Sustained-Release Naltrexone for Treatment of Opioid Use Disorder

Does sustained-release naltrexone reduce the risks of nonprescribed opioid use, overdose, and death in people with opioid use disorder (opioid dependence)?

Compared with nonpharmacologic treatment as usual, sustained-release naltrexone reduces the risk of nonprescribed (ie, illicit) opioid use but does not decrease the risk of overdose or death.¹ (Strength of Recommendation [SOR]: B, patient-oriented evidence.)

Compared with oral naltrexone, sustained-release naltrexone reduces the risk of nonprescribed opioid use but does not reduce the risk of death or serious adverse events.¹ (Strength of Recommendation: B, patient-oriented evidence.)

Compared with buprenorphine or methadone therapy, sustained-release naltrexone increases the risk of nonprescribed opioid use and does not reduce the risk of overdose or death.¹ (SOR: B; patient-oriented evidence.)

Opioid use disorder is a chronic condition defined by recurrent opioid use causing psychosocial and health impairments, including risks of infectious diseases, overdose, and premature death.² Although pharmacotherapy for opioid use disorder is widely accepted as standard of care, only 17% of the 4.8 million people in the United States with opioid use disorder in 2024 received medications for treatment.³

Three medications are approved by the US Food and Drug Administration for treatment of opioid dependence: buprenorphine (a partial opioid agonist), methadone (a full opioid agonist), and naltrexone (an opioid antagonist). Naltrexone is available as a pill, sustained-release monthly injection, or long-acting implant (not currently approved in the United States). Oral naltrexone is not a widely recommended treatment for opioid use disorder given adherence concerns limiting its overdose protection benefit.² The authors of this Cochrane review investigated the effectiveness of sustained-release naltrexone (injection or implant) for the treatment of opioid use disorder.¹

The authors identified 22 parallel-group randomized controlled trials (RCTs) from the United States and five other countries (N = 3,416). Participants were adults (all studies) and adolescents 15 years and older (one study) with opioid use disorder in varied outpatient settings (eg, following residential treatment, detoxification, incarceration). Studies compared sustained-release naltrexone with nonpharmacologic treatment as usual (nine studies), placebo (six studies), oral naltrexone (five studies), or opioid agonists (three studies). Mean intervention duration was 6 months (range 2–12 months). Primary outcomes were nonprescribed opioid use measured by urine drug testing, treatment retention, treatment acceptability (measured by number of patients initiating allocated treatment), and serious adverse events (ie, overdose, death, or treatment discontinuation due to adverse event). The authors also found one study comparing sustained-release naltrexone to psychosocial treatments but could not identify any data applicable to their primary outcomes.

Nonpharmacologic treatment as usual varied across studies, with some studies providing only a list of community-based resources. Compared with treatment as usual, sustained-release naltrexone reduced nonprescribed opioid use (risk ratio [RR] = 0.72; 95% CI, 0.57–0.90; number needed to treat [NNT] = 6; four RCTs; n = 479) and reduced the risk of serious adverse events, including treatment discontinuation, overdose, and death as a combined category (RR = 0.59; 95% CI, 0.36–0.95; NNT = 14; six RCTs; n = 1,009). However, when overdose and death risk were studied as independent outcome variables, no significant difference was identified. Of interest, sustained-release naltrexone was found to be less acceptable (fewer patients initiated allocated treatment) compared with treatment as usual (RR = 0.79; 95% CI, 0.69–0.90; number needed to harm = 6; eight RCTs; n = 1,094).

Studies comparing sustained-release naltrexone with placebo showed that naltrexone improved treatment retention (RR = 2.10; 95% CI, 1.23–3.60; NNT = 4; four RCTs; n = 594). Based on one relatively small study, sustained-release naltrexone was associated with a reduced risk of nonprescribed opioid use compared with oral naltrexone (RR = 0.65; 95% CI, 0.45–0.93; NNT = 4; n = 69). Three studies showed improved retention in treatment with sustained-release naltrexone compared with the oral formulation (RR = 2.40; 95% CI, 1.64–3.52; NNT = 4; n = 464). There was no difference between sustained-release naltrexone and oral naltrexone in treatment acceptability. Whether there was any difference in the risk of death or overdose could not be determined.

Compared with buprenorphine or methadone, sustained-release naltrexone was associated with an increased risk of nonprescribed opioid use (RR = 1.15; 95% CI, 1.01–1.31; number needed to harm = 11; one RCT; n = 570). There was little to no difference between sustained-release naltrexone and buprenorphine or methadone in treatment retention; treatment acceptability; or serious adverse events, including overdose and death.

The Cochrane authors identified potential biases within the studies, including inadequate blinding, incomplete outcome data, selective reporting, and pharmaceutical industry involvement. The authors also noted limitations in the existing literature, including the need for larger and higher-quality studies with long-term outcome data.

American Society of Addiction Medicine guidelines emphasize the importance of medications in management of opioid use disorder to reduce harms of opioid use, including overdose risk.² These guidelines include extended-release naltrexone as a recommended treatment for opioid use disorder in patients who are no longer physiologically opioid dependent (ie, have completed opioid withdrawal).

Editor’s Note: The numbers needed to treat and harm in this review were calculated by the authors based on raw data provided in the original Cochrane review.

The practice recommendations in this activity are available at https://www.cochrane.org/CD006140​.