Rhinitis, sinusitis, and upper airway disease
Pharmacodynamic modeling of cough responses to capsaicin inhalation calls into question the utility of the C5 end point

https://doi.org/10.1016/j.jaci.2013.04.042Get rights and content

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 (Emax) and the capsaicin dose inducing half-maximal response (ED50). HVs and asthmatic patients were not statistically different for either parameter and therefore combined for analysis (mean ED50, 38.6 μmol/L [relative SE, 28%]; mean Emax, 4.5 coughs [relative SE, 11%]). Compared with HVs/asthmatic patients, patients with CC had lower ED50 values (14.7 μmol/L [relative SE, 28%], P = .008) and higher Emax values (8.6 coughs [relative SE, 11%], P < .0001). Emax values highly correlated with 24-hour cough frequency (r = 0.71, P < .001) and were 37% higher in female compared with male subjects, regardless of disease group (P < .001).

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.

Section snippets

Subjects

Twenty HVs, 18 patients with mild-to-moderate asthma, and 20 patients with unexplained CC of a duration of greater than 8 weeks were recruited. Asthmatic patients all had documented evidence of bronchial hyperreactivity (positive methacholine challenge result, reversibility in FEV1 >12%, or both), and those with unexplained CC had undergone full investigation and treatment trials for possible causes of cough in a specialist cough clinic (see the Methods section in this article's Online

Subjects' characteristics

Twenty HVs, 18 asthmatic patients, and 20 patients with CC completed the study, with equal numbers of male and female subjects in each group. Subjects' characteristics are summarized in Table I. There were no statistical differences in age, body mass index, lung function, anxiety, or depression scores between groups.

Model structure

The structural model was successfully implemented in NONMEM. Baseline cough frequency (E0) was fixed to zero, which is consistent with the average cough response to inhaled placebo

Discussion

To the best of our knowledge, this is the first study to apply nonlinear mixed-effects modeling to formally characterize capsaicin dose response in patients with CC, asthmatic patients, and HVs. Dose-response parameters, ED50 and Emax values, were compared by disease group and sex. In summary, although there were no statistical differences in either parameter between HVs and asthmatic patients, patients with CC had significantly higher Emax values and significantly lower ED50 values compared

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    Supported by MRC Training Fellowship and MRC Clinician Scientist Award G0701918.

    Disclosure of potential conflict of interest: E. C. Y. Hilton has received research support from the Medical Research Council and is employed by Novo Nordisk UK. P. G. Baverel is employed by Pfizer. A. Woodcock has a patent from Vitalograph. P. H. Van Der Graaf is employed by and owns stock in Pfizer. J. A. Smith has received research support from the Medical Research Council, has received consultancy fees from GlaxoSmithKline and Merck, and the University Hospital South Manchester owns a patent that she has invented on describing methods for cough detection from sound recordings.

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