Multimodal opioid-free anesthesia containing esketamine versus opioid-based anesthesia: a systematic review and meta-analysis

The paradigm shift toward opioid-free anesthesia (OFA) is gaining traction, yet evidence regarding specific viable alternatives remains fragmented. This meta-analysis comprehensively evaluates the efficacy and safety of multimodal OFA regimens containing esketamine compared to traditional opioid-based anesthesia (OBA). This study conducted a systematic review and meta-analysis by searching the electronic databases PubMed, The Cochrane Library, Web of Science, and Embase, including randomized controlled trials published from inception to September 20, 2024. The included studies had to feature at least one OFA group (defined as a multimodal regimen containing esketamine), where opioids were not used during the preoperative phase, anesthetic induction, intraoperative maintenance, or before anesthesia recovery. A total of 14 RCTs (1,703 patients) were analyzed. Regarding the primary outcomes, postoperative pain scores at 24 h (MD = -0.07; 95% CI: -0.27, 0.13; moderate certainty) and 48 h (MD = 0.00; 95% CI: -0.29, 0.30; moderate certainty) showed no statistically significant differences between the groups. However, multimodal OFA regimens containing esketamine demonstrated a reduced risk of chronic postoperative pain based exclusively on data from only two thoracic surgery trials (RR = 0.64; 95% CI: 0.44, 0.92; low certainty). Regarding secondary outcomes, the OFA group showed a significantly lower incidence of intraoperative hypotension (RR = 0.29; 95% CI: 0.17, 0.49; high certainty) and postoperative nausea and vomiting (PONV) (RR = 0.47; 95% CI: 0.27, 0.79; high certainty). No statistically significant differences were detected in extubation time, PACU length of stay, rescue analgesia requirements, or the incidence of nightmares or hallucinations. Notably, substantial statistical heterogeneity was observed across several outcomes, including pain scores, PONV, extubation time, and PACU length of stay. Multimodal OFA regimens containing esketamine provide comparable postoperative analgesia to opioid-based anesthesia while reducing PONV and intraoperative hypotension. However, these findings represent combined multimodal effects across heterogeneous settings, and potential benefits for chronic pain prevention should be viewed strictly as hypothesis-generating.