A moderate body of research has shown that naltrexone is more effective than no medication in reducing opioid use but less effective than buprenorphine and methadone. A recent meta-analysis of 22 randomized trials found that, compared to no medications, naltrexone reduces the risk of opioid use by 28%. Compared to buprenorphine and methadone, however, individuals taking naltrexone had a 15% higher risk of opioid use.

Naltrexone is not as effective at reducing opioid overdose mortality as buprenorphine or methadone. There is mixed data on whether naltrexone is more effective than receiving no medications in reducing opioid mortality. In a large national observational study, individuals taking naltrexone showed no difference in opioid-related overdose compared to receiving no medications for opioid use disorder, while individuals taking either buprenorphine or methadone had a 76% reduction in opioid-related overdoses.

In a study of Massachusetts data, naltrexone treatment was not associated with any change in opioid-related deaths in the 12 months following a non-fatal overdose, while buprenorphine and methadone were associated with 38% and 59% reductions, respectively. By contrast, an analysis of two clinical trials found that naltrexone was protective against opioid-related death during active treatment, but was associated with elevated risk of overdose in the year immediately following cessation of naltrexone.

Treatment retention, or the duration of time individuals stay in treatment, is typically measured by attendance at outpatient appointments or regular receipt of scheduled naltrexone injections. Although there have been a moderate number of randomized trials evaluating this outcome, there is no clear evidence that naltrexone increases treatment retention compared to buprenorphine or methadone and compared to no medications for opioid use disorder. A meta-analysis found that retention was 63% higher among patients receiving naltrexone than among patients who were not receiving naltrexone, but the results were not significant. By contrast, meta-analyses have shown that both buprenorphine and methadone improve treatment retention.