Abstract
INTRODUCTION: Methadone has emerged as a promising option for perioperative pain management, primarily due to its rapid onset of action and prolonged duration of effect, which provides sustained analgesic benefits. Despite its clinical advantages and minimal reported risks for postoperative respiratory depression, concerns about its potential respiratory complications persist. This protocol outlines a meta-analysis aimed at evaluating the risk of respiratory depression associated with methadone administration in the perioperative setting compared with other opioids or placebo. METHODS AND ANALYSIS: We will perform a systematic review of literature published in English from 1 January 1970 to the present using Ovid MEDLINE, Ovid Embase and Cochrane CENTRAL. Eligible studies will consist of randomised controlled trials, cohort studies and case-control studies reporting respiratory depression in surgical patients receiving intravenous methadone. Case reports, reviews and non-English studies will be excluded. The primary outcome is respiratory depression, defined as naloxone administration, a respiratory rate of fewer than 8 breaths per minute, or an arterial oxygen saturation below 90%. Secondary outcomes include the timing and dose-response effect of methadone on respiratory depression. Bias will be evaluated using the Cochrane Risk of Bias Assessment 2 and ROBINS-I tools. Meta-analyses will be performed, and effect estimates will be presented as relative risks or ORs with 95% CIs. The certainty of the evidence will be assessed using Grading of Recommendations Assessment, Development and Evaluation methodology. ETHICS AND DISSEMINATION: Ethics approval is not necessary for this systematic review and meta-analysis. The results will be published in a peer-reviewed journal and presented at national and international conferences focused on perioperative medicine and pain management. PROSPERO REGISTRATION NUMBER: CRD42025630383.