Efficacy and safety of P2X3 receptor antagonists in refractory or unexplained chronic cough: an updated systematic review and meta-analysis

Background Refractory chronic cough and unexplained chronic cough are increasingly understood as clinical expressions of cough hypersensitivity. P2X3 receptor antagonists have been developed to reduce ATP-mediated airway sensory nerve activation, but their benefit must be balanced against taste-related adverse events. Methods Randomized placebo-controlled trials evaluating oral P2X3 receptor antagonists in adults with refractory or unexplained chronic cough were included. Objective cough frequency and taste-related adverse events were selected as primary efficacy and safety/tolerability outcomes. Secondary outcomes included Leicester Cough Questionnaire (LCQ) total score, cough severity visual analogue scale (VAS), overall adverse events, and discontinuation due to adverse events. Effects were pooled using random-effects inverse-variance models. Sensitivity analyses, publication-bias assessment, and GRADE certainty ratings were performed. Results Eleven trial reports involving 3568 participants were included, yielding 13 independent comparisons for objective cough frequency. P2×3 receptor antagonists reduced objective cough frequency compared with placebo (ratio 0.71, 95% CI 0.63–0.79), corresponding to a 29.3% relative reduction. They also improved LCQ total score (MD 1.44, 95% CI 0.78–2.09) and cough severity VAS (MD -12.73 mm, 95% CI -17.10 to −8.36). Taste-related adverse events were increased (RR 7.36, 95% CI 4.84–11.21), as were overall adverse events (RR 1.21, 95% CI 1.07–1.38) and discontinuation due to adverse events (RR 3.62, 95% CI 2.65–4.93). Leave-one-out analyses did not alter the direction of any pooled estimate. Egger and Begg tests suggested small-study effects for objective cough frequency, but not for safety outcomes with sufficient comparisons. The certainty of evidence was rated as moderate for all prespecified outcomes. Conclusion P2×3 receptor antagonists were associated with reductions in objective cough frequency and improvements in patient-reported outcomes in refractory or unexplained chronic cough. These benefits should be balanced against increased safety and tolerability concerns, especially taste disturbance, although receptor selectivity appears to attenuate this risk. Systematic Review Registration https://www.crd.york.ac.uk/prospero/ , identifier CRD420261422476.