# Beyond codeine – the evidence landscape of conventional, natural, and emerging antitussive therapies: a systematic review and meta-analysis

## TL;DR

This study compares the effectiveness and safety of traditional, natural, and new cough treatments, finding that new P2X3 receptor antagonists show the most promise.

## Contribution

The study provides a systematic comparison of emerging antitussive therapies, highlighting P2X3 antagonists as a promising alternative to codeine.

## Key findings

- P2X3 antagonists consistently reduced chronic cough frequency compared to placebo.
- Conventional and natural antitussives showed inconsistent efficacy.
- The observed effect of P2X3 antagonists appears to be a class-related response.

## Abstract

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.

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.

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.

Conventional and natural antitussives show inconsistent efficacy. P2X3 receptor antagonists appear most promising, marking a shift beyond codeine toward targeted chronic cough therapies.

The meta-analysis was performed according to the protocol described in PROSPERO, identifier CRD420251172660.