Factors associated with the percentage of individuals who initiate and discontinue naltrexone as a relapse prevention pharmacotherapy in opioid use disorder: A systematic review, meta-analysis and meta-regression

Background and Aims:
Naltrexone is a pharmacotherapeutic option for relapse prevention in opioid use disorder (OUD); however, studies highlight low rates of initiation and high rates of discontinuation as limiting its effectiveness. We aimed to 1) estimate the percentage of individuals with OUD who (having undergone withdrawal and wish to remain abstinent) initiate and discontinue naltrexone and 2) examine participant- and study-level factors that contribute to variation in initiation and discontinuation rates.

Methods:
We undertook a systematic review, random-effects meta-analysis and meta regression searching Medline, Embase, PsychINFO and CENTRAL from database inception to 19 February 2025 for studies of any design from any geographical region involving individuals with OUD eligible to receive naltrexone as a relapse prevention pharmacotherapy (i.e., those completing opioid withdrawal and wishing to remain abstinent). Measurements included the percentage of individuals who initiate or discontinue oral, long-acting injectable depot or implantable formulations of naltrexone at one, three or six months. Certainty was assessed using the GRADE framework.

Results:
Twenty-two studies, including 124,016 individuals, reported initiation and 95 studies, including 16,969 individuals, reported discontinuation. The pooled percentage initiating oral naltrexone among those eligible was 60.3% (95% confidence interval [CI] 38.9% to 80.0%, 2,014 participants,15 studies) and depot was 18.2% (2.7% to 42.5%, 57,383 participants, 4 studies). The pooled percentage discontinuing oral was 50.0% (41.9% to 58.1%, 7,340 participants, 34 studies) at one month, 61.3% (50.9% to 71.2%, 2,347 participants, 29 studies) at three months and 71.0% (57.3% to 83.0%, 1,889 participants, 19 studies) at six months. The pooled percentage discontinuing depot was 26.1% (19.5% to 33.3%, 3,589 participants, 33 studies) at one month, 46.7% (38.4% to 55.1%, 3,302 participants, 33 studies) at three months and 60.0% (43.2% to 75.8%, 3,071 participants, 22 studies) at six months. Statistically significantly higher percentages initiated oral naltrexone if it was the only offered pharmacotherapy (meta-regression coefficient +33.6%, 95%CI +8.1% to +59.2%, p=0.014) and statistically significantly lower percentages discontinued oral naltrexone at three and six months if administration was supervised (meta-regression coefficient -18.6%, -36.6% to -1.0%, p=0.043 and 27.3%, 50.1% to 4.4%, p=0.022, respectively). There was no clear evidence that study setting (i.e., if the study was conducted in routine clinical care or an investigational setting) substantially explained or contributed to the variation in any estimates. All outcomes were very low certainty.

Conclusions:
Very low certainty evidence suggests that, among people with opioid use disorder who have undergone withdrawal and wish to remain abstinent, a substantial percentage are willing to initiate naltrexone with marked early discontinuation.