Are Opioid Agonist Treatments Effective in the Fentanyl Era?

Medscape

14-07-2025

Opioid agonist treatments (OATs) such as methadone and buprenorphine-naloxone are standard therapy for opioid use disorder, but treatment duration is decreasing as fentanyl becomes more prevalent in the illicit opioid supply. Given that retention in OAT is a core measurement of treatment effectiveness, the finding underscores the urgent need for research and policy changes, according to a population-based, retrospective cohort analysis from Ontario.
Illicit opioids in Canada now contain more fentanyl than before. In 2022, almost 70% of opioid samples submitted for analysis in Canada contained fentanyl or fentanyl analogs.
'Fentanyl is substantially more potent than the prescription opioids and heroin that were previously most commonly used, and the fentanyl available today often has other substances mixed in,' study author Robert Kleinman, MD, told Medscape Medical News. 'We were interested in investigating these changes because many patients report that methadone and buprenorphine-naloxone are not as effective for them as they were before the fentanyl era.' Kleinman is a scientist at the Institute for Mental Health Policy Research within the Centre for Addiction and Mental Health and an assistant professor of psychiatry at the University of Toronto, Toronto.
The article was published online on July 1 in JAMA Network Open .
Differences by Treatment
The researchers compared the duration of methadone and buprenorphine-naloxone treatment during 2014-2016 (before fentanyl was common), 2017-2019 (as fentanyl was becoming more common), and 2020-2022 (the 'fentanyl era'). The population included 72,717 patients who were at least 15 years old and who began OAT during those periods. A total of 45,256 (62.2%) participants were men, and the population's median age was 35 years. In all, 34,538 patients (47.5%) received methadone, and 38,179 (52.5%) received buprenorphine-naloxone.
Administrative data were obtained from ICES, an independent nonprofit research institute in Ontario. The data contained demographic information, as well as information about outpatient methadone and buprenorphine-naloxone dispensation, including dispensing dates and number of take-home doses supplied.
The median duration for methadone use was 193 days in the 2014 to 2016 period, dropping to 86 days in 2020 to 2022. Patients who started methadone in later periods were more likely to stop treatment sooner. The risk for stopping methadone was higher among patients whose treatment was initiated in 2017-2019 (adjusted hazard ratio [aHR], 1.18; P < .001) and yet higher for those who started in 2020-2022 (aHR, 1.45; P < .001).
Buprenorphine-naloxone treatment duration decreased from 51 days during 2014-2016 to 38 days during 2020-2022. Patients who initiated buprenorphine-naloxone during 2020-2022 had a higher risk for discontinuation (aHR, 1.11; P < .001). It was unclear why methadone treatment duration decreased more prominently than did buprenorphine-naloxone treatment, according to the researchers.
Treatment was more likely to be discontinued early among younger individuals, particularly those aged 15-24 years. Other factors associated with early discontinuation included rurality, lower neighborhood income, and comorbidities.
'Opioid agonist treatments remain the most effective treatments for opioid use disorder, including for people using fentanyl,' Kleinman said. 'However, this study suggests that the effectiveness of the treatments may be lower than they were in the past. There are new approaches to providing these that either have been or are being developed, and research is continuing to evaluate these approaches among patients using fentanyl.'
'Compelling Data'
One of the study's limitations was that its source of data does not capture OAT dispensed in hospitals, long-term care homes, or prisons. Also, since the information was obtained through ICES databases, individuals who began OAT outside Ontario were not included in the analysis. Other individuals, such as members of the Indigenous population, may receive OAT through federal benefits and would also be excluded from the analysis.
Commenting on the study for Medscape Medical News , addiction medicine specialist Ryan Marino, MD, associate professor at the CWRU School of Medicine at Case Western Reserve University, Cleveland, said, 'These researchers have compelling data to show that there has been a significant decrease in the duration of time people are in treatment. I think the biggest takeaway is that we should really be wondering why.
'[This] isn't something that anyone was expecting to see, at least such a dramatic difference. Hopefully this will promote more investigation.'
The Centre for Addiction and Mental Health Discovery Fund, the Centre for Addiction and Mental Health Foundation, the Rangerman RAPID Lab, and the University of Toronto Department of Psychiatry Academic Scholar Award funded this study. Kleinman and Marino reported having no relevant financial relationships.