Effects of opioid-free and opioid-sparing anesthesia on postoperative delirium: A systematic review and meta-analysis

Background: Postoperative delirium (POD) is a common neurocognitive condition linked with increased morbidity, long-term cognitive decline, and death. Perioperative opioid exposure may contribute to delirium through sedation, neuroinflammation, and neurotransmitter dysregulation. Opioid-free anesthesia and opioid-sparing anesthesia using agents such as ketamine, esketamine, and dexmedetomidine have emerged as a potential strategy to reduce POD. This meta-analysis evaluated the effects of opioid-free and opioid-sparing anesthetic regimens on POD in adult surgical patients. Methods: Embase, PubMed, and Web of Science were searched from inception to April 2026. Randomized controlled trials comparing ketamine-, esketamine-, or dexmedetomidine-based opioid-free and opioid-sparing strategies with placebo, conventional opioid-based anesthesia, or standard care were included. The primary outcome was POD. Risk ratios (RRs) with 95% confidence intervals (CIs) were pooled using a random-effects model. Results: Forty-one randomized controlled trials involving 7852 patients were analyzed. POD occurred in 488 of 4013 patients receiving opioid-free/opioid-sparing interventions and 633 of 3839 controls. Overall, these strategies significantly reduced the risk of delirium (RR = 0.641, 95% CI: 0.525–0.784; I 2 = 52.2%). Subgroup analyses showed reductions with esketamine (RR = 0.745, 95% CI: 0.526–1.053) and dexmedetomidine (RR = 0.612, 95% CI: 0.471–0.796), while ketamine demonstrated a nonsignificant trend toward benefit (RR = 0.598, 95% CI: 0.251–1.423). No significant publication bias was detected. Conclusions: Opioid-free and opioid-sparing anesthetic strategies reduce POD in adult surgical patients, with dexmedetomidine and esketamine showing the most consistent benefits. These findings support multimodal opioid-sparing anesthesia for perioperative neurocognitive protection.