Extended-release naltrexone via monthly intramuscular injection may promote improved treatment adherence in comparison to oral naltrexone.282 Several randomized controlled trials have found that injectable naltrexone is superior to placebo in terms of improved retention in treatment, increased abstinence rates, and decreased opioid cravings.288-290 In addition, two systematic reviews evaluating extended-release naltrexone were published in 2018.291,292

One systematic review synthesized the existing literature on extended-release naltrexone induction and  adherence and opioid use during treatment.291 While acknowledging that the heterogeneity of study designs (randomized controlled trials, non-randomized studies, and cohort studies) and outcome measures were not conducive to performing a meta-analysis,  the authors drew 2 key conclusions: The first is that many people aiming to initiate treatment with extended-release naltrexone do not successfully initiate treatment, likely due to the requirement to discontinue opioid use prior to initiation. The second is that the majority of those who successfully start treatment with extended-release naltrexone prematurely discontinue treatment.291

The other systematic review compared extended-release naltrexone to buprenorphine/naloxone and found extended-release naltrexone to be non-inferior on a variety of abstinence-related outcomes.292 Extended-release naltrexone was also associated with a significant reduction in heroin use, but not other unregulated opioids. However, extended-release naltrexone was found to be inferior to buprenorphine/naloxone in terms of both relapse rates and discontinuation during induction.292 These findings were based on two key studies described below.293,294 

More recently, a 2020 systematic review and meta-analysis among justice-involved individuals, assessed the effectiveness of both oral (4 RCTs) and extended-release (7 RCTs) naltrexone in treatment retention. The findings showed that extended-release naltrexone had a statistically significant impact on treatment retention while no statistically significant change in retention was observed with oral naltrexone.295

A 2018 multi-site randomized controlled trial randomized participants to either extended-release naltrexone (n=283) or buprenorphine/naloxone (n=287).293 Far fewer participants were initiated onto naltrexone than buprenorphine/naloxone (72% [204/283] vs. 94% [270/287]). While per-protocol analysis found similar 24-week relapse rates across groups (52% for extended-release naltrexone vs. 56% buprenorphine/naloxone), extended-release naltrexone relapse rates were higher than buprenorphine/naloxone (65% vs. 57%) in intent-to-treat analysis. The difference was almost entirely accounted for by early relapse in those participants unable to successfully initiate treatment with extended-release naltrexone. Per-protocol analysis of urine drug tests and opioid abstinent days found little difference. Participants’ self-reported cravings were lower with extended-release naltrexone initially, but comparable to buprenorphine/naloxone by week 24.293 

This accords with a 2017 multi-site non-inferiority trial which randomized participants to either extended-release naltrexone (n=80) or sublingual buprenorphine/naloxone (n=79) and found extended-release naltrexone to be non-inferior in terms of retention, proportion of opioid-negative urine drug tests, and use of heroin and other unregulated opioids.294 It should be noted, however, that the trial was only 12 weeks long, meaning that any conclusions drawn can only be made about short-term abstinence from unregulated opioid use. A secondary analysis of this study with 36-week follow-up, published in 2022, compared the changes in life satisfaction scores in the two groups and found a moderate increase in life satisfaction in both randomized treatment groups, with a significant difference between the groups in favor of the extended-release naltrexone group within the first 8 weeks of the study.296  However, this difference diminished and the scores equalized in subsequent weeks.296 

At present, extended-release naltrexone is not available in Canada. However, it should be noted that 52% of participants in two Vancouver-based cohort studies of people who use unregulated drugs reported a high level of willingness to take extended-release naltrexone.297  Since, this medication is substantially more expensive than traditional daily-dosed medications used to treat opioid use disorder, the assembly of expert therapeutic guideline committees may be warranted to identify patient populations who would most benefit from extended-release naltrexone, if made available.