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Abstract Purpose This study aims to investigate the effects of combining esketamine with sufentanil for postoperative patient-controlled intravenous analgesia (PCIA) in patients undergoing elective impacted tooth surgery or open reduction and internal fixation. Methods In this single-center, prospective, double-blinded, randomized, parallel-controlled trial, 91 patients were randomly divided into two groups. The experimental group (group ES, n = 46) received a combination of sufentanil 1.5 µg/kg and esketamine 1.0 mg/kg, while the control group (group S, n = 45) received sufentanil 2 µg/kg alone for PCIA after surgery. Primary outcome was assessed using the Visual Analogue Scale (VAS) for patients at rest and during mouth opening at 6 h, 12 h, 24 h, and 48 h post-surgery. Secondary outcomes included the Ramsay Sedation Scale (RSS) scores, the Quality of Recovery-15 (QoR-15) scores, patient satisfaction with analgesia, and the occurrence of adverse events within 48 h post-surgery. The frequency of PCIA button presses and the number of patients requiring rescue analgesia were also recorded. Results The resting VAS scores and the mouth-opening VAS scores at 6 h, 12 h, 24 h, and 48 h post-surgery were significantly lower in Group ES than in Group S (P |