Review of: Degenhardt L et al, Lancet Psychiatry 2023;10:386–402.

Study type: Meta–Analysis of Randomized Controlled Trials and Observational Studies

Effective treatment of opioid use disorder (OUD) remains a significant clinical challenge. Methadone and buprenorphine are both first-line treatment options, but how should prescribers choose between them? The last large meta-analysis in 2014 concluded that buprenorphine and methadone were both effective for OUD, but methadone was associated with better treatment retention (Mattick RP et al, Cochrane Database Syst Rev 2014;2014(2):CD00207). Researchers have conducted a larger study to see how these results hold up 10 years later.

Their massive systematic review and meta-analysis included 83 randomized controlled trials and 193 observational studies comprising over a million participants. Primary outcomes were treatment retention, treatment adherence, and non-prescription opioid use. A few of the many secondary outcomes examined included drug overdose, non-opioid drug use, suicidality, and various measures of physical and mental health. 

In terms of treatment retention, the two medications were equivalent one month after starting treatment, but methadone had the edge at 3, 6, and 12 months, a finding that held for RCTs and observational studies. In terms of the other primary outcomes, buprenorphine was associated with lower rates of non-prescription opioid use, though this finding only held in a subgroup of RCTs. Treatment adherence was similar between methadone and buprenorphine groups. 

Analyses of secondary outcomes in small subgroups of studies revealed some interesting findings. For example, buprenorphine was associated with less self-reported cocaine use, anxiety, and QTc prolongation; whereas methadone was associated with lower rates of hospitalization and alcohol use.

As with all meta-analyses, heterogeneity between studies is a limitation. There was no assessment of dosage effects, accessibility issues, and differences between buprenorphine formulations, and we don’t know if the improved treatment retention with methadone led to better physical or mental health outcomes. Finally, the authors acknowledge that they were unable to quantify how the influx of fentanyl into the illicit opioid market may have affected their results, though it isn’t clear which treatment this might favor.

Carlat Take:
This study is the best evidence to date that methadone and buprenorphine are both effective for OUD. While methadone is associated with improved treatment retention, the medications were largely comparable in other primary and secondary outcomes. Without a clear winner, these results underscore the importance of personalized treatment; consider methadone for those who might have adherence challenges or benefit from greater structure; consider buprenorphine for those unable to access methadone, have a history of good treatment adherence, or specific cardiac issues.