Understanding of the complexity of the cough reflex using experimental models and randomised clinical trials

My contribution to understanding the cough reflex spans experimental models of rodent airways, patient and volunteer responses to inhaled tussive agents, and randomised placebo-controlled drug trials. Through studying sensory pathways, I aimed to understand how menthol may relieve a cough. My early work focused on menthol's potential bronchodilator effects. In anaesthetised guinea pigs, menthol reduced capsaicin and neurokinin-A induced increases in airway resistance and caused dose-dependent relaxation of pre-constricted bronchi. This Dose dependency supported a drug-receptor interaction, confirmed by ligand-binding studies, identifying an L-menthol binding site in guinea pig lung membranes. Since then, TRPM8 (cold and menthol receptor 1 ) has been characterised as a therapeutic target for chronic cough (CC). My early work contributed to the current development of AX8, a synthetic cooling compound shown to reduce cough in patients with recalcitrant CC, likely via TRPM8-mediated sensory nerve modulation.
To explore a central pathway in cough, I conducted the first randomised placebo-controlled study of slow-release morphine in refractory and unexplained cough. Morphine significantly improved daily diary scores and Leicester cough questionnaire outcomes compared to placebo, with post hoc analysis indicating that sedation does not underlie its antitussive effects. This work informed subsequent trials of morphine in Idiopathic pulmonary fibrosis (IPF)-related cough, and supported repurposing of the opiate nalbuphine for treatment of cough associated with IPF and refractory chronic cough, both studies showing clinically meaningful cough reductions.
Progress in novel antitussives requires rigorous cough challenge methodologies. I validated the European Respiratory Society standard citric acid cough challenge, improving reproducibility by adopting a doubling dose protocol and physiological thresholds (C2 and C5). This standardisation confirmed the efficacy of Gefapixant, a first-in-class P2X3 antagonist, which significantly reduced ATP- and distilled water-induced coughs in both healthy volunteers and patients with chronic cough, indicating peripheral target engagement. My work contributes to the licensing of Gefapixant in the European Union, the first licensed antitussive since 1953.
Together, these studies provide valuable insight into cough mechanisms spanning peripheral receptor activity through to central nervous system modulation. They highlight the importance of standardised human cough methodology to advance our understanding and facilitate the development of effective antitussive therapies.
This body of work highlights the complexities of chronic cough and the need for integrated approaches targeting peripheral receptors, central modulation and sensory nerve pathways.