Efficacy and safety of neurokinin receptor antagonists compared with placebo for menopausal vasomotor symptoms: a GRADE-assessed systematic review and meta-analysis of randomized controlled trials

Menopausal vasomotor symptoms (VMS) are highly prevalent and have serious clinical consequences. However, menopausal hormone therapy remains unsuitable for a substantial proportion of women owing to absolute or relative contraindications, long-term safety concerns, and patient preference. Neurokinin receptor antagonists have emerged as a mechanistically directed class of non-hormonal pharmacotherapies. However, their pooled efficacy and safety profiles across randomized placebo-controlled studies require systematic quantitative evaluation. This systematic review and meta-analysis was conducted according to the PRISMA guidelines. Searches of PubMed, Scopus, and Embase yielded 183, 329, and 487 records, respectively. Eligible studies comprised randomized placebo-controlled trials that evaluated neurokinin receptor antagonists for the treatment of menopausal VMS. The primary outcome was the change in the daily frequency of moderate-to-severe VMS from baseline. Secondary outcomes included changes in daily VMS severity scores, treatment-emergent adverse events (TEAE), drug-related TEAE, serious TEAE, and adverse events leading to treatment discontinuation. Pooled estimates were obtained using random-effects models, except for drug-related TEAEs, which used a fixed-effect odds ratio, and the certainty of the evidence was appraised using the GRADE framework. Seven trials were included in the quantitative analysis. Neurokinin receptor antagonists produced statistically significant reductions in daily moderate-to-severe VMS frequency compared with placebo (MD −2.30 episodes/day, 95% CI −2.72 to −1.88; I 2 =0%) and severity (MD −0.33, 95% CI −0.41 to −0.25; I 2 =47%). Any TEAE was marginally but significantly more frequent with neurokinin receptor antagonists (RR 1.06, 95% CI 1.01–1.11), and drug-related TEAEs were also significantly elevated (OR 1.42, 95% CI 1.20–1.67). Serious TEAEs increased in relative terms (RR 1.63, 95% CI 1.08–2.46), although the absolute event counts remained low across the included trials. Adverse events leading to treatment discontinuation did not reach statistical significance (RR 1.46, 95% CI 0.94–2.27). Drug-specific trial reports remain the primary basis for assessing tolerability, whereas combined safety estimates are exploratory because of differences in agents, doses, and follow-up periods. Neurokinin receptor antagonists confer clinically meaningful and evidence-supported reductions in the frequency and severity of menopausal VMS. Safety signals necessitate individualized clinical interpretation; however, treatment discontinuation was not significantly increased compared to placebo. These agents should be considered effective non-hormonal therapeutic options for women seeking symptom control in whom hormone therapy is contraindicated, undesirable, or clinically inappropriate. Trial registration This systematic review was registered with PROSPERO. Registration ID: CRD420261432009.