Efficacy and safety of ketamine and esketamine for preventing opioid-induced cough: a systematic review and meta-analysis of randomized controlled trials.

Background: Opioid-induced cough (OIC) is a common side effect during anesthetic induction. This systematic review and meta-analysis aimed to evaluate the efficacy and safety of ketamine/esketamine in preventing OIC during anesthetic induction.

Methods: We systematically searched Medline, Embase, Cochrane Library, and Google Scholar from inception through December 2024 for randomized controlled trials that examined the efficacy of ketamine/esketamine in preventing OIC (Registration: INPLASY2024120102). Studies were included if they: (1) evaluated surgical patients receiving short-acting opioids (e.g., fentanyl) during anesthetic induction; (2) compared ketamine or esketamine against placebo/no treatment; and (3) reported OIC incidence. Studies were assessed using the Cochrane Risk of Bias 2.0 tool. Random-effects meta-analysis was performed using risk ratios (RR) for dichotomous outcomes and mean differences (MD) for continuous outcomes, with 95% confidence intervals (CI). The primary outcome was the overall incidence of OIC within 3 min after opioids administration.

Results: Twelve trials involving ketamine (nine trials) and esketamine (three trials) were analyzed. Notably, both agents significantly reduced the overall incidence of OIC compared to placebo (RR: 0.30; 95% CI: 0.22-0.41; p < 0.00001, I² = 61%, moderate certainty). All studies demonstrated low risk of bias across all domains for primary outcome. These agents also demonstrated efficacy against mild cough (RR: 0.41, 95% CI: 0.28-0.59, high certainty) and moderate-to-severe cough (RR: 0.26, 95% CI: 0.18-0.38, moderate certainty). The intervention delayed cough onset by 2.77 s (95% CI: 1.25-4.29, moderate certainty) and showed mild improvement in oxygen saturation (MD: 0.55%, 95% CI: 0.15-0.95, high certainty) without significant effects on heart rate or blood pressure. Subgroup analyses confirmed consistent benefits across adult and pediatric populations, as well as between ketamine and esketamine.

Conclusions: Our findings suggest that ketamine and esketamine are effective in reducing OIC during anesthetic induction. However, given the short delay in cough onset and mild improvements in oxygen saturation, the clinical significance of these findings may be limited in routine practice. Their use may be most beneficial in selected patients at risk of OIC-related complications. Further research is warranted to assess their value in high-risk populations and their role in combination prevention strategies.