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Single preoperative gabapentinoid (gabapentin and pregabalin) administration has been associated with respiratory depression during Phase I anaesthesia recovery. In this study, we assess for associations between chronic (home) use and perioperative administration (preoperative and postoperative) of gabapentinoids, and risk for severe over-sedation or respiratory depression as inferred from the use of naloxone.From 2011 to 2016, we identified patients undergoing general anaesthesia discharged to standard postoperative wards and administered naloxone within 48 h of surgery in a single centre. These patients were 2:1 matched on age, sex, and type of procedure. Patient and perioperative characteristics were abstracted and compared to assess for risk for naloxone administration.We identified 128 patients that received naloxone after operation [odds ratio 1.2; 95% confidence interval (CI) 1.0, 1.4 per 1000 general anaesthetics]. Patients on chronic or postoperative gabapentinoid therapy were at significantly higher risk for receiving naloxone after operation. Multivariable analysis detected significant interactions between chronic and postoperative use of gabapentinoids, where continuation of chronic gabapentinoid medications into the postoperative period was associated with an increased rate of naloxone administration (6.30, 95% CI 2.4, 16.7; P=0.001). Obstructive sleep apnoea (P=0.005) and preoperative disability (P=0.003) were also associated with an increased risk for postoperative naloxone administration. Patients who received naloxone had longer hospital stays and higher rates of postoperative delirium.Continuation of chronic gabapentinoid medications into the postoperative period is associated with the increased use of naloxone to reverse over-sedation or respiratory depression. Such patients requiring this therapy warrant high levels of postoperative monitoring.