Pharmacodynamic modeling of cough responses to capsaicin inhalation calls into question the utility of the C5 end point

Background Inhaled capsaicin elicits cough reproducibly in human subjects and is widely used in the study of cough and antitussive therapies. However, the traditional end points C2 and C5 (the concentrations of capsaicin inducing at least 2 or 5 coughs, respectively) display extensive overlap between health and disease and therefore might not best reflect clinically relevant mechanisms. Objectives We sought to investigate capsaicin dose responses in different disease groups. Methods Two novel capsaicin cough challenges were compared in patients with chronic cough (CC; n = 20), asthmatic patients (n = 18), and healthy volunteers (HVs; n = 20). Increasing doubling doses of capsaicin (0.48-1000 μmol/L, 4 inhalations per dose) were administered in challenge 1, whereas the order of the doses was randomized in challenge 2. A nonlinear mixed-effects model compared dose-response parameters by disease group and sex. Parameters were also correlated with objective cough frequency. Results The model classified subjects based on maximum cough response evoked by any concentration of capsaicin (E max ) and the capsaicin dose inducing half-maximal response (ED 50 ). HVs and asthmatic patients were not statistically different for either parameter and therefore combined for analysis (mean ED 50 , 38.6 μmol/L [relative SE, 28%]; mean E max , 4.5 coughs [relative SE, 11%]). Compared with HVs/asthmatic patients, patients with CC had lower ED 50 values (14.7 μmol/L [relative SE, 28%], P  = .008) and higher E max values (8.6 coughs [relative SE, 11%], P max values highly correlated with 24-hour cough frequency ( r  = 0.71, P P Conclusions Nonlinear mixed-effects modeling demonstrates that maximal capsaicin cough responses better discriminate health from disease and predict spontaneous cough frequency and therefore provide important insights into the mechanisms underlying CC.