In patients with an opioid overdose in the past year, starting methadone was associated with a reduced risk for death during the subsequent year compared with starting buprenorphine-naloxone, according to a retrospective cohort study emulating a target trial.

Among close to 5900 matched participants, 5.6% of those who started methadone died within a year compared with 7.1% of those who started buprenorphine-naloxone. But the authors highlight the need for further, robust evaluation in epidemiologic studies and pragmatic trials.

“This is an observational study with inherent limitations, and the study requires replication in other jurisdictions,” lead author Robert Kleinman, MD, MSc, a scientist at the Centre for Addiction and Mental Health in Toronto, told Medscape News Canada. “Methadone and buprenorphine-naloxone are helpful for treating opioid use disorder, and both treatment options should be available to patients after opioid overdose.”

The study was published on August 25 in JAMA Network Open.

Short Treatment Durations

The researchers conducted a retrospective, matched cohort study with target trial emulation that included 5882 individuals. Participants’ mean age was 35.8 years, and 32.1% were women. The participants started methadone or buprenorphine-naloxone treatment in Ontario between January 2017 and December 2023.

Eligible participants had an emergency department visit for an opioid overdose in the past year and had not used either medication for 7 days. The primary outcome was death from any cause within 1 year, and the secondary outcomes were opioid overdose and treatment discontinuation.

In the group that started methadone, 165 individuals (5.6%) died within a year, compared with 210 (7.1%) in the buprenorphine-naloxone-initiating group (hazard ratio [HR], 0.78).

During the 1-year follow-up, 87.6% of those initiating methadone and 88.6% of those starting buprenorphine-naloxone discontinued treatment. The median time to treatment discontinuation was 25 days in the methadone group compared with 16 days in the buprenorphine-naloxone group (HR, 0.78).

Overall, 1544 participants (26.2%) in the matched cohort experienced an opioid overdose (either fatal or nonfatal) during the 1-year follow-up. In the methadone-initiating group, 797 individuals (27.1%) had an opioid overdose compared with 747 (25.4%) in the buprenorphine-naloxone-initiating group — a nonsignificant difference.

Treatment durations were short, particularly among participants starting buprenorphine-naloxone, and there was no significant difference in mortality during receipt of opioid agonist treatment (OAT), according to the authors. “These findings may be explained by unmeasured confounding, and epidemiologic studies in other jurisdictions are needed to confirm these findings,” they wrote.

‘Persistently Poor Outcomes’

In an accompanying editorial, Evan Wood, MD, PhD, professor of social medicine at the University of British Columbia in Vancouver, and Leen Naji, MD, PhD, assistant clinical professor of family, community, and preventive medicine at The University of Arizona in Phoenix, wrote that “the most noteworthy finding…may not be the potential modest relative differences between medications, but rather the persistently poor outcomes observed among overdose survivors, regardless of treatment choice. Approximately 6% of participants died within 1 year, more than one quarter experienced another overdose, and nearly 90% discontinued treatment during follow-up.”

The findings are consistent with evidence from other settings, they continued and suggest that “future questions may be less about determining whether one OAT medication confers a modest advantage over another, and more about how to ensure that patients are offered low-threshold access to evidence-based treatment and exploration of innovative efforts to better support patients to remain engaged in OAT care.”

Furthermore, they concluded, “it is long overdue that researchers, clinicians, and policymakers move beyond debating the potential differences in the relative merits of different forms of OAT and begin to start asking and addressing some of the bigger questions, including why initiating and remaining on OAT is so unattractive to most patients.”

Similarly, Kora DeBeck, PhD, distinguished professor of substance use and drug policy at Simon Fraser University in Vancouver, told Medscape News Canada, “[m]ethadone initiation was associated with lower 1-year mortality, but the mortality difference disappeared during periods when patients remained on treatment. This and other evidence suggest that retention and adherence are likely the major drivers of the protective effects of medications.” DeBeck did not participate in the study.

“For clinicians, policymakers, and service providers, the key priority should be reducing barriers to sustained treatment engagement,” she said. The findings are also relevant to involuntary treatment initiatives, she added. They underscore that “simply initiating treatment is unlikely to be sufficient if individuals do not remain engaged. This is particularly important in the fentanyl era, where treatment interruption may carry substantial risk due to loss of tolerance and ongoing exposure to a highly potent drug supply.”

The study was funded by the Innovation Fund Alternative Funding Plan for the Academic Health Sciences Centres of Ontario, the University of Toronto Department of Psychiatry Academic Scholar Award, and the Fonds de Recherche du Québec Santé. The study also was supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health and the Ministry of Long-Term Care. Kleinman reported receiving grants from the University of Toronto Department of Psychiatry Academic Scholar Award, the Innovation Fund of the Alternative Funding Plan of the Academic Health Sciences Centres of Ontario, and the Centre for Addiction and Mental Health Foundation during the conduct of the study. He reported holding stock in Pfizer and Novo Nordisk outside the submitted work. DeBeck reported no relevant financial relationships.

Marilynn Larkin, MA, is an award-winning medical writer and editor based in New York City whose work has appeared in numerous publications, including Medscape Medical News and its sister publication MDedge, The Lancet (where she was a contributing editor), and Reuters Health.