Methadone, Buprenorphine, and the Math of Fentanyl

"Methadone and buprenorphine are the best evidence-based treatments for OUD, and their use is associated with marked reductions in mortality rates (Santo et al., 2021). Nevertheless, a large and growing body of evidence suggests that MOUD initiation has become more difficult in the fentanyl era, with uptake of MOUD and engagement in treatment among people with OUD remaining low in the United States (Jones et al., 2023). Our results suggest that a major reason for this may be the relatively lower MME provided by typical methadone doses compared to typical illicit fentanyl consumption patterns. For instance, typical starting doses of methadone for OUD, ranging from 20 to 40 mg daily, are approximately equivalent to 94–188 MME daily. Even a high-end dose of 180 mg of methadone daily would be equivalent to 846 MME, representing only a small fraction of the estimated almost 9000 MME consumed daily by a typical participant in our sample. Methadone doses in this range are unusual, in part because of concerns about dose-dependent QT prolongation.

"Although it is generally not necessary or clinically appropriate to fully replace illicit opioid dosing during MOUD initiation, the provision of higher induction and maintenance doses of methadone, equivalent to a larger fraction of MME consumed via illicit fentanyl ingestion, may be warranted among patients using illicit fentanyl. Alternatively, augmenting methadone with other agents, such as slow-release oral morphine, may have similar benefits without the QT prolongation risk (Klimas et al., 2019). This may also help explain improved outcomes seen by some providers when initiating buprenorphine with higher doses, i.e. ‘macrodosing’ (Tsui et al., 2025), although the unique pharmacological properties of buprenorphine make a direct MME comparison more difficult. Through a nuanced understanding of their patients’ illicit fentanyl consumption patterns, and local drug checking results, physicians prescribing MOUD initiation may be able to better tailor dosing to improve patient comfort and improve retention in treatment."