Slow-Release Oral Morphine vs Methadone for Opioid Use Disorder in the Fentanyl Era

Slow-release oral morphine (SROM) is approved for the treatment of opioid use disorder (OUD) in several European countries and has been used off label in Canada since 2017. However, the evidence base to support its use is limited and predates the fentanyl era.

To compare the discontinuation rates and mortality risks of SROM vs methadone for the treatment of OUD.

This comparative effectiveness study with a target trial emulation approach used data from observational linked health administrative databases in the Vancouver Coastal Health Authority (VCHA) region in British Columbia, Canada, between July 1, 2017, and June 30, 2024. Participants were adults aged 19 to 65 years with OUD.

New prescription of SROM or methadone for OUD (ie, no dispensation of medications for OUD in the 7 days prior) within VCHA clinical services.

Estimated 12-month risk of treatment discontinuation (≥7 days without medication dispensation) and all-cause mortality, as well as treatment adherence (proportion of days covered [PDC]) over 12 months of follow-up. Both intention-to-treat (ITT) and per-protocol (PP; restricted to episodes where SROM or methadone was dispensed within 4 days of the prescription) analyses were conducted.

A total of 3254 unique individuals (median age, 37 [IQR, 30-46] years; 2088 [64.2%] male) contributed to 4059 person-trials (2737 [67.4%] methadone, 1322 [32.6%] SROM) for the ITT analysis, and 1992 unique individuals contributed to 2276 person-trials (1653 [72.6%] methadone, 623 [27.4%] SROM) for the PP analysis. In ITT analyses, the standardized cumulative incidence of discontinuation at 12 months was 99.3% (95% CI, 99.0%-99.5%) and 97.9% (95% CI, 97.5%-98.2%) in the SROM and methadone arms, respectively (adjusted risk difference [ARD], 1.4 percentage points [pp]; 95% CI, 1.0-1.9 pp). PDC was also lower in the SROM group (adjusted risk ratio, 0.89; 95% CI, 0.87-0.91), while mortality risk was similar between arms (ARD, 1.1 pp; 95% CI, -1.3 to 4.1 pp). Of 121 total deaths, only 2 (1.7%) occurred when people were receiving MOUD. PP analyses yielded similar results.

In this comparative effectiveness study of adults with OUD in a Canadian setting, treatment discontinuation was common. Compared with methadone, SROM was associated with a slightly higher risk of treatment discontinuation and lower adherence but similar mortality risk. The findings suggest either medication may be appropriate if measures are in place to support retention.