Initiation and Dose of Methadone Monotherapy vs Combination Therapy, 2015 to 2023

The increased potency of the fentanyl-dominated drug supply has precipitated a shift in patient-reported opioid tolerance and methadone prescribing guidance. However, adoption of new methadone prescribing approaches remains unknown.

To examine methadone initiation trends within the context of changing prescribing guidance and an increasingly volatile unregulated drug supply.

This repeated cross-sectional study was performed among a cohort of methadone initiations in Ontario, Canada, between January 2015 and July 2023.

Release of new methadone prescribing guidance.

The primary outcomes were monthly rates (per 100 000 Ontario population) of methadone initiated as monotherapy vs in combination with slow-release oral morphine and trends for the maximum methadone dose dispensed on treatment days 1, 2 to 7, and 8 to 14. Interventional autoregressive integrated moving average models were used to examine the association of new guidance with observed trends. Secondary outcomes assessed medication use in the 2 weeks following initiation.

A total of 70 564 initiations of methadone monotherapy and 3069 initiations of combination therapy were identified. Most of the 35 309 unique study participants were aged 25 to 44 years (51 999 episodes [70.6%]) and male (45 212 episodes [61.4%]). The release of new methadone prescribing guidance was associated with a significant decrease in monotherapy initiations (ramp estimate, -0.27 per 100 000; 95% CI, -0.48 to -0.07 per 100 000; P = .01), and a parallel increase in combination therapy initiations. Starting in 2018, a shift toward attainment of higher doses was noted. This trend was accelerated following release of new guidance, which was associated with decreased initiation at doses less than 30 mg (ramp estimate, -1.57%; 95% CI, -2.87% to -0.27%; P = .02) and increased attainment of doses of 40 mg to less than 50 mg (ramp estimate, 0.63%; 95% CI, 0.13% to 1.13%; P = .01) in treatment week 1 and 60 mg or higher (ramp estimate, 0.71%; 95% CI, 0.25% to 1.17%; P = .002) in treatment week 2. The proportion of monotherapy episodes without a dose increase in the first 2 weeks increased significantly from 38.5% (18 390 episodes initiated before September 2020) to 45.7% (10 416 episodes) afterward. The absolute amount by which methadone doses were titrated remained generally stable over time.

In this repeated cross-sectional study of methadone initiations, a shift toward higher starting doses and in combination with slow-release oral morphine was noted. Provision of subsequent rapid dose titration remained limited, representing a potential missed opportunity for quicker attainment of therapeutic doses.