Key messages
• It is unclear whether people treated with sustained-release naltrexone use illicit opioids, such as heroin, less frequently than people treated with opioid agonists, such as buprenorphine or methadone.
• People treated with sustained-release naltrexone may use illicit opioids less frequently than people treated with oral naltrexone, placebo or treatment as usual.
• Treatment with sustained-release naltrexone may be less safe than opioid agonist treatment, but safer than treatment as usual.
• Clinicians and patients should weigh the availability and characteristics of treatment options, noting that sustained-release naltrexone aids abstinence without restricting freedom but requires detoxification; more evidence is needed on long-term safety and retention.
What is dependence on opioid drugs?
Opioid drugs, including heroin and prescription painkillers like oxycodone, carry the risk of addiction and serious health consequences. Treatment often involves replacing these opioids with safer alternatives such as methadone or buprenorphine, although other options like therapy or naltrexone are available. However, overcoming opioid dependence remains a persistent challenge due to its complex nature and the associated risks of relapse and overdose.
What did we want to find out?
In this review we sought to compare sustained-release naltrexone treatment with other treatments or no treatment for opioid dependence. Naltrexone should not be confused with naloxone, which is a short-acting drug used for opioid overdose reversal. Other treatments include opioid agonist treatment (such as methadone or buprenorphine), oral naltrexone (taken by mouth, tablets), placebo (sham treatment, that does not contain any medicine but looks or tastes identical to the medicine being tested), treatment as usual and psychosocial treatments (therapeutic approaches that address both psychological and social aspects of mental health conditions, e.g. psychotherapy, psychoeducation and support groups).
What did we do?
We searched scientific databases for studies up to December 2023. We identified 22 randomised controlled trials (studies where people were allocated at random to one of two or more treatment or control conditions) involving 3416 adults and adolescents with opioid dependence. Seventy-four per cent of the people in the studies were male, and they had an average age of 40 years. Twelve of the 22 studies were conducted in the USA or Canada, five in Russia, three in Norway, and one in the UK and Australia, respectively. The main outcomes we examined were opioid use and treatment safety.
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.
What did we find?
We found that when comparing sustained-release naltrexone to opioid agonist treatment, illicit opioid use probably increases slightly. On the other hand, when comparing sustained-release naltrexone to treatment as usual, sustained-release naltrexone reduces illicit opioid use. Compared to oral naltrexone, illicit opioid use may decrease, and compared to placebo, there may be little or no difference. We found no studies comparing sustained-release naltrexone with psychosocial treatments for any of our primary outcomes.
It is generally unclear whether people remain longer in sustained-release naltrexone treatment than in other treatments or placebo.
We do not know whether more people will initiate sustained-release naltrexone treatment than opioid agonist treatment. When compared to oral naltrexone or placebo, there may be little or no difference in the proportion of people who will initiate treatment. Compared to treatment as usual, it may be that fewer people will initiate sustained-release naltrexone treatment.
Compared to opioid agonist treatment, sustained-release naltrexone may increase serious adverse (unwanted or harmful) events slightly. It is unclear whether sustained-release naltrexone results in more or fewer serious adverse events than oral naltrexone. When compared to placebo, there may be little or no difference in the proportion of people who will experience serious adverse events. Sustained-release naltrexone probably reduces serious adverse events in comparison to treatment as usual.
What were the limitations of the evidence?
Overall, we have limited confidence in the evidence. One of the reasons is that it is very likely that participants knew which treatments they were assigned to, even if the researchers in many cases tried to conceal the assigned treatment condition for participants and treatment providers. Opioid dependence comes with strong drug cravings and an increased risk of relapse during any treatment. Therefore, participants experiencing cravings and those who maybe even tried to use drugs like heroin would have understood what type of treatment they were assigned to. Another major reason for our limited confidence in the evidence was that the number of studies, and people participating in them, was often too small to obtain precise results. Other reasons for lowering our confidence were inconsistencies in study results and national treatment policies in some studies that make it difficult to apply the results in other countries.
How up-to-date is this evidence?
The evidence is current to December 2023.
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.
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.
To assess the benefits and harms of sustained-release naltrexone for the treatment of opioid dependence.
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.
Randomised controlled trials comparing the effects of injectable or implantable naltrexone with other treatment, no treatment or placebo in adults with opioid dependence.
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.
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.