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<p>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; <i>N</i> = 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%; <i>p</i> = 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%; <i>p</i> &lt; 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&#xa0;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.</p>

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

  • 期刊论文

  • 发表日期：

    2026年6月19日

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  • Jeevarathinam Thirumalai,
  • Indra Sivakumar,
  • Saravanan Sekaran

摘要

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.