Optimising post-operative pain management is crucial for recovery in orthopaedic surgery. Methadone has attracted interest due to its long half-life, N-methyl-D-aspartate -receptor antagonism and potential to reduce post-operative opioid consumption. Existing reviews combine multiple surgical populations, limiting applicability to orthopaedic settings. This protocol outlines a systematic review assessing the analgesic efficacy and safety of peri-operative methadone in adult and adolescent orthopaedic patients.

This review will include randomised controlled trials evaluating intravenous peri-operative methadone vs placebo or standard analgesic regimens in orthopaedic surgery. Primary outcomes are post-operative rescue opioid consumption and pain intensity within 72 hours. Secondary outcomes include adverse events, mobility scores and the length of hospital stay. If available data permit, a methadone dose–response pattern may be investigated. Searches will be conducted in MEDLINE (Ovid), Embase (Ovid), CINAHL, CENTRAL, Web of Science and ClinicalTrials.gov without date restrictions. Two reviewers will independently screen studies, extract data and assess risk of bias using the Cochrane risk-of-bias tool for randomised trials. When appropriate, random-effects meta-analysis methods will be performed. Certainty of evidence will be assessed using Grading of recommendations assesment, development and Evaluation (GRADE).

As this study uses previously published data, ethical approval is not required. Findings will be disseminated through a peer-reviewed publication and conference presentations.

CRD42025616291.