ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Respiratory Pharmacology
Beyond codeine – the evidence landscape of conventional, natural, and emerging antitussive therapies: a systematic review and meta-analysis
Provisionally accepted
- Medical University of Lodz, Łódź, Poland
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Background: For decades, cough treatment has relied on centrally acting agents like codeine despite inconsistent efficacy. Advances in cough neurobiology enabled targeted therapies. Natural remedies remain widely used, though evidence for their effectiveness and safety is limited. This study aimed to compare evidence on the efficacy and safety of conventional, natural, and novel antitussives. Methods: A systematic review and meta-analysis of randomized clinical trials assessed cough frequency, Visual Analogue Scale (VAS), Leicester Cough Questionnaire (LCQ) and adverse events versus placebo. Results: Subgroup meta-analysis showed no significant differences between P2X3 antagonists, indicating a consistent class effect. All subgroups reduced chronic cough frequency [standardized mean difference (SMD) = -0.50, 95% confidence interval (CI) [-0.67 -0.34], P = 0.0001], suggesting that the observed effect is a class-related response rather than a compound-specific effect. Conclusion: Conventional and natural antitussives show inconsistent efficacy. P2X3 receptor antagonists appear most promising, marking a shift beyond codeine toward targeted chronic cough therapies.
Keywords: antitussive, codeine alternatives, Cough suppression, Natural therapies, P2X3
Received: 28 Nov 2025; Accepted: 28 Jan 2026.
Copyright: © 2026 Marko and Pawliczak. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Rafał Pawliczak
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