Sustained-release naltrexone for opioid dependence.

Background: Opioid dependence is a severe and often lifelong disorder with a high risk of overdose and premature death, as well as severe psychosocial difficulties. Sustained-release naltrexone is a treatment option that works by blocking the euphoric and overdose effects of opioids. When injected intramuscularly, naltrexone provides blockade for one month, while the blocking effects with implants can last for up to six months.

Objectives: To assess the benefits and harms of sustained-release naltrexone for the treatment of opioid dependence.

Search methods: For this update, we searched the following databases from 2007 up to 20 December 2023: the Cochrane Drugs and Alcohol Specialised Register of Trials, the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, PsycINFO, ISI Web of Science, LILACS, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform. We manually searched the reference lists of identified studies, published reviews and relevant websites.

Selection criteria: Randomised controlled trials comparing the effects of injectable or implantable naltrexone with other treatment, no treatment or placebo in adults with opioid dependence.

Data collection and analysis: Primary outcomes were illicit opioid use, retention in treatment, treatment acceptability and adverse events. Secondary outcomes were opioid craving, recreational use of substances other than opioids, mental health, quality of life and criminal activity. We assessed the risk of bias using the Cochrane risk of bias tool (RoB 1). We combined the results of individual trials through meta-analysis where possible using a random-effects model. Two review authors independently assessed the certainty of the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.

Main results: We identified 22 studies (3416 participants) that met our inclusion criteria. Three studies compared sustained-release naltrexone with opioid agonist treatment, five with oral naltrexone, six with placebo, nine with treatment as usual and one with psychosocial intervention. Sustained-release naltrexone compared with opioid agonist treatment We found moderate-certainty evidence that sustained-release naltrexone probably increases in-treatment illicit opioid use slightly (risk ratio (RR) 1.15, 95% confidence interval (CI) 1.01 to 1.31; 1 study, 570 participants). The evidence is very uncertain about the effect of sustained-release naltrexone on retention in treatment (RR 1.17, 95% CI 0.78 to 1.76; 3 studies, 773 participants) and treatment acceptability (RR 0.92, 95% CI 0.73 to 1.16; 3 studies, 773 participants). There was low-certainty evidence that sustained-release naltrexone may increase serious adverse events slightly in comparison with opioid agonist treatment for serious adverse events (RR 1.40, 95% CI 0.92 to 2.11; 2 studies, 713 participants). Sustained-release naltrexone compared with oral naltrexone treatment We found low-certainty evidence that sustained-release naltrexone may reduce in-treatment illicit opioid use (RR 0.65, 95% CI 0.45 to 0.93; 1 study, 69 participants). The evidence is very uncertain about the effect of sustained-release naltrexone on retention in treatment (RR 2.40, 95% CI 1.64 to 3.52; 3 studies, 464 participants) and on serious adverse events (RR 1.25, 95% CI 0.46 to 3.36; 2 studies, 260 participants). There was low-certainty evidence that sustained-release naltrexone may result in little to no difference in treatment acceptability in comparison with oral naltrexone treatment (RR 1.00, 95% CI 0.99 to 1.01; 3 studies, 474 participants). Sustained-release naltrexone compared with placebo We found low-certainty evidence that sustained-release naltrexone may result in little to no difference in in-treatment illicit opioid use (RR 0.83, 95% CI 0.66 to 1.03; 3 studies, 443 participants), treatment acceptability (RR 1.00, 95% CI 0.98 to 1.02; 1 study, 204 participants) and serious adverse events (RR 0.74, 95% CI 0.17 to 3.23; 3 studies, 443 participants). The evidence is very uncertain about the effect of sustained-release naltrexone on retention in treatment in comparison with placebo (RR 2.10, 95% CI 1.23 to 3.60; 4 studies, 594 participants). Sustained-release naltrexone compared with treatment as usual We found high-certainty evidence that sustained-release naltrexone reduces in-treatment illicit opioid use (RR 0.72, 95% CI 0.57 to 0.90; 4 studies, 479 participants). There was low-certainty evidence that sustained-release naltrexone may result in little or no difference in retention in treatment (RR 1.20, 95% CI 0.79 to 1.82; 3 studies, 126 participants) and that it may result in a slight reduction in treatment acceptability (RR 0.79, 95% CI 0.69 to 0.90; 8 studies, 1094 participants). There was moderate-certainty evidence that sustained-release naltrexone probably reduces serious adverse events in comparison with treatment as usual (RR 0.59, 95% CI 0.36 to 0.95; 6 studies, 1009 participants). Our primary outcome measures were not reported for sustained-release naltrexone compared with psychosocial treatments. Amongst the most common methodological weaknesses were the risk of performance bias and imprecision due to few studies and small sample size for many outcomes.

Authors' conclusions: Sustained-release naltrexone may slightly increase illicit opioid use and serious adverse events compared to opioid agonists, with uncertain effects on retention and acceptability. It may reduce illicit opioid use compared to oral naltrexone but has uncertain effects on other outcomes. Compared to placebo, it may have little to no impact on key outcomes. Compared to treatment as usual, it reduces illicit opioid use and may reduce serious adverse events but has little effect on retention and slightly reduces acceptability. Significant gaps remain in the evidence on sustained-release naltrexone for opioid dependence. Future research should include comparisons with psychosocial treatments, larger and higher-quality studies, and analyses of differences between formulations and comparator treatments. Improved study designs are needed to reduce bias, and more inclusive research should address under-represented populations and synthetic opioid users. The lack of long-term outcome data limits understanding of sustained effects, highlighting the need for extended follow-up and exploration of diverse treatment settings and populations.