Efficacy and safety of N-methyl-d-aspartate receptor antagonists for preventing acute postoperative pain: A systematic review and network meta-analysis of randomized controlled trials.

Abstract

<h4>Background</h4>Acute postoperative pain is highly prevalent following surgical procedures. Identifying N-methyl-d-aspartate (NMDA) receptor antagonists with potential for preventing acute postoperative pain is clinically critical, yet individual randomized controlled trials (RCT) often lack sufficient statistical power. Network meta-analysis mitigates this limitation by boosting statistical power, enabling comprehensive comparison of multiple interventions to identify the most effective therapeutic options for preventing acute postoperative pain.<h4>Methods</h4>We systematically searched Pubmed, Embase, Cochrane and MEDLINE databases for RCTs evaluating the efficacy of NMDA receptor antagonists in preventing acute postoperative pain. Studies were carefully selected based on the PICOS framework. We performed the network meta-analysis with R using the GeMTC and BUGSnet packages. The primary outcome was defined as the pain score at 24 h postoperatively. Secondary outcomes included morphine consumption at 24 h postoperatively, time to the first postoperative analgesic request, rescue analgesic requirements and incidence of postoperative nausea and vomiting (PONV).<h4>Results</h4>A total of 47 eligible RCTs involving 3055 participants were included in this analysis. In terms of reducing 24-h postoperative pain scores, esketamine (MD -1.39; 95% credible interval [Crl] -2.57 to -0.37), high-dose dextromethorphan (MD -1.17; 95% Crl -1.81 to -0.53) and medium-dose ketamine (MD -0.93; 95% Crl -1.74 to -0.08) exhibited significant effects. For secondary outcomes, medium-dose dextromethorphan (MD -10.50; 95% Crl -19.66 to -1.45) was optimal for reducing 24-h postoperative morphine consumption; high-dose dextromethorphan (MD 206.41; 95% Crl 24.39 to 394.30) effectively prolonged the time to first postoperative analgesic request; and magnesium sulphate (OR 6.91; 95% Crl 1.64 to 24.97) was the only intervention that significantly reduced rescue analgesic requirements. Medium-dose dextromethorphan (OR 15.32; 95% CrI 1.48 to 334.61) and ketamine administered via patient-controlled epidural analgesia (OR 5.88; 95% CrI 1.31 to 30.88) significantly reduced the incidence of PONV.<h4>Conclusions</h4>Esketamine and high-dose dextromethorphan achieved clinically meaningful reductions in VAS pain scores at 24 h postoperatively. Additionally, medium-dose dextromethorphan decreased 24-h morphine consumption, high-dose dextromethorphan significantly prolonged the time to first analgesic request, and magnesium sulphate reduced rescue analgesia requirements. Medium-dose dextromethorphan and ketamine administered via patient-controlled epidural analgesia reduced the incidence of PONV. However, the increasingly limited clinical availability of dextromethorphan restricts the generalizability of our findings. Furthermore, the certainty of evidence for most outcomes was low to very low, mainly due to residual heterogeneity and imprecision, supporting the need for further high-quality studies.<h4>Systematic review registration</h4>PROSPERO (CRD420251116678).

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