| Summary: | Abstract Background Although opioids are commonly prescribed in clinical anaesthesia, the significant side effects attributed to their overuse are raising increasing concerns. One way to reduce perioperative opioid consumption is to apply opioid-reduced anaesthesia (ORA) and even opioid-free anaesthesia (OFA), which involves regional techniques, neuraxial anaesthesia, nonopioid analgesics or combined use. The aim of this study was to investigate whether the application of OFA by using esketamine in intraoperative analgesia could minimize the side effects of postoperative nausea and vomiting (PONV), as well as other short-term side effects related to anaesthesia. Methods/design The study was designed as a prospective, randomized, controlled, multicentre trial. A total of 278 patients were enrolled; participants were nonsmoking female patients aged 18–50 years and scheduled for laparoscopic appendectomy or cholecystectomy, ASA at I–III, with no serious physical or mental diseases. Both groups received usual perioperative care except for the analgesic medication of either esketamine or sufentanil. The primary outcome was the incidence of PONV 3 days after surgery. Secondary outcomes included recovery status, pain, sedation level and overall recovery, delirium and cognition, anxiety and depression and total consumption of analgesic agents. Discussion This trial may show that the synergy of esketamine and propofol anaesthesia reduces PONV as well as other short-term adverse events, thereby providing a better safety and satisfaction profile of ERAS for laparoscopic appendectomy and cholecystectomy. Trial registration Chinese Clinical Trial Registry ChiCTR2100047169. Registered on June 9, 2021
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