(A-077) Association between early methadone dose titration and opioid toxicity and discontinuation: A population-based cohort study

Background: New methadone prescribing guidance recommends dose titration during the first four to six days of treatment, rather than six to eight for individuals at low risk of methadone toxicity to support faster attainment of a therapeutic dose and improve treatment retention. However, the risk of methadone accumulation and subsequent toxicity remains unknown.

Objectives: To investigate the association between early methadone dose titration and opioid toxicity and methadone discontinuation.

Methods: We conducted a retrospective population-based cohort study among incident recipients of methadone monotherapy in Ontario, Canada between January 1, 2017, to December 31, 2022. We compared individuals who received their first dose titration between treatment days four to six (i.e., exposed) to those without a dose increase within the first six days (i.e., unexposed). Index date was defined as date of dose increase and randomly assigned during the fourth to sixth day of treatment among those exposed and unexposed, respectively. The number of days in between treatment initiation and index date followed the same distribution in the exposed and unexposed groups. Unexposed individuals who were not alive or not dispensed methadone on index date were excluded from the study. We used Cox proportional hazard models with 95% confidence intervals (CI) and inverse propensity score weighting to estimate the hazard of methadone discontinuation and opioid toxicity within 181 days of index.

Results: The final cohort included 19,689 individuals initiating methadone monotherapy, of which 11,620 (59.0%) received early dose titration while 8,069 (41.0%) were dispensed the same dose for the first six days of treatment. The median age was 29 to 42 years old, with 35.8% being female. Demographic and clinical characteristics were generally well balance between exposure groups. However, prior to application of propensity-score weighting a significantly greater proportion of exposed individuals were dispensed methadone the day prior to index (91.1% vs. 78.1%) and every day between the date of initiation and index date (85.3% vs. 61.0%) compared to those unexposed. Crude hazard of opioid toxicity (10.8 vs. 14.3 events per 100 person years; hazard ratio [HR] = 0.75, 95% CI = 0.67, 0.84) and methadone discontinuation (236.4 vs. 415.8 events per 100 per years; median time to discontinuation 87 vs. 29 days; HR = 0.62, 95% CI = 0.6, 0.65) was significantly lower among those exposed versus unexposed.

Conclusions: Preliminary findings demonstrate the benefits of early dose titration in improving methadone retention and preventing opioid toxicity.