BMJ Open. 2026 Aug 14;16(8):e118322. doi: 10.1136/bmjopen-2026-118322.
ABSTRACT
INTRODUCTION: Methadone is a long-acting opioid used to treat opioid use disorder, cancer pain and provide perioperative analgesia. Methadone administration has been associated with QTc interval prolongation and consequently an increased risk of ventricular arrhythmias. This mechanism appears to be mediated by HERG channel inhibition, drug-drug interactions and genetic susceptibility. This protocol describes the methodology for a systematic review and meta-analysis aiming to evaluate the association between methadone administration and QTc prolongation and estimate the odds of major cardiac events. Our leading hypothesis is that methadone exerts a dose-dependent and time-dependent effect on QT prolongation.
METHODS AND ANALYSIS: We will conduct a systematic literature search of randomised controlled trials, prospective and retrospective cohort studies and case-control studies involving adult or paediatric patients receiving oral or intravenous methadone for opioid use disorder, cancer-related pain and surgical pain. Searches will be performed in Ovid MEDLINE, Ovid Embase, Cochrane CENTRAL, Web of Science and ClinicalTrials.gov. The primary outcome will be QTc interval length (in milliseconds). Secondary outcomes will include odds of clinically significant QTc prolongation and major adverse cardiac events. Comparator groups will include baseline pre-methadone QTc measurements and an external control group not exposed to methadone. Random-effects meta-analyses will be conducted, reporting mean differences with 95% CIs. Prespecified subgroup analyses based on methadone dose and duration of exposure will be performed when feasible. Risk of bias will be assessed using the Cochrane Risk of Bias 2 tool for randomised studies and Risk Of Bias In Non-Randomised Studies-of Interventions for non-randomised studies. The certainty of evidence will be evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework.
ETHICS AND DISSEMINATION: Ethical approval is not required. We will include data obtained exclusively from previously published peer-reviewed studies available in reputable databases. The results of this study are intended for dissemination via publication in a peer-reviewed journal.
PROSPERO REGISTRATION NUMBER: CRD420251143441.
PMID:42601094 | DOI:10.1136/bmjopen-2026-118322