Risk factors and clinical implications of QTc prolongation in methadone maintenance therapy: a systematic review

Objective Methadone, a synthetic opioid agonist widely used for opioid substitution therapy and chronic pain management, has been increasingly associated with concerns regarding cardiac safety, particularly QTc prolongation and its potential to precipitate ventricular arrhythmias. The aim of this systematic review was to summarize the available evidence on the relationship between methadone maintenance therapy and QTc prolongation, and to identify key clinical and treatment-related factors. Methods A comprehensive search of Embase, PubMed, and Scopus databases was conducted up to 2025 in accordance with PRISMA guidelines. The two reviewers independently selected the studies, extracted the data, and evaluated the quality of the reports based on the STROBE checklist. Due to heterogeneity across studies, a narrative synthesis was undertaken. Results In all, 25 studies met the inclusion criteria and were included in the final narrative synthesis. Overall, the available evidence suggests a consistent association between methadone use and QTc prolongation. The effect appears to be dose-related and is more pronounced in female patients and those receiving concomitant medications, particularly benzodiazepines. Notably, several studies have reported QTc prolongation even at relatively low methadone doses. Conclusions In summary, methadone maintenance therapy is associated with a clinically relevant risk of QTc prolongation, which may increase susceptibility to ventricular arrhythmias in vulnerable patients. These findings underscore the importance of careful cardiac monitoring and individualized risk assessment in clinical practice.