering concerns that buprenorphine-naloxone may be less effective in the context of the increasingly toxic drug supply,216, 275 it may be necessary to review clinical guidelines and whether buprenorphine-naloxone should still be listed as a first line treatment for OUD among AYA. Another explanation for the low interest in buprenorphine-naloxone that has been described previously is the required abstinence from illicit and licit opioids prior to buprenorphine-naloxone induction, which is associated with a significant increase in toxic drug poisoning risk.69, 209 One approach that has been implemented to address this challenge us the use of a buprenorphine-naloxone micro-dosing induction technique, where AYA are concurrently provided prescription 172 opioids alongside buprenorphine-naloxone and then titrated to an adequate buprenorphine-naloxone while being tapered off of prescription opioids.193 Also referred to as the ‘Bernese method’,37 this technique avoids the need for abstinence from opioids and also prevents precipitated withdrawal symptoms, which may be more favorable to AYA.36, 37, 206 Nevertheless, it is more time-consuming process given that patients are titrated to an effective dose over a comparatively longer duration of time, though there are several treatment settings where these approaches may be effectively implemented (e.g., detoxification programs, in-patient settings).210 For MMT, quantitative findings point to high levels of treatment discontinuation, while qualitative findings highlighted the challenges that many AYA experienced around witnessed dispensation, securing take-home doses, and navigating missed dose protocols. For example, daily witnessed dispensation proved challenging for AYA at various points along the treatment continuum – ranging from AYA who had initially enrolled in OAT while still navigating street-involvement to AYA who were employed but experienced challenges in receiving their dose due to limited pharmacy hours. Adding to this, AYA who miss three consecutive doses required to re-initiate OAT at the recommended starting induction dose,66 which may be impractical for AYA who missed their doses because they were using fentanyl or other opioid analogues and subsequently prevent AYA from considering OAT. To address this, there have been recommendations to provide greater flexibility around take-home dosing to alleviate the burden of daily witnessed dispensation required for many OAT.183 While this is permitted within existing clinical guidelines for buprenorphine-naloxone, which has an improved safety profile in comparison to other OAT,66 the increasing toxicity of the illicit drug 173 supply warrants the expansion of take-home dosing for wider range of OAT for AYA. Evidence from Crosstown Clinic, North America’s first injectable OAT program, has demonstrated the feasibility of this approach, where the allowable missed dose period was extended from 3 to 10 days.265 As noted, rapid urine drug testing to accounting for patients’ self-reported illicit drug use patterns, frequency, and street-sourced drug expenditures can be used as diagnostic criteria to optimize dosage levels upon treatment initiation or re-initiation.66, 238, 265 To date, evidence has demonstrated that the increased flexibility in take-home dosing during the COVID-19 pandemic was safe, effective, and improved treatment retention for a range of OAT.183, 276-278 Additionally, findings support revising clinical guidelines to recommend that prescribers’ work alongside AYA who have missed their MMT doses to identify an optimal re-initiation dose. This can include employing a range of diagnostic criteria – from rapid urine drug testing to accounting for patients’ self-reported illicit drug use patterns, frequency, and expenditures – to identify an optimal dosage upon treatment initiation or re-initiation.66, 238, 265 Alternatively, another approach that has been employed in Vancouver, Canada to support an easier transition to MMT while also ensuring people do not have to source opioids from the illicit drug supply includes the use of a rapid MMT induction technique, which involves co-prescribing oral morphine and hydromorphone tablets alongside MMT until a therapeutic MMT dose is achieved.264 This approach can be effective at reducing cravings while also preventing withdrawal symptoms, and has been successfully tested and demonstrated promising results.264 More broadly, the existing OAT gaps and barriers elucidated through this dissertation suggest the need to update and revise clinical guidelines to reflect the context of the increasingly toxic drug 174 supply. One approach with the potential to reducing challenges to OAT retention includes incorporating the interim RMG into clinical guidelines, which is supported by a qualitative finding from this dissertation that RMG supported OAT retention. This complements recent evidence on the effectiveness of RMG at improving health outcomes among people who were quarantining in COVID-19 isolation hotels, though any future changes should reflect recommendations for higher dosing levels that were identified.67 Updated clinical guidelines could also provide guidance on how to pursue shared decision-making processes with AYA that consider the types, frequency, patterns, and routes of opioid use when initiating OAT; the supports they needs to remain engaged in OAT and to realize their treatment goals; and their preferences and expectations around discontinuing or tapering off of OAT when and if they are prepared to do so.85, 177-179 Lastly, updated clinical guidelines must expand OAT access to younger adolescents, many of whom experience unique challenges in relation to older adolescents and young adults when accessing health and social services.47 Additionally, qualitative findings emphasize the importance of respecting AYAs’ autonomy and independence in relation to their treatment decision-making, and that perceived or real pressure or coercion may deter interest or engagement in OAT. This aligns with previous literature that has suggested that stringent requirements around OAT dispensation, such as the daily witnessed dispensation required for MMT, constitutes a form of social control that acts to deter people from accessing and engaging in OAT.279 While care is always to some extent a form of control, it is possible to meaningfully include AYA with lived and living experience in the planning, design, and delivery of substance use and mental health services through a patient-centered approach,273 and policy makers should continue to engage AYA to understand their diverse needs and identify 175 how to effectively deconstruct health policy barriers to OAT. This includes ensuring that the voices of racialized, gender diverse and lesbian, gay, bisexual, transgender, queer or questioning, intersexual, asexual, and Two-Spirit (LGBTQQIA2S+), dis/abled, and other underrepresented AYA are heard, and that policy approaches are reflective of the unique intersections that many AYA with OUD occupy. Similarly, it is also critical that efforts be made to address anti-Indigenous racism within OAT programming, which this dissertation found to be negatively associated with being interested in accessing buprenorphine-naloxone. As described in In Plain Sight: Addressing Anti-Indigenous Racism within B.C. Health Care,204 there is an urgent need to address ongoing interpersonal and systemic anti-Indigenous racism within mental health and substance use services, including OAT. For example, the In Plain Sight Report calls for the engagement of First Nations, Inuit, and Métis peoples in substance use treatment program design and implementation, emphasizing the importance of focusing specifically on Indigenous AYA.204 This also includes respecting and incorporating traditional medicines, Indigenous ways of knowing, and cultural activities into mental health and substance use programming, which is something that Indigenous AYA have reported they would value within treatment programming.144 The In Plain Sight Report also notes the importance of measuring, evaluating, and monitoring the implementation and expansion of such programming through meaningful engagement with Indigenous communities.204 Dissertation findings also support evidence on the potential harms of overmedicalizing and pathologizing approaches in substance use treatment, perhaps particularly among Indigenous AYA. More specifically, previous qualitative evidence among AYA in Vancouver, Canada and 176 British Columbia have suggested that an overemphasis on OAT within treatment policies and programming has had a deterring effect on AYA.24, 47 This may explain the low levels of buprenorphine-naloxone interest and high levels of MMT discontinuation observed within this dissertation, which is concerning given the known effectiveness of these medications. To address this, AYA with lived and living experience must be engaged to understand the types of AYA-specific treatments, services, and supports needed, and effort must be made to expand access to socioeconomic supports like housing, education, employment, among others. Despite the aforementioned recommendations, quantitative and qualitative findings from this dissertation indicate that OAT alone may be insufficient to meet AYAs’ treatment needs and goals. For example, while reductions in daily illicit opioid use were observed among AYA who were retained on OAT, the absence of reductions across other substance use and patterns is concerning and complements previous qualitative research among AYA in Vancouver, Canada that found high levels of ambivalence towards OAT.24, 25 Therefore, it is important to recognize the need to expand access to a range of harm reduction and treatment supports alongside OAT for AYA, in addition to ensuring that AYA have access to housing, education, employment, and other socioeconomic supports and resources. 7.4 Study strengths and limitations There are several strengths to this dissertation that are worth noting. Firstly, this dissertation used data from a large, prospective, longitudinal cohort of street-involved youth. This allowed for the use of high-quality study designs, including quasi-experimental methods and multivariable 177 analyses, in turn responding to calls for higher quality evidence into the treatment experiences of AYA.27, 85, 98 Additionally, this dissertation qualitatively explored how AYA navigate OAT programming, offering a more nuanced understanding of the complexities that were identified in the empirical chapters of this dissertation as well as ways that clinical treatment guidelines may be improved to address AYAs’ treatment needs. Lastly, this dissertation is solely focused on the experiences of AYA, which is a largely neglected population within existing discourse around substance use and OAT. Hence, by examining the use of OAT within this population, this dissertation has provided insight into potential ways to update OAT programming to improve AYAs’ treatment experiences and outcomes. Despite these strengths, there are several methodological limitations to this dissertation aside from specific limitations listed in Chapters 2-6. As ARYS is a non-randomized cohort study, recruitment is not random and therefore this research cannot be generalized to other populations of AYA who use drugs, nor to general AYA populations. Nevertheless, significant efforts to recruit a diversity of street-involved AYA, including through the employment of peers and the use of street-based outreach, sought to increase the representativeness of the study sample. Additionally, quantitative analyses of this dissertation were conducted up until the introduction of the youth-specific clinical treatment guidelines for OUD,26 and therefore did not directly assess these clinical guidelines nor RMG. However, the qualitative analysis did explore AYAs’ perspectives and experiences with OAT after the implementation of these clinical guidelines26 and RMG,66 in turn providing some insight into the impacts of the clinical guidelines and RMG on how AYA navigated OAT. Lastly, the ARYS cohort primarily consists of young adults, and while the perspectives of adolescents 178 were captured in the qualitative analysis of this dissertation, these findings may be less generalizable to adolescent populations. Furthermore, cohort data is self-reported, which introduces potential social desirability and recall bias. For example, social desirability bias could arise when participants are being asked to disclose sensitive or illegal activities, which could have resulted in participants’ underreporting substance use, treatment access, or other activities. This could also have led to the exclusion of some participants who may have met study inclusion criteria, or it could have influenced study results. For example, the underreporting of opioid use in the before and after OAT analysis could impact whether participants contributed to the case or control trio groups and therefore the observed improvements in substance use or other patterns. Nevertheless, evidence derived from people who use drugs suggests that self-reported data is credible and reliable280 and the study instrument is constructed in a way to allow interviewees to build rapport with participants. This is done by reserving sensitive or difficult questions for the end of the questionnaire to address potential social desirability bias that could arise from asking sensitive questions at the onset of the interview. Additionally, a study nurse with expertise in conducting health assessments and serological testing asks sensitive health-related questions, as opposed to a study interviewer that is not well equipped to ask such questions. Additionally, participants could also have difficulty in recalling specific past events, such as their treatment engagement patterns over the past six months. To address this, interviewers employed memory recall tools, such as calendars and follow-up prompts, to help participants remember specific events. 179 Next, while the risk environment74 and patient-centered health care accessibility75 frameworks guided these dissertation analyses, the variables available for the analyses were limited to those collected in the ARYS questionnaires. Therefore, I may not have been able to examine all dimensions of these conceptual frameworks. For example, this dissertation was unable to discern the impact of economic factors on treatment accessibility because there were no questions that asked participants’ whether their economic status has impacted their ability to engage in treatment. As a result, important factors that may impact AYAs’ OAT experiences may have been excluded and missed in this dissertation. Similarly, this dissertation was unable to discern how accommodating treatment services were as there were no questions that examine participants’ degree of comfort when engaging in OAT programming. This is an important consideration given that treatment satisfaction at discharge is associated with positive long-term outcomes, including among people accessing OAT.281 Despite this limitation, findings from the qualitative analysis of this dissertation provide insights into barriers to OAT and attempt to better understand factors that improve or worsen satisfaction with OAT programming. Lastly, gender was not examined in this dissertation due to inconsistencies in the way that the variable was collected over the study period. This is an important limitation given that gender is an important social determinant of health, even more so than sex.282 Therefore, the unique experiences of gender-diverse AYA are largely absent from this dissertation, though efforts were made to bring their voices and experiences forward in the qualitative analysis of this dissertation. 180 7.5 Recommendations for future research There are several future areas identified by this dissertation that are deserving of future research attention. Firstly, the identified negative associations between self-reported Indigenous identity, racial or ethnic identity and MOUD access or buprenorphine-naloxone interest is concerning and aligns with recent calls for the integration of Indigenous cultural safety and anti-racism education throughout the health care system.204 While evidence among Indigenous AYA has demonstrated a favorability and desire for culturally safe treatment,144 there is limited research examining the implementation of such programs in the context of OAT. For this reason, future research seeking to understand ways that OAT programming could be made culturally safe is important to addressing discrepancies in treatment access among AYA who self-report Indigenous, or other racial or ethnic identity. Additionally, there is a need to gain better insight into the OAT experiences and perspectives of gender diverse and LGBTQIA2S+ AYA.283, 284 Given known prejudice and discrimination experienced by this population within the health care system,285 future research seeking to elucidate the degree of engagement of this population with OAT programming, their treatment outcomes, as well as ways that OAT programming can be tailored to their needs may provide better insight into existing treatment gaps and ways they may be addressed. While this dissertation examined sex-based differences in the empirical analyses due to the way the variable was collected over the study period, gender is an important social determinant of health 181 that typically has a greater impact on treatment experiences in comparison to biological sex.282 Therefore, future research should similarly attempt to understand the OAT experiences and perspectives of AYA based on gender identify as opposed to sex. This includes disaggregating gender variables whenever possible in order to gain insight into the unique perspectives and experiences of gender diverse AYA, as recommended in the Disaggregated demographic data collection in British Columbia: The grandmother’s perspective Report authored by British Columbia’s Office of the Human Rights Commissioner.286 Although this dissertation identified the need to provide AYA with realistic and transparent tapering strategies, there is an absence of literature examining long-term OAT utilization and ways to support tapering off of OAT for AYA. For some people, long-term OAT is a necessary and essential component to their recovery and ceasing OAT may not be a realistic goal.287 However, many AYA have reported that they do not envision OAT as part of their long-term recovery,24 and so there is a need to better understand how to identify when AYA are prepared to taper off of OAT and what approaches are safe, effective, and respectful of AYAs’ needs and wishes. There is also limited evidence on the combination of health, treatment, and social supports that would be beneficial to provide AYA alongside OAT to improve health outcomes while reducing harms.98 Within the study setting, a mix of private and public treatment services and providers may pose additional barriers to AYA seeking treatments and supports, suggesting the need for alternative policy approaches around the provision of substance use disorder treatment. Hence, future research seeking to identify common treatment pathways for AYA may be important to understand the treatment continuum for AYA who use opioids, and it may also be beneficial to 182 explore whether the increased regulation and coordination of treatment services results in improved treatment outcomes. Lastly, this dissertation identified gaps within existing treatment guidelines that require further research attention, especially in the context of an increasingly toxic drug supply. More specifically, several barriers to OAT access, induction, continuation, and discontinuation were identified, demonstrating the importance of formalizing and integrating interim RMG66 into existing clinical guidelines,66 as well as updating clinical guidelines to reduce barriers to OAT engagement and retention identified in this dissertation. Hence, future research on the application of update guidelines in community settings could be beneficial at reducing harms and more effectively engaging AYA in care. 7.6 Knowledge translation plan There are several ways that findings from this dissertation will be mobilized to precipitate change in the OAT experiences of AYA with OUD. Firstly, this work was conducted in collaboration with healthcare decision-makers and clinicians at Vancouver Coastal Health (VCH), which is the health authority that encompasses the region where this research was conducted. This partnership ensured that research results and interpretations accounted for the clinical experiences of study collaborators, while allowing for the sharing of findings with those in leadership positions at VCH. Secondly, through my role as the Research and Policy Lead with the Indigenous Health department at VCH, these findings are being mobilized internally and elevated within the Mental Health and Substance Use team. This is particularly relevant in the context of improving cultural safety within 183 OAT treatment programming, and findings will inform the expansion of Indigenous-specific and -designed interventions to reduce harms among Indigenous AYA in the study setting. Lastly, findings are also being mobilized through conventional academic routes, including through publishing findings in scientific journals and by presenting findings at relevant national and international conferences, with the intent of highlighting the importance of improving treatment guidelines and policies based on the lived and living experience of AYA with OUD. 7.7 Conclusions The purpose of this dissertation was to provide insight into the OAT experiences and outcomes of AYA, which is in response to limited evidence on OAT among AYA and considering calls for higher quality evidence on this topic.27, 85, 98 Given existing knowledge gaps, this dissertation employed a range of study designs to gain a more nuanced understanding of AYAs’ perspectives and experiences on OAT, demonstrating that AYA recognize OAT as one of many interventions and stages in their treatment journey. Adding to this, findings indicate that OAT alone may be ineffective at supporting the cessation of illicit drug use among AYA, emphasizing the importance of providing additional health and social services and supports to AYA alongside OAT. Furthermore, findings demonstrate that interest in certain OAT, such as buprenorphine-naloxone, was low and decreased over time despite it being listed as a first-line treatment for AYA. This, coupled with high levels of MMT discontinuation observed in this dissertation, suggests the need to provide access to a broader range of OAT (e.g., slow-release oral morphine, diacetylmorphine, fentanyl), especially in the context of the toxic drug supply crisis, and improving access to essential socioeconomic supports, like housing, education, and employment, among others. 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Thesis/Dissertation
eng
Interdisciplinary Studies
Vancouver : University of British Columbia Library
Attribution-NonCommercial-NoDerivatives 4.0 International
Graduate
Buxton, Jane A.
DeBeck, Kora
Medications for opioid use disorder among young people : evidence to improve treatment experiences and outcomes in Vancouver, Canada
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