PurposeOpioids are considered the gold standard for controlling postoperative acute pain. However, side effects such as nausea, vomiting, respiratory depression, and pain sensitization have gained significant attention. The risks are higher in children with enlarged tonsils and sleep apnea, making effective pain management while minimizing analgesia-related side effects a pressing concern. Study DesignThis was a randomized (1:1), single-blind, parallel-group superiority trial. MethodA prospective single-blind study was conducted on 44 children aged 3-7 years who planned to undergo tonsillectomy under general anesthesia. They were randomized into two groups: the experimental group and the control group using computer-assisted randomization. The control group received standardized opioid drugs for general anesthesia induction and maintenance. In the experimental group, the opioid drugs used for anesthesia induction and maintenance were replaced with nonopioid alternatives such as esketamine and dexmedetomidine. The primary outcome of interest was the pain score within 48 hours after surgery, while the secondary outcomes included the time to first food ingestion, sleep quality, nausea, vomiting, respiratory depression, insufficient analgesia, number of children requiring hydromorphone rescue analgesia, and differences in psychological symptoms such as excitement and hallucinations, postoperative bleeding, and caregiver satisfaction. FindingsThe experimental group experienced significantly lower pain scores within 48 hours post-surgery compared to the control group, with statistical significance at P<0.0.1 for 6, 12, and 24 hours, and at P<0.05 for 48 hours post-surgery. In terms of the incidence of adverse events, children in the experimental group reported better sleep quality, less nausea and vomiting, and needed fewer instances of hydromorphone rescue analgesia than those in the control group. Additionally, the experimental group had higher caregiver satisfaction (P<0.0.5). ConclusionNonopioid anesthesia and analgesia regimens can improve pain scores within 48 hours after tonsillectomy in children, improve sleep quality, shorten the time to first food ingestion, reduce the incidence of insufficient analgesia and nausea and vomiting, and increase caregiver satisfaction.