(46) QTc Prolongation of Slow-Release Oral Morphine vs Methadone for Opioid Use Disorder

Background & Introduction: With the unprecedented opioid crisis in North America, additional therapeutic options for medications for opioid use disorder (MOUD) are needed. Slow-release oral morphine (SROM) has been approved as a treatment for opioid use disorder (OUD) in several European countries and for off-label use in Canada [1]. Small studies have suggested comparable efficacy to methadone, with possible improved treatment satisfaction and adverse event profile such as less QTc prolongation [2, 3]. QTc interval prolongation is a predictor of torsades de pointe (TdP), a life-threatening cardiac arrhythmia [4]. While methadone has been associated with increased QTc prolongation compared to SROM in small studies, the real-world differences, magnitude of the effect, and whether this translates into a clinically meaningful difference is unknown. Therefore, this purpose of this study was to compare the QTc prolongation between SROM vs methadone using population-level data.

Methods: We evaluated QTc prolongation as a prespecified secondary outcome of the pRESTO target emulated trial based on population-level data from British Columbia, Canada [5]. Linked administrative data was analyzed from adults (aged 18-65 years) with opioid use disorder (OUD) with an outpatient visit within Vancouver Coastal Health, British Columbia, Canada between July 1, 2017 and June 30, 2024. We included patients with both a baseline off-treatment ECG and ECG during treatment with SROM or methadone. Patients with a cancer diagnosis within one year, long QT syndrome, history of cardiac arrest, torsades or other unspecified cardiac arrythmias were excluded. The primary outcome was change in QTc duration in milliseconds (ms) at baseline vs. on treatment. Secondary outcomes included QTc prolongation >500 ms on treatment (a common threshold that predicts increased risk of TdP) and cardiac arrythmias or arrest events on treatment. Multivariable analyses with a difference in differences design for the primary outcome was performed, adjusting for year of ECG and known predictors of QTc, including age, gender, comorbidities, other QTc prolonging medications, and methadone/SROM dose. Propensity score matching using inverse probability weighting was used to balance characteristics between the SROM and methadone groups.

Results: A total of 1371 patients (n=962 for methadone, n=409 for SROM) met eligibility criteria and were included in the analysis. The sample consisted of 71.6% males, with a median age of 45 (interquartile range, IQR 36-54). Baseline QTc prior to treatment was 431±30 ms for the methadone and 426±29 ms for the SROM groups. The average dose of medication for 3 days prior to the ECG on treatment was 90 mg for methadone and 550 mg for SROM, which are both considered therapeutic doses, with the average dose considered a high dose for methadone and a moderate dose for SROM. The median days on treatment prior to the ECG was 68 days for the methadone group and 41 days for the SROM group. Multivariable analysis demonstrated significant treatment effects on the QTc interval. The QTc on methadone was 438 ms (95% Confidence Interval (CI) 435, 440) and 425 ms (95% CI 422, 428) with SROM treatment. The QTc with methadone treatment increased by 6.6 ms (95% confidence interval, CI 4.1, 9.0) compared to a reduction of 0.9 ms (95% CI -4.5, 2.7) in the SROM group after treatment (p < 0.001). The number of participants with QTc >500 ms on treatment was 43 (4.3%) with methadone and 11 (2.7%) with SROM (p=0.51); however, we were underpowered to assess for differences between groups. There were 6 (0.6%) new cardiac arrest and/or arrythmias events in the methadone group and no new events in the SROM group during the study period, although the study was underpowered to performed multivariable analysis on this outcome.

Conclusion & Discussion: This study is the first to compare QTc prolongation between methadone vs SROM using real-world data. There was a statistically significant increase in QTc interval with methadone treatment compared to SROM. Notably, while the study was underpowered to assess the difference between treatments in proportion of patients with QTc >500 ms and cardiac arrhythmia events, these were numerically higher in the methadone group. Overall, this study is consistent with the current literature that methadone is associated with increased QTc prolongation compared to SROM. Future research is needed to evaluate whether the QTc prolongation with methadone compared to SROM translates into a clinically meaningful increased risk of cardiac arrhythmia/arrest.

References: [1] Verthein U, Beck T, Haasen C, et al. Mental symptoms and drug use in maintenance treatment with slow-release oral morphine compared to methadone: results of a randomized crossover study. Eur Addict Res 2015; 21: 97–104.
[2] Hämmig R, Köhler W, Bonorden-Kleij K, et al. Safety and tolerability of slow-release oral morphine versus methadone in the treatment of opioid dependence. J Subst Abuse Treat 2014; 47: 275–281.
[3] Ferri M, Minozzi S, Bo A, et al. Slow-release oral morphine as maintenance therapy for opioid dependence. Cochrane database Syst Rev; 2013. Epub ahead of print 5 June 2013. DOI: 10.1002/14651858.CD009879.PUB2.
[4] Trinkley KE, Lee Page R, Lien H, et al. QT interval prolongation and the risk of torsades de pointes: essentials for clinicians. Curr Med Res Opin 2013; 29: 1719–1726.
[5] Anand R, Penta S, Cui Z, et al. Redesigning a Stopped Clinical Trial as an Emulated Trial Using Real-World Data to Explore the Effectiveness of Slow-Release Oral Morphine as a Treatment for Opioid Use Disorder. Subst use Addict J 2025; 46: 384–390.