Effectiveness of slow-release oral morphine versus other OAT regimens in key sub-populations: protocol for population-based target trial emulation

IntroductionSlow-release oral morphine (SROM) was introduced as an alternative form of opioid agonist treatment (OAT) in British Columbia (BC), Canada in 2017. While clinical guidelines in BC recommend SROM based on expert consensus and experience, there is limited real-world evidence on populations most likely to benefit from SROM compared to other forms of OAT, particularly in the context of widespread fentanyl exposure. We will estimate the comparative effectiveness of SROM versus methadone and buprenorphine/naloxone on OAT discontinuation and all-cause mortality among key sub-populations in BC. MethodsWe will conduct a population-level retrospective cohort study using linked data from nine provincial health administrative databases. The study population includes adults ([≥]18 years) in BC who initiated SROM, methadone, or buprenorphine/naloxone between June 1, 2017, and December 31, 2022. Key sub-populations will include incident users with no prior OAT history and prevalent new users with prior OAT experience stratified by OAT type, stability, and medication switching history. The primary outcomes are time to OAT discontinuation and all-cause mortality, while overdose-related acute care visits will be examined as a secondary outcome. To estimate both the initiator effect and the effect of treatment at guideline-recommended doses, we will apply marginal structural models using inverse probability treatment weighting and clone-censor-weights approach to address confounding by indication and time-varying confounding. Sensitivity analyses will evaluate the robustness of our findings, including cohort and timeline restrictions, alternative outcome definitions, and alternative estimation strategies including high-dimensional propensity score and instrumental variable approaches. DiscussionThis study will generate real-world evidence on the comparative effectiveness of SROM versus methadone and buprenorphine/naloxone across clinically distinct OAT sub-populations. The findings will support evidence-informed updates to OAT guidelines and clinical decision-making in BC and other jurisdictions facing escalating opioid-related harms.