Comparative effectiveness of alternative initial doses of opioid agonist treatment for individuals with opioid use disorder: a protocol for a retrospective population-based study using target trial emulation in British Columbia, Canada

Abstract

Introduction: Selecting an optimal initial dosage of opioid agonist treatment (OAT) balances effectiveness and safety, as initial doses that are too low may be insufficient, potentially prompting clients to seek unregulated drugs to alleviate withdrawal symptoms, which may increase the likelihood of treatment discontinuation. Conversely, initial doses that are too high carry a risk of overdose. As opioid tolerance levels have risen in the fentanyl era, linked population-level data capturing initial doses in the real world provide a valuable opportunity to refine existing guidance on optimal OAT dosing at treatment initiation. Our objective is to determine the comparative effectiveness of alternative initial doses of methadone, buprenorphine-naloxone and slow-release oral morphine at OAT initiation, 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 nine provincial health administrative databases in BC, Canada (1 January 2010 to 31 December 2022). Our study includes two time-to-event primary outcomes: OAT discontinuation and all-cause mortality during follow-up. We propose 'initiator' target trial analyses for each medication using both propensity score weighting and instrumental variable analyses to compare the effect of different initial OAT doses on the hazard of time-to-OAT discontinuation and all-cause mortality. A range of sensitivity analyses will be used to assess the robustness of the 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.

Keywords: EPIDEMIOLOGIC STUDIES; EPIDEMIOLOGY; PUBLIC HEALTH.

Figure 1. Directed acyclic graph detailing the relationship between starting dose and outcome for individuals who initiated OAT in British Columbia, Canada Panel A represents the scenario in which we assume there is no unmeasured confounding in the primary analysis. Panel B shows the scenario in which unmeasured confounding exists, and we propose to use the instrumental variable approach to eliminate it in sensitivity analysis. (A) Exposure strategies of starting dose of OAT assigned at time zero; Y: outcomes including OAT discontinuation and all-cause mortality; L₀: any baseline confounders that are time-fixed and that impact OAT starting dose and outcomes, including age at OAT initiation, sex, receipt of urine drug testing, carry receipt, unstable housing, receipt of income assistance, mental health conditions, alcohol use disorder, non-opioids substance use disorder, HCV, chronic pain, tobacco use disorder, sedative medication, prescription opioid, psychiatric medication, Charlson Comorbidity Index, Chronic Disease Score, drug overdose in the last 30 days, drug-related hospitalisation or emergency department visits, psychiatric hospitalisations, incarceration in a provincial corrections facility in the past year, physician attachment, receipt of an opioid-based medication for pain, use of virtual care, receipt of treatment by delivery and whether prescribed safer supply; Z: preference-based instrumental variables; U: unmeasured confounders that may impact OAT starting dose and outcomes and may be affected by baseline confounders, such as individuals’ ongoing illicit drug usage. We do not observe the unmeasured confounders and plan to control their impact via the preference-based instrumental variable. HCV, Hepatitis C virus; OAT, opioid agonist treatment.