Nalbuphine and esketamine combination prevented postoperative hyperalgesia in patients undergoing laparoscopic cholecystectomy: a factorial design, double-blind, randomized controlled trial

Abstract Perioperative continuous infusion of remifentanil can lead to postoperative hyperalgesia. Nalbuphine and esketamine are adjunctive analgesics in general anesthesia. This study aimed to investigate the effect of the preoperative combined application of esketamine and nalbuphine on remifentanil-induced hyperalgesia in patients. 148 patients were randomly assigned to Group C (received normal saline preoperatively), Group N (received 0.2 mg/kg nalbuphine preoperatively), Group S (received 0.15 mg/kg esketamine preoperatively), and Group NS (received 0.2 mg/kg nalbuphine and 0.15 mg/kg esketamine preoperatively). The primary outcome was the pain threshold around the incision measured by von Frey filaments up to 24 h after surgery. The secondary outcomes were the pain threshold values of the inner forearm, the visual analog scale after surgery, and any other adverse reactions. There was no interaction between nalbuphine and esketamine ( P > 0.05), and the main effects of the two drugs were all significant ( P < 0.05). Compared with Group C, patients in Group N, Group S, and Group NS had higher pain thresholds ( P < 0.05). Compared with Group N and S, patients in Group NS had higher pain thresholds of the inner forearm at 1 h and around the wound at 1 h and 24 h postoperatively ( P < 0.05). Compared with Group C, patients in Group N and Group NS had lower postoperative VAS scores ( P < 0.05). Compared with Group N and S, patients in Group NS had lower postoperative VAS scores ( P < 0.05). Factorial analysis demonstrated significant main effects of nalbuphine and esketamine on postoperative mechanical pain thresholds, with no significant interaction between the two interventions. In patients undergoing laparoscopic cholecystectomy, nalbuphine and esketamine can independently contribute to prevent postoperative hyperalgesia. Trial Registration : The research protocol was registered in the China Clinical Trial Registration Center (ChiCTR2200061927). Date: 11/ 07/ 2022.