Selective P2X3 versus dual P2X2/3 receptor antagonists in refractory chronic cough: a systematic review and dose-response meta-analysis of randomized controlled trials.

Extracellular adenosine triphosphate (ATP)-mediated purinergic signalling via P2X3 and heteromeric P2X2/3 ion channel receptors underlies hypersensitisation of vagal airway afferents in refractory chronic cough (RCC), making this pathway a key therapeutic target. Two pharmacological strategies have emerged: dual P2X2/3 receptor antagonism and selective P2X3 inhibition. While dual antagonists (gefapixant) demonstrate robust antitussive efficacy, their clinical use is limited by taste disturbance resulting from P2X2/3 inhibition in gustatory pathways. We conducted a systematic review and dose-response meta-analysis of randomised controlled trials evaluating purinergic receptor antagonists in RCC, with nine RCTs (21 active arms; N = 1,934) identified from major databases. The primary outcome was percentage change in 24-h cough frequency (24-h CF) versus placebo. Dual P2X2/3 antagonists produced greater reductions in 24-h CF than selective P2X3 antagonists (- 38.12% vs - 19.93%; p = 0.016), consistent with broader receptor blockade. However, selective P2X3 antagonists demonstrated a markedly improved safety profile, with substantially lower dysgeusia incidence (8% vs 51%; p < 0.0001), reflecting sparing of P2X2/3-mediated gustatory signalling. Dose-response analysis indicated steeper efficacy gains with dual antagonists but disproportionately higher taste-related adverse effects. Among selective agents, camlipixant (≥ 50 mg BID) achieved clinically meaningful cough reduction (- 34%) with minimal dysgeusia (5-7%). These findings demonstrate a mechanistically defined benefit-risk trade-off in purinergic receptor targeting, supporting selective P2X3 antagonism as a more favourable strategy for modulating ATP-driven airway sensory signalling in RCC while preserving tolerability.