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

Authors

Jeevarathinam Thirumalai, Indra Sivakumar, Saravanan Sekaran

Published in

Purinergic signalling. Volume 22. Issue 4. Jun 19, 2026. Epub Jun 19, 2026.

Abstract

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.

PMID:
42319606
Bibliographic data and abstract were imported from PubMed on 19 Jun 2026.

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