Background: Total hip arthroplasty (THA) and total knee arthroplasty (TKA) are commonly performed procedures, but post-operative recovery is often complicated by significant pain, opioid-related side effects, and psychological distress. Esketamine has been proposed as an adjunct due to its analgesic and antidepressant properties, but its efficacy and safety remain unclear. Methods: A systematic review and meta-analysis of randomized controlled trials (RCTs) was performed by searching PubMed, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials (CENTRAL) up to July 2025. Dichotomous and continuous outcomes were synthesized using risk ratios (RRs) and standardized or mean differences, each reported with 95% confidence intervals (CIs). Results: Seven RCTs involving 1,101 patients were included. Esketamine did not significantly reduce pain at rest at 12 or 24 hours. Low-certainty evidence suggested that esketamine may reduce pain during activity at 12 hours (standardized mean difference (SMD): -0.28; 95% CI: -0.45, -0.12; p < 0.001), although this effect was not sustained at 24 hours. Very low-certainty evidence suggested a possible reduction in anxiety scores at post-operative day 7, with no significant effect observed at day 1. No clear effect on depression was observed at any time point. Esketamine was associated with a higher incidence of hallucinations (RR: 4.36; 95% CI (1.48, 12.88); p = 0.01), with no significant differences in delirium, nightmares, or post-operative nausea and vomiting. Conclusions: Low- to very low-certainty evidence suggests that esketamine may provide modest short-term improvement in activity-related pain and delayed anxiety reduction following THA and TKA. However, findings should be interpreted cautiously given the limited number of studies, clinical heterogeneity, and instability observed in sensitivity analyses. Esketamine was also associated with an increased risk of hallucinations.
AlAyyaf et al. (2026) studied this question.