Intraoperative Mild Hypothermia Alleviate Acute Postoperative Pain Through Attenuating Sufentanil Metabolism: A Prospective Cohort Study with Experimental Validation.

Background: Inadvertent perioperative hypothermia is common during anesthesia, but its association with acute postoperative pain remains unclear. We investigated whether the cumulative intraoperative temperature exposure below 36°C was associated with postoperative pain after laparoscopic surgery and explored a potential mechanism involving sufentanil disposition and hepatic CYP3A activity. Methods: This single-center prospective observational cohort, included 229 adults undergoing elective laparoscopic abdominal surgery under general anesthesia with continuous tympanic temperature monitoring. The primary clinical endpoint was moderate-to-severe postoperative pain, defined as any numerical rating scale (NRS) score ≥4 within 24 h after surgery. Temperature exposure was summarized as the percentage of the recorded intraoperative period spent below 36°C (percentage of hypothermia time, POH), with POH ≥30% evaluated as the main exposure threshold. Complementary experiments used a mouse plantar-incision model to assess mechanical withdrawal thresholds, plasma sufentanil pharmacokinetics, and hepatic CYP3A catalytic activity under controlled lower-temperature and normothermic conditions. Results: In the clinical cohort, 76 of 229 patients (33.2%) developed NRS ≥4 pain within 24 h. POH ≥30% was independently associated with lower odds of moderate-to-severe postoperative pain (adjusted odds ratio, 0.23; 95% confidence interval, 0.08-0.65; P=0.005), lower early postoperative NRS scores, and less rescue analgesics use. Temperatures <35°C was uncommon, and perioperative complications did not differ between groups. In mice, lower body temperature (32.26±0.48°C) prolonged sufentanil analgesia compared with normothermia (37.32±0.32°C), increased early plasma sufentanil exposure, prolonged elimination half-life, reduced clearance, and decreased hepatic CYP3A catalytic activity. Conclusion: Greater cumulative exposure to mild intraoperative hypothermia was associated with less acute postoperative pain and lower rescue analgesic use after laparoscopic surgery. Experimental findings suggest that lower temperature may prolong sufentanil exposure by suppressing CYP3A-mediated metabolism. These findings do not support inducing hypothermia but indicate that intraoperative temperature may influence opioid pharmacokinetics and should be considered when integrating thermal management with perioperative analgesic strategy.