Sex-Related Analgesic Effects of Opioid-Based Anesthesia and Low-Opioid Anesthesia with Non-Opioid Postoperative Analgesia—A Clinical Observational Study

<b>Background/Objectives:</b> Sex is a crucial factor in modulating the perioperative aspects of anesthesia. A growing number of studies demonstrate that women and men experience pain differently and respond differentially to analgesics. <b>Methods:</b> This study evaluated the analgesic trajectory of low-opioid anesthesia (LOA) and opioid-based anesthesia (OBA) in women and men after laparoscopic cholecystectomy. The primary objective was to assess pain intensity at various time intervals after surgery (0-2, 2-6, 6-12, and 12-24 h) using the Numerical Rating Scale (NRS). The secondary objective was to assess the difference in mean pain intensity on the first postoperative day between the women and men. <b>Results:</b> The mean pain intensity did not differ significantly for men using LOA and OBA, but the value was significantly lower in the LOA group for women (<i>p</i> = 0.0002). The analgesic trajectory in women and men undergoing LOA presented a negative trend, but the pain intensity at 0-2, 2-6, 6-12, and 12-24 h in women was statistically lower than that of the OBA group (<i>p</i> = 0.01, <i>p</i> = 0.008, <i>p</i> = 0.002, and <i>p</i> = 0.001). Total fentanyl doses of 0.3 mg (sensitivity 44%, specificity 76%, AUC 0.55) and 0.35 mg achieved a mean NRS of <2 for pain intensity in the female and male OBA groups (sensitivity 33%, specificity 100%, AUC 0.53). <b>Conclusions:</b> A model combining low-opioid anesthesia and non-opioid postoperative analgesia presents a favorable therapeutic effect for women. OBA does not provide proper analgesic effects after laparoscopic cholecystectomy.