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Background: The Surgical Pleth Index (SPI) is an objective tool that can reflect nociception-antinociception balance and guide the use of intraoperative analgesics. Multimodal analgesia has been neglected in many previous studies. The aim of this study was to compare fentanyl consumption using SPI-guided analgesia versus conventional analgesia techniques under multimodal analgesia in laparoscopic cholecystectomy. Methods: A total of 80 patients aged 18–65 years with American Society of Anaesthesiologists (ASA) grade I-II and a body mass index (BMI) of 18.5 to 30 kg/m2 who were scheduled for laparoscopic cholecystectomy under total intravenous anaesthesia from March 2020 to September 2020 were selected. Multimodal analgesia, including local infiltration of the surgical incision, nonsteroidal anti-inflammatory drugs and opioids, was adopted perioperatively. Fentanyl boluses of 1.0 µg/kg were administered to maintain the SPI value between 20 and 50 in the SPI group. By contrast, fentanyl boluses of 1.0 µg/kg were administered whenever the heart rate (HR) or mean arterial pressure (MAP) increased to 20 % above baseline or when the HR was greater than 90 beats per minute (bpm) in the control group. Preoperative and postoperative blood glucose, plasma cortisol and interleukin-6 (IL-6) levels were evaluated. Intraoperative haemodynamic events and propofol and fentanyl doses were noted. The extubation time, postoperative visual analogue scale (VAS) score, use of remedial analgesics and opioid-related adverse reactions were recorded. Results: In total, 18 of 80 patients withdrew for various reasons, and data from 62 patients were finally analysed. Intraoperative fentanyl consumption was significantly lower in the SPI group than in the control group (177.1 ± 65.9 vs. 213.5 ± 47.5, P = 0.016). The postoperative extubation time was shorter in the SPI group than in the control group (16.1 ± 5.2 vs. 22.1 ± 6.3, P < 0.001). Preoperative and postoperative blood glucose, plasma cortisol and IL-6 levels, intraoperative haemodynamic changes, postoperative VAS scores, remedial analgesic consumption and opioid-related adverse reactions were comparable in the two groups. Conclusions: Lower doses of fentanyl are required intraoperatively with shorter extubation times when SPI is used to guide intraoperative analgesia compared to conventional analgesia techniques under multimodal analgesia in laparoscopic cholecystectomy. Trial registration: Chictr.org.cn ChiCTR2000030145. Retrospectively Registered (Date of registration: February 24, 2020). [ABSTRACT FROM AUTHOR]