A protocol paper registered on medRxiv describes a planned population-based retrospective cohort study using linked data from nine British Columbia health administrative databases covering adults who initiated methadone or buprenorphine/naloxone between January 2010 and June 2022. Using a target trial emulation framework with a clone-censor-weight approach, researchers will compare alternative dose titration schedules on two primary outcomes: completed induction (no dose increase for ≥2 weeks without intervening decrease) and all-cause mortality, alongside overdose-related acute care visits and treatment discontinuation as secondary endpoints.
This is a protocol paper, not a results paper — no findings exist yet, and as a preprint it has not undergone peer review, meaning the methodology itself may face revision. That said, the research question is clinically urgent. Traditional methadone and buprenorphine titration guidelines were developed before illicitly manufactured fentanyl dominated the North American drug supply. Fentanyl's extreme potency and variable street-supply concentration create higher baseline opioid tolerance in treatment-naive patients, potentially making standard incremental titration schedules dangerously slow or therapeutically inadequate. The target trial emulation design is methodologically sophisticated — it partially addresses confounding inherent in observational OUD research. However, administrative database studies cannot fully capture unmeasured confounders like drug use patterns or social determinants. British Columbia's findings may not generalize to other jurisdictions with different drug supply compositions. If results confirm that accelerated titration reduces mortality without increasing adverse events, clinical guidelines across North America would face meaningful revision.