Slow-release oral morphine  (SROM) is widely used for pain management, but there is also a growing evidence base for its use as an OAT medication. In Canada, slow-release oral morphine for treatment of OUD has been eligible for coverage under Health Canada’s Non-Insured Health Benefits (NIHB) program since November 2014 (now Plan W in BC), and as a regular benefit under British Columbia’s provincial drug plan (PharmaCare) since June 2017. 

Four systematic reviews—including two meta-analyses—of randomized trials have been published since 2013.204-206 A 2013 Cochrane Review including three randomized trials (n=195) comparing slow-release oral morphine to methadone or buprenorphine/naloxone found no significant differences between treatments in retention, medication adherence, or non-medical opioid use.204 However, due to the small number of trials that met inclusion criteria, the quality of this evidence was assessed as low (i.e., high likelihood that new evidence could change direction or magnitude of findings) and insufficient to make any conclusions regarding its use in clinical practice.204  The authors also noted a higher incidence of adverse events for slow-release oral morphine compared to other opioid agonist treatments.204 

A 2017 Norwegian systematic review compared slow-release oral morphine to methadone. Three studies (n=460) were included in the review. The study authors concluded that there is probably no or little difference in treatment retention (moderate certainty); there may be little or no difference in unregulated opioid use (low certainty); there may be little or no difference in adverse events (low certainty); there is insufficient evidence to determine effect on patient satisfaction and criminal activity.205 Overall, the evidence was assessed as having weaknesses that conferred low certainty in evidence of effect. Thus, the authors were unable to conclude whether SROM and methadone are equivalent. This study included 2 of the 3 studies included in the Cochrane review, as well as a 2014 RCT.207 

A 2019 systematic review and meta-analysis included both published trials and unpublished data (n=471) on two outcomes: unregulated opioid use and retention in treatment.206 This systematic review included all of the studies included in the prior two systematic reviews, as well as unpublished data. The meta-analysis found no significant differences between SROM and methadone for both outcomes. Results from two studies also suggest that SROM is superior to methadone in reducing opioid cravings; however, this was not included in the meta-analysis. The study authors concluded that, while gaps remain in the evidence base for SROM, this meta-analysis confirms the apparent non-inferiority of SROM with methadone.206

Finally, a 2022 systematic review and network meta-analysis (N=79; 4 studies involving SROM) compared the effectiveness of methadone, SROM, buprenorphine/naloxone, and naltrexone in terms of treatment retention.123 Slow-release oral morphine had the highest average percentage of treatment retention across all studies (77.6%), followed by methadone and buprenorphine/naloxone respectively (64.1% and 54.3%). However, using a Bayesian ranking framework, the authors estimated SROM’s treatment retention to be superior to buprenorphine and naltrexone and marginally inferior to methadone. The authors emphasized that confidence in estimates involving SROM was very low due to the small number of high-quality trials.123 It was also noted that SROM was compared only with methadone, and all other pairwise comparisons involving SROM were based on indirect evidence.123 

Several non-randomized studies have also assessed the safety and efficacy of slow-release oral morphine for treatment of OUD.208 A multi-centre study including patients intolerant to or insufficiently responding to methadone (n=67) found that transitioning from methadone to slow-release oral morphine was relatively simple and well-tolerated by patients, with significant advantages observed over time, including reduced withdrawal symptoms and cravings, and improved physical and psychological health.209 Similarly, a small open-label crossover study (n=18) assessed outcomes of transitioning patients from methadone to six weeks of slow-release oral morphine treatment, after which methadone treatment was resumed.210 

Compared to methadone, slow-release oral morphine was associated with improved social functioning and reduced heroin craving, with no change in heroin use, depression symptoms, and overall health scores.210 The majority of patients (78%) expressed a preference for slow-release oral morphine over methadone, with reasons including fewer and less severe side effects, feeling more “normal”, and improved withdrawal suppression, sleep quality, and energy levels.210 Several additional small non-randomized, uncontrolled studies have reported similar improvements in quality of life, withdrawal symptoms, opioid craving, and heroin use compared to baseline or pre-treatment levels.211-213 

A 2021 observational study (n=4778) examining OAT retention rates in the Austrian healthcare system found that SROM had a substantially higher retention rate at 2 years compared to both methadone and buprenorphine/naloxone (OR=2.141, 95% CI 1.885–2.430).214 At the start of the two-year study period, 36% of participants started SROM (compared to 30% starting a methadone formulation and 32% starting a buprenorphine formulation). At the end of the study period, the percentage of participants on SROM had increased to 39.9%. Slow-release oral morphine appeared to be the preferable option among this larger sample of individuals on OAT in the Austrian system.214

The evidence supporting the use of slow-release oral morphine for opioid use disorder has some limitations, including a relatively small body of evidence of low-to-moderate methodological quality and moderate heterogeneity and risk of bias.206 There is also an absence of data establishing the extent of SROM’s impact on opioid-related mortality. Although there is a less robust evidence base supporting the use of slow-release oral morphine for opioid use disorder compared to buprenorphine and methadone, clinical judgment and patient preference should guide what medication is selected. 

Finally, it is important to note that only the once-daily, 24-hour formulation of slow-release oral morphine has been studied in clinical trials for the treatment of OUD. Other formulations of oral morphine, such as twice-daily, 12-hour sustained- or extended-release formulations have not been empirically studied in this context and are not recommended at the time of publication.