Comparative Analysis of Instrumental Variables on the Assignment of Buprenorphine/Naloxone or Methadone for the Treatment of Opioid Use Disorder.

BACKGROUND: Instrumental variable (IV) analysis provides an alternative set of identification assumptions in the presence of uncontrolled confounding when attempting to estimate causal effects. Our objective was to evaluate the suitability of measures of prescriber preference and calendar time as potential IVs to evaluate the comparative effectiveness of buprenorphine/naloxone versus methadone for treatment of opioid use disorder (OUD). METHODS: Using linked population-level health administrative data, we constructed five IVs: prescribing preference at the individual, facility, and region levels (continuous and categorical variables), calendar time, and a binary prescriber's preference IV in analyzing the treatment assignment-treatment discontinuation association using both incident-user and prevalent-new-user designs. Using published guidelines, we assessed and compared each IV according to the four assumptions for IVs, employing both empirical assessment and content expertise. We evaluated the robustness of results using sensitivity analyses. RESULTS: The study sample included 35,904 incident users (43.3% on buprenorphine/naloxone) initiated on opioid agonist treatment by 1585 prescribers during the study period. While all candidate IVs were strong (A1) according to conventional criteria, by expert opinion, we found no evidence against assumptions of exclusion (A2), independence (A3), monotonicity (A4a), and homogeneity (A4b) for prescribing preference-based IV. Some criteria were violated for the calendar time-based IV. We determined that preference in provider-level prescribing, measured on a continuous scale, was the most suitable IV for comparative effectiveness of buprenorphine/naloxone and methadone for the treatment of OUD. CONCLUSIONS: Our results suggest that prescriber's preference measures are suitable IVs in comparative effectiveness studies of treatment for OUD.

Buprenorphine/Naloxone vs Methadone for the Treatment of Opioid Use Disorder.

Importance: Previous studies on the comparative effectiveness between buprenorphine and methadone provided limited evidence on differences in treatment effects across key subgroups and were drawn from populations who use primarily heroin or prescription opioids, although fentanyl use is increasing across North America. Objective: To assess the risk of treatment discontinuation and mortality among individuals receiving buprenorphine/naloxone vs methadone for the treatment of opioid use disorder. Design, Setting, and Participants: Population-based retrospective cohort study using linked health administrative databases in British Columbia, Canada. The study included treatment recipients between January 1, 2010, and March 17, 2020, who were 18 years or older and not incarcerated, pregnant, or receiving palliative cancer care at initiation. Exposures: Receipt of buprenorphine/naloxone or methadone among incident (first-time) users and prevalent new users (including first and subsequent treatment attempts). Main Outcomes and Measures: Hazard ratios (HRs) with 95% compatibility (confidence) intervals were estimated for treatment discontinuation (lasting ≥5 days for methadone and ≥6 days for buprenorphine/naloxone) and all-cause mortality within 24 months using discrete-time survival models for comparisons of medications as assigned at initiation regardless of treatment adherence ("initiator") and received according to dosing guidelines (approximating per-protocol analysis). Results: A total of 30 891 incident users (39% receiving buprenorphine/naloxone; 66% male; median age, 33 [25th-75th, 26-43] years) were included in the initiator analysis and 25 614 in the per-protocol analysis. Incident users of buprenorphine/naloxone had a higher risk of treatment discontinuation compared with methadone in initiator analyses (88.8% vs 81.5% discontinued at 24 months; adjusted HR, 1.58 [95% CI, 1.53-1.63]), with limited change in estimates when evaluated at optimal dose in per-protocol analysis (42.1% vs 30.7%; adjusted HR, 1.67 [95% CI, 1.58-1.76]). Per-protocol analyses of mortality while receiving treatment exhibited ambiguous results among incident users (0.08% vs 0.13% mortality at 24 months; adjusted HR, 0.57 [95% CI, 0.24-1.35]) and among prevalent users (0.08% vs 0.09%; adjusted HR, 0.97 [95% CI, 0.54-1.73]). Results were consistent after the introduction of fentanyl and across patient subgroups and sensitivity analyses. Conclusions and Relevance: Receipt of methadone was associated with a lower risk of treatment discontinuation compared with buprenorphine/naloxone. The risk of mortality while receiving treatment was similar for buprenorphine/naloxone and methadone, although the CI estimate for the hazard ratio was wide.

Prescribing practices in opioid agonist treatment and changes in compliance to clinical dosing guidelines in British Columbia, Canada.

BACKGROUND AND AIM: In British Columbia, Canada, clinical guidelines for the treatment of opioid use disorders (OUD) were updated in 2017, during a period in which the potency and composition of the illicit drug supply changed rapidly. We aimed to describe changes in opioid agonist treatment (OAT) prescribing practices at the population level in a setting in which fentanyl and its analogs have become the primary illicit opioid of use. DESIGN, SETTING AND PARTICIPANTS: This was a population-based retrospective cohort study using three linked health administrative databases in British Columbia (BC), Canada. All individuals with at least one OAT dispensation in BC between 1 January 2014 and 31 August 2021 took part. MEASUREMENTS: To assess changes in OAT prescribing practices over time, we calculated initiation doses, dose titration intervals, maintenance doses and take-home dosing intervals stratified by medication [methadone, buprenorphine-naloxone and slow-release oral morphine (SROM)] according to recommended guidelines. FINDINGS: A total of 265 410 OAT episodes (57.5% on methadone, 34.5% on buprenorphine-naloxone and 8.0% on SROM) were initiated during the study period. Compared with the guideline recommendation, observed initiation doses were higher among all medications from 2014 (2017 for SROM) to 2021 (buprenorphine-naloxone: 14-29%; methadone: 53-66%; SROM: 26-55%). Titration intervals were shorter for all medications, consistent with guidelines for buprenorphine-naloxone (26-49%), but shorter than recommended for methadone or SROM (28-51% and 12-41%, respectively). Higher maintenance dosing was observed for methadone (68-78%) and SROM (3-21%). Take-home allowances extending beyond the recommended guideline length increased across medications (buprenorphine-naloxone: 18-35%; methadone: 50-64%; SROM: 34-39%). Changes in prescribing patterns were similar for first-time OAT initiators. CONCLUSION: In British Columbia, Canada, from 2014 to 2021, prescribers of opioid agonist treatment (OAT) appeared to initiate both new and experienced OAT clients at higher doses than guideline recommendations, titrate them more rapidly and maintain clients at higher doses. Take-home dose allowances also gradually increased.

Influence of physician networks on the implementation of pharmaceutical alternatives to a toxic drug supply in British Columbia.

BACKGROUND: Characterizing the diffusion of adopted changes in policy and clinical practice can inform enhanced implementation strategies to ensure prompt uptake in public health emergencies and other rapidly evolving disease areas. A novel guidance document was introduced at the onset of the COVID-19 pandemic in British Columbia (BC), Canada, which supported clinicians to prescribe opioids, stimulants, and benzodiazepines. We aimed to determine the extent to which uptake and discontinuation of an initial attempt at a prescribed safer supply (PSS) program were influenced through networks of prescribers. METHODS: We executed a retrospective population-based study using linked health administrative data that captured all clinicians who prescribed to at least one client with a substance use disorder from March 27, 2020, to August 31, 2021. Our main exposure was the prescribing patterns of an individuals' peers, defined as the proportion of a prescribers' professional network (based on shared clients), which had previously prescribed PSS, updated monthly. The primary outcome measured whether a clinician had prescribed their initial PSS prescription during a given calendar month. The secondary outcome was the discontinuation of PSS prescribing, defined as an absence for PSS prescriptions for at least 3 months. We estimated logistic regression models using generalized estimated equations on monthly repeated measurements to determine and characterize the extent to which peer networks influenced the initiation and discontinuation of PSS prescribing, controlling for network, clinician, and caseload characteristics. Innovators were defined as individuals initiating PSS prior to May 2020, and early adopters were individuals initiating PSS after. RESULTS: Among 14,137 prescribers treating clients with substance use disorder, there were 228 innovators of prescribed safer supply and 1062 early adopters through the end of study follow-up, but 653 (50.6%) were no longer prescribing by August 2021. Prescribers with over 20% of peers whom had adopted PSS had a nearly fourfold higher adjusted odds of PSS prescribing themselves (aOR: 3.79, 95% CI: (3.15, 4.56)), compared to those with no connected safer supply prescribers. CONCLUSIONS: The uptake of PSS in BC was highly dependent on the behavior of prescribers' peer networks. Future implementation strategies to support PSS or other policies would benefit from leveraging networks of prescribers.

Receipt of Opioid Agonist Treatment in provincial correctional facilities in British Columbia is associated with a reduced hazard of nonfatal overdose in the month following release.

BACKGROUND: In many jurisdictions, policies restrict access to Opioid Agonist Treatment (OAT) in correctional facilities. Receipt of OAT during incarceration is associated with reduced risk of fatal overdose after release but little is known about the effect on nonfatal overdose. This study aimed to examine the association between OAT use during incarceration and nonfatal overdose in the 30 days following release. METHODS AND FINDINGS: Using linked administrative healthcare and corrections data for a random sample of 20% of residents of British Columbia, Canada we examined releases from provincial correctional facilities between January 1, 2015 -December 1, 2018, among adults (aged 18 or older at the time of release) with Opioid Use Disorder. We fit Andersen-Gill models to examine the association between receipt of OAT in custody and the hazard of nonfatal following release. We conducted secondary analyses to examine the association among people continuing treatment initiated prior to their arrest and people who initiated a new episode of OAT in custody separately. We also conducted sex-based subgroup analyses. In this study there were 4,738 releases of 1,535 people with Opioid Use Disorder. In adjusted analysis, receipt of OAT in custody was associated with a reduced hazard of nonfatal overdose (aHR 0.55, 95% CI 0.41, 0.74). This was found for prescriptions continued from community (aHR 0.49, 95%CI 0.36, 0.67) and for episodes of OAT initiated in custody (aHR 0.58, 95%CI 0.41, 0.82). The effect was greater among women than men. CONCLUSIONS: OAT receipt during incarceration is associated with a reduced hazard of nonfatal overdose after release. Policies to expand access to OAT in correctional facilities, including initiating treatment, may help reduce harms related to nonfatal overdose in the weeks following release. Differences in the effect seen among women and men indicate a need for gender-responsive policies and programming.

Implementation of pharmaceutical alternatives to a toxic drug supply in British Columbia: A mixed methods study.

BACKGROUND: North America has been in an unrelenting overdose crisis for almost a decade. British Columbia (BC), Canada declared a public health emergency due to overdoses in 2016. Risk Mitigation Guidance (RMG) for prescribing pharmaceutical opioids, stimulants and benzodiazepine alternatives to the toxic drug supply ("safer supply") was implemented in March 2020 in an attempt to reduce harms of COVID-19 and overdose deaths in BC during dual declared public health emergencies. Our objective was to describe early implementation of RMG among prescribers in BC. METHODS: We conducted a convergent mixed methods study drawing population-level linked administrative health data and qualitative interviews with 17 prescribers. The Consolidated Framework for Implementation Research (CFIR) informs our work. The study utilized seven linked databases, capturing the characteristics of prescribers for people with substance use disorder to describe the characteristics of those prescribing under the RMG using univariate summary statistics and logistic regression analysis. For the qualitative analysis, we drew on interpretative descriptive methodology to identify barriers and facilitators to implementation. RESULTS: Analysis of administrative databases demonstrated limited uptake of the intervention outside large urban centres and a highly specific profile of urban prescribers, with larger and more complex caseloads associated with RMG prescribing. Nurse practitioners were three times more likely to prescribe than general practitioners. Qualitatively, the study identified five themes related to the five CFIR domains: 1) RMG is helpful but controversial; 2) Motivations and challenges to prescribing; 3) New options and opportunities for care but not enough to 'win the arms race'; 4) Lack of implementation support and resources; 5) Limited infrastructure. CONCLUSIONS: BC's implementation of RMG was limited in scope, prescriber uptake and geographic scale up. Systemic, organizational and individual barriers and facilitators point to the importance of engaging professional regulatory colleges, implementation planning and organizational infrastructure to ensure effective implementation and adaptation to context.

What is the ideal time to begin tapering opioid agonist treatment? A protocol for a retrospective population-based comparative effectiveness study in British Columbia, Canada.

INTRODUCTION: Opioid agonist treatment (OAT) tapering involves a gradual reduction in daily medication dose to ultimately reach a state of opioid abstinence. Due to the high risk of relapse and overdose after tapering, this practice is not recommended by clinical guidelines, however, clients may still request to taper off medication. The ideal time to initiate an OAT taper is not known. However, ethically, taper plans should acknowledge clients' preferences and autonomy but apply principles of shared informed decision-making regarding safety and efficacy. Linked population-level data capturing real-world tapering practices provide a valuable opportunity to improve existing evidence on when to contemplate starting an OAT taper. Our objective is to determine the comparative effectiveness of alternative times from OAT initiation at which a taper can be initiated, with a primary outcome of taper completion, as observed in clinical practice in British Columbia (BC), Canada. METHODS AND ANALYSIS: We propose a population-level retrospective observational study with a linkage of eight provincial health administrative databases in BC, Canada (01 January 2010 to 17 March 2020). Our primary outcomes include taper completion and all-cause mortality during treatment. We propose a 'per-protocol' target trial to compare different durations to taper initiation on the likelihood of taper completion. A range of sensitivity analyses will be used to assess the heterogeneity and robustness of the results including assessment of effectiveness and safety. ETHICS AND DISSEMINATION: The protocol, cohort creation and analysis plan have been classified and approved as a quality improvement initiative by Providence Health Care Research Ethics Board and the Simon Fraser University Office of Research Ethics. Results will be disseminated to local advocacy groups and decision-makers, national and international clinical guideline developers, presented at international conferences and published in peer-reviewed journals electronically and in print.

Incremental expenditures attributable to daily dispensation and witnessed ingestion for opioid agonist treatment in British Columbia: 2014-20.

BACKGROUND AND AIM: While daily witnessed opioid agonist treatment (OAT) ingestion is common in British Columbia (BC), Canada, and elsewhere, sparse evidence supports this resource-intensive practice. Many settings across North America relaxed restrictions for take-home dosing during the COVID-19 pandemic and have reported consistent or improved patient outcomes. This study measured excess expenditures attributed to daily witnessed pharmacy dispensing compared with weekly or biweekly dispensation schedules. DESIGN, SETTING AND PARTICIPANTS: This study was a population-level retrospective analysis. We included all methadone, buprenorphine/naloxone and slow-release oral morphine dispensations in BC from 1 January 2014 to 30 December 2020. A total of 24 357 107 OAT dispensations among 51 195 unique individuals with 122 793 person-years of follow-up were included during the study period. MEASUREMENTS: Total expenditures for each person-week of OAT with an estimated expenditure under two scenarios are as follows: (1) a weekly dispensation scenario and (2) a biweekly dispensation scenario. FINDINGS: We estimated excess expenditures attributable to current dispensing practices of between $38 million (2014) and $47.4 million (2018) compared with a hypothetical weekly dispensing schedule, and $43.9 million (2014) to $54.9 million (2018) compared with biweekly dispensing. The majority of these expenditures (58-64%) were attributed to pharmacy dispensing fees ($23 million in 2014 to $30 million in 2018 compared with weekly dispensing; $26.6 million in 2014 to $34.7 million in 2018 compared with biweekly dispensing). CONCLUSION: Daily witnessed opioid agonist treatment ingestion results in more than $30 million in excess expenditures annually in the province of British Columbia, Canada compared with the costs of weekly or biweekly dispensation schedules.

Comparative effectiveness of urine drug screening strategies alongside opioid agonist treatment in British Columbia, Canada: a population-based observational study protocol.

INTRODUCTION: Urine drug tests (UDTs) are commonly used for monitoring opioid agonist treatment (OAT) responses, supporting the clinical decision for take-home doses and monitoring potential diversion. However, there is limited evidence supporting the utility of mandatory UDTs-particularly the impact of UDT frequency on OAT retention. Real-world evidence can inform patient-centred approaches to OAT and improve current strategies to address the ongoing opioid public health emergency. Our objective is to determine the safety and comparative effectiveness of alternative UDT monitoring strategies as observed in clinical practice among OAT clients in British Columbia, Canada from 2010 to 2020. METHODS AND ANALYSIS: We propose a population-level retrospective cohort study of all individuals 18 years of age or older who initiated OAT from 1 January 2010 to 17 March 2020. The study will draw on eight linked health administrative databases from British Columbia. Our primary outcomes include OAT discontinuation and all-cause mortality. To determine the effectiveness of the intervention, we will emulate a 'per-protocol' target trial using a clone censoring approach to compare fixed and dynamic UDT monitoring strategies. A range of sensitivity analyses will be executed to determine the robustness of our results. ETHICS AND DISSEMINATION: The protocol, cohort creation and analysis plan have been classified and approved as a quality improvement initiative by Providence Health Care Research Ethics Board and the Simon Fraser University Office of Research Ethics. Results will be disseminated to local advocacy groups and decision-makers, national and international clinical guideline developers, presented at international conferences and published in peer-reviewed journals electronically and in print.

Assessing the determinants of completing OAT induction and long-term retention: A population-based study in British Columbia, Canada.

BACKGROUND: Pharmacological treatments for opioid use disorder are essential, life-saving medications, yet successful induction of them and long-term retention on them is limited in many settings. Induction into opioid agonist treatment (OAT) features the highest risk of mortality throughout the treatment course, and greatest risk of discontinuation. We aimed to identify determinants of completing OAT induction and, among those completing induction, time to OAT discontinuation in British Columbia (BC), Canada. METHODS: We conducted a retrospective study using linked population-level health administrative databases to capture all individuals in BC receiving at least one OAT dispensation from January 1, 2008, to September 30, 2018. We constructed covariates capturing client demographics, clinical history, and characteristics of the treatment episode and the primary prescribing physician. We estimated a two-part model to identify determinants of the probability of completing induction using a generalized linear mixed model with logit link and the time to OAT discontinuation among those completing induction using a Cox proportional hazards frailty model. RESULTS: We observed 220,474 OAT episodes (73.9% initiated with methadone, 24.7% with buprenorphine, and 1.4% with slow-release oral morphine) among 45,608 individuals over the study period. Less than 60% of all OAT episodes completed induction (59.0% for methadone episodes, 56.7% for buprenorphine/naloxone, 41.0% for slow-release oral morphine) and half of all episodes that completed induction reached the minimum effective dosage (51.0% for methadone episodes [60 mg/day], 48.2% for buprenorphine/naloxone [12 mg/day], 59.4% for slow-release oral morphine [240 mg/day]). In multiple regression analysis, the adjusted odds of completing induction with buprenorphine improved over time, exceeding that of methadone in 2018: 1.46 (1.40, 1.51). For those who completed induction, buprenorphine use was associated with shorter times to discontinuation throughout the study period, but the estimated rate of discontinuation decreased over time (adjusted hazard ratio, vs. methadone in 2008: 2.50 (2.35, 2.66); in 2018: 1.79 (1.74, 1.85)). CONCLUSION: We found low rates of completing OAT induction and, for those who did complete it, low rates of reaching the minimum effective dose.

Opioid agonist treatment uptake within provincial correctional facilities in British Columbia, Canada.

BACKGROUND AND AIMS: Multiple interventions and policy changes related to opioid agonist treatment (OAT) have been introduced in British Columbia, Canada to increase engagement and retention in OAT. We aimed to estimate the impact of policy changes and the announcement of the opioid overdose-related public health emergency on the use of OAT for incarcerated individuals with opioid use disorder. DESIGN: Interrupted time-series analysis. Events of interest included the expansion of buprenorphine/naloxone into provincial health-care insurance coverage in October 2015 and the public health emergency declared in April 2016. SETTING AND PARTICIPANTS: Our study included 9220 incarcerated individuals from 12 provincial corrections facilities in British Columbia, Canada for a total of 75 649 calendar months of incarceration. MEASUREMENTS: Monthly measures of OAT use during incarceration from 1 January 2013 to 30 September 2017. We estimated changes in OAT use, controlling for individual and facility-level factors, using a general estimating equation, specified with a logit link and an autoregressive correlation matrix. FINDINGS: After the provincial health insurance coverage expansion, a sharp increase in OAT use during incarceration was observed [adjusted odds ratio (aOR) = 1.16, 95% confidence interval (CI) = 1.13, 1.19]. The public health emergency coincided with an immediate but temporary increase in OAT receipt (aOR = 1.34, 95% CI = 1.22, 1.47). During the entire study period, we estimated a 10-fold increase in the adjusted odds of OAT use during incarceration (aOR = 10.10, 95% CI = 8.98, 11.37). CONCLUSION: Following an expansion of health-care insurance coverage to include buprenorphine/naloxone, receipt of opioid agonist treatment (OAT) within correctional facilities in British Columbia, Canada increased, largely driven by an increase in buprenorphine/naloxone prescriptions among individuals without recent OAT experience.