Comparative effectiveness of maintenance doses of opioid agonist treatment among individuals with opioid use disorder: a target trial emulation protocol using a population-based observational study

Abstract

Introduction: Opioid agonist treatment (OAT) prescribing patterns have shifted in recent years in British Columbia (BC), Canada due to the increasingly toxic unregulated drug supply. Experimental evidence to support guidelines on the effectiveness of maintaining clients at different maintenance dosage levels is incomplete and outdated for the fentanyl era. Our objective is to assess the risk of treatment discontinuation and mortality among individuals receiving different maintenance dosage strategies for OAT with methadone, buprenorphine/naloxone or slow-release oral morphine (SROM) at the population level in BC, Canada.

Methods and analysis: We propose a retrospective population-level study of BC residents initiating OAT on methadone, buprenorphine/naloxone or SROM between 1 January 2010 and 31 December 2022 who were ≥18 years of age with no known pregnancy, no history of cancer diagnosis or receiving palliative care and not currently incarcerated. Our study will employ health administrative databases linked at the individual level to emulate a target trial per OAT type where individuals will be assigned to discrete maintenance dosing strategies, according to the full range observed in BC during the study period. Primary outcomes include treatment discontinuation and all-cause mortality. To determine the effectiveness of alternative maintenance doses, we will emulate a 'per-protocol' trial using a clone-censor-weight approach to adjust for measured time-dependent confounding by indication.

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. All data are deidentified, securely stored and accessed in accordance with provincial privacy regulations. Results will be disseminated and shared with local advocacy groups and decision-makers, developers of national and international clinical guidelines, presented at national and international conferences and published in peer-reviewed journals electronically and in print.

Keywords: EPIDEMIOLOGY; STATISTICS & RESEARCH METHODS; Substance misuse.

Figure 1

Example of censoring process for a hypothetical individual receiving methadone. When an individual’s data are no longer consistent with an assigned strategy after allowing time to titrate dose up and down to an assigned strategy from an initial dose, we artificially censor the corresponding replicate at the point of deviation from protocol. The horizontal line under each strategy indicates a follow-up time from time zero. (A): as a primary analysis, we compare methadone dose strategies based on a maximum as (1) ≤60 mg; (2) 60–≤80 mg; (3) 80–≤120 mg; (4) 120–≤150 mg; (5) 150–≤260 mg. We will censor when a client is given a dosage higher than indicated by an assigned strategy. The replicates with the strategies ≤60 mg and ≤80 mg are censored at week 6 and week 9, respectively, when the individual is given a higher dose than the strategy assigned. The replicates ≤120 mg, ≤150 mg and ≤260 mg are followed until the outcome occurs because the dose has not exceeded the maximum dose assigned; (B): as a sensitivity analysis, we compare methadone dose strategies based on dosing interval as (1) ≤60 mg; (2) 60–≤80 mg; (3) 80–≤120 mg; (4) 120–≤150 mg; (5) 150–≤260 mg. We will censor when (1) a client is given a dosage higher than indicated by an assigned strategy at least 2 weeks or (2) when a client is given the same dosage lower than the minimum threshold of the strategy assigned for at least 3 weeks The replicates with the strategies ≤60 mg and 60–≤80 mg are censored at week 9 and week 10, respectively, when the individual is given a higher dose than the strategy assigned for 2 weeks. The last two replicates with the strategies 120–≤150 mg and 150–≤260 mg are censored at week 11, at which 100 mg (ie, a dose lower than the strategy) is maintained for 3 weeks.