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Stanton R, Lujan J, Valerio C. Sustained-release naltrexone for opioid dependence. afp. 2026;113(3):217A-217B. Accessed April 23, 2026. https://www.aafp.org/pubs/afp/issues/2026/0300/mbtn-naltrexone-opioid-dependence.html

Study Population: Adults and adolescents with opioid dependence from multiple settings (clinical, residential, outpatient, prison or parole, voluntary or mandated treatment); one study included adolescents and adults 15 to 21 years of age; all other studies included adults 18 years or older

Efficacy Endpoints

Illicit opioid use (nonprescription use), treatment retention (median retention assessment at 6 months), treatment acceptability (number of patients initiating treatment)

Harm Endpoints

Severe adverse events (death, overdose, study treatment discontinued because of adverse event)

Narrative

Opioid use disorder is a public health crisis that can lead to dependence, overdose, and death. Despite efforts to curb prescription opioid misuse (eg, state-sponsored prescription drug-monitoring programs), availability of illicit heroin and fentanyl has rapidly increased. People who use heroin and fentanyl are more likely to experience poverty, homelessness, blood-borne diseases, and death from overdose.1^, 2

The standard treatment for opioid use disorder is long-acting noninjectable opioids or opioid agonists such as methadone or buprenorphine. These treatments have been shown to reduce illicit opioid use but do not address dependence.

Naltrexone, an opioid antagonist, is a nonopioid alternative that binds to opioid receptors, blocking euphoric effects and potentially preventing relapse. Although naltrexone supports abstinence, daily oral dosing remains a barrier to its implementation as a standard treatment. Sustained-release naltrexone (Vivitrol) delivered via implant or injection, with redosing between 2 weeks and 9 months depending on formulation, was developed to overcome adherence barriers while maintaining the opioid receptor blockade. Currently, the only sustained-release naltrexone formulation approved by the US Food and Drug Administration is an intramuscular injection given every 4 weeks.

This 2025 Cochrane review evaluated the effectiveness and safety of sustained-release naltrexone compared with existing treatments.3 A total of 3,416 participants in 22 randomized controlled trials were evaluated. Sustained-release naltrexone was compared with opioid agonists (three studies), oral naltrexone (five studies), placebo (six studies), treatment as usual (nine studies), and psychosocial intervention (one study).

Moderate-certainty evidence demonstrated that sustained-release naltrexone may have slightly increased in-treatment illicit opioid use compared with opioid agonists (risk ratio [RR] = 1.15; 95% CI, 1.01–1.31; absolute risk difference [ARD] = 8.5%; number needed to harm = 11; one study; n = 570). Low- or very low-certainty evidence showed that there may be little to no difference in retention, acceptability, or serious adverse events between sustained-release naltrexone and opioid agonists.

When comparing sustained-release naltrexone with oral naltrexone, low-certainty evidence showed reduced in-treatment illicit opioid use (RR = 0.65; 95% CI, 0.45–0.93; ARD = 27.8%; number needed to treat [NNT] = 4; one study; n = 69). Very low-certainty evidence also demonstrated increased treatment retention (RR = 2.40; 95% CI, 1.64–3.52; ARD = 25.2%; NNT = 4; three studies; n = 464). Low- or very low-certainty evidence showed that there may be little to no difference in acceptability or serious adverse events between sustained-release naltrexone and oral naltrexone.

Very low-certainty evidence demonstrated increased treatment retention with sustained-release naltrexone compared with placebo (RR = 2.10; 95% CI, 1.23–3.60; ARD = 31.4%; NNT = 4; four studies; n = 594). Low- or very low-certainty evidence showed that there may be little to no difference in in-treatment illicit opioid use, acceptability, or serious adverse events between sustained-release naltrexone and placebo.

Compared with treatment as usual, high-certainty evidence demonstrated reduced in-treatment illicit opioid use with sustained-release naltrexone (RR = 0.72; 95% CI, 0.57–0.90; ARD = 18.7%; NNT = 6; four studies; n = 479). Moderate-certainty evidence demonstrated fewer serious adverse events with sustained-release naltrexone vs treatment as usual (RR = 0.59; 95% CI, 0.36–0.95; ARD = 5.7%; NNT = 18; six studies; n = 1,009). However, low-certainty evidence showed that treatment as usual may decrease treatment initiation compared with sustained-release naltrexone (RR = 0.79; 95% CI, 0.69–0.90; ARD = 16.6%; NNH = 6; eight studies; n = 1,094). Low-certainty evidence demonstrated no apparent difference between groups in treatment retention.

No data examining sustained-release naltrexone and psychosocial treatments for opioid dependence were identified.

Caveats

Several factors limit the applicability of these findings. Most studies were conducted outside the United States, and treatment availability and policies differed greatly between countries. Vulnerable populations, including pregnant women, refugees, undocumented migrants or refugees, and individuals with significant mental health disorders, were excluded, limiting generalizability. The trials often were underpowered, were industry funded, and showed inconsistent results, with low- or very low-certainty evidence. Performance and detection bias were common because blinding was difficult, and heterogeneity in study design and outcomes further reduced confidence. Finally, differences in the formulation of the sustained-release naltrexone affects comparability across settings.

The original manuscript was published in Medicine by the Numbers, American Family Physician as part of the partnership between TheNNT.com and AFP.

Author

Ross Stanton, MD, JD, MPH; Joshua Lujan, DO; Christina Valerio, MD, MPH
Supervising Editors: Shahriar Zehtabchi, MD

Published/Updated

April 23, 2026