Methadone initiation linked to lower mortality compared to buprenorphine-naloxone after opioid overdose
1. In this retrospective cohort study examining people who had survived a recent opioid overdose, initiating methadone was associated with lower all-cause mortality over the following year compared with initiating buprenorphine-naloxone.
2. Methadone initiation was also associated with longer treatment retention, although overdose risk was higher during active treatment.
Evidence Rating Level: 2 (Good)
Study Rundown: Survivors of nonfatal opioid overdose remain at particularly high risk for subsequent overdose and death. Opioid agonist treatment with methadone or buprenorphine is a cornerstone of opioid use disorder care and is associated with lower mortality, but comparatively little evidence has established whether one medication offers greater benefit for patients who have recently overdosed, particularly in the fentanyl era. In this population-based retrospective cohort study, researchers used a target trial emulation approach to compare people initiating methadone with matched individuals initiating buprenorphine-naloxone after an emergency department visit for opioid overdose. Methadone initiation was associated with lower all-cause mortality during the subsequent year as well as with longer treatment retention. The groups did not significantly differ in overall risk of recurrent opioid overdose. However, analyses restricted to periods when participants remained on their initially prescribed treatment showed no significant mortality difference, while methadone was associated with greater overdose risk during active treatment. Strengths included population-level health data, extensive adjustment for measured confounders, and complementary initiator and per-protocol analyses. Still, treatment selection was not randomized, leaving meaningful potential for residual confounding, particularly because prior opioid agonist treatment histories differed substantially before matching. Overdoses not resulting in emergency care were also not captured, and changes in treatment exposure after initiation were not modeled in the primary analysis. These findings suggest that sustained engagement with effective opioid agonist therapy may be equally important to the initial medication selected.
Click to read the study in JAMA
Relevant Reading: Mortality risk and causes of death among people who use opioids in a take-home naloxone cohort
In-Depth [retrospective cohort]: This population-based retrospective cohort study used linked administrative health data from Ontario, Canada, to emulate a target trial comparing methadone with sublingual buprenorphine-naloxone among individuals aged 15 years or older who initiated opioid agonist treatment between 2017 and 2023 after an emergency department visit for opioid overdose within the preceding year. Matching was performed in a 1:1 ratio using propensity scores, sex, and treatment initiation date. The primary outcome was all-cause mortality within 1 year using an initiator analysis; secondary outcomes included treatment discontinuation and opioid overdose. The matched cohort included 5,882 individuals, with 2,941 participants in each treatment group. During 1 year of follow-up, 165 participants initiating methadone died compared with 210 initiating buprenorphine-naloxone (5.6% vs 7.1%; hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.63 to 0.95; P=0.01). Methadone was also associated with a lower hazard of treatment discontinuation (HR, 0.78; 95% CI, 0.74 to 0.82; P<0.001). Median treatment duration was 25 days with methadone and 16 days with buprenorphine-naloxone. There was no significant difference in overall time to recurrent opioid overdose (HR, 1.07; 95% CI, 0.97 to 1.18; P=0.17). In the per-protocol analysis restricted to periods of active treatment, mortality did not significantly differ between methadone and buprenorphine-naloxone (HR, 0.84; 95% CI, 0.48 to 1.47; P=0.55). Methadone was, however, associated with an increased hazard of opioid overdose during active treatment (HR, 1.52; 95% CI, 1.19 to 1.93; P<0.001). Overall, the high rates of treatment discontinuation and death in this study highlight the importance of improving outcomes among those with opioid use disorder.
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