title: Pharmacodynamic modeling of cough responses to capsaicin inhalation calls into question the utility of the C5 end point.
abstract: 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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Respiratory Research Group, University of Manchester, Manchester, United Kingdom.
authors.forename: Emma C Y
authors.initials: EC
authors.lastname: Hilton
authors.forename: Paul G
authors.initials: PG
authors.lastname: Baverel
authors.forename: Ashley
authors.initials: A
authors.lastname: Woodcock
authors.forename: Piet H
authors.initials: PH
authors.lastname: Van Der Graaf
authors.forename: Jaclyn A
authors.initials: JA
authors.lastname: Smith
mesh_terms: D000280:Administration, Inhalation; D000328:Adult; D000368:Aged; D000996:Antitussive Agents / Q000008:administration & dosage*; D001249:Asthma / Q000188:drug therapy*; D002211:Capsaicin / Q000008:administration & dosage*; D002908:Chronic Disease; D003371:Cough / Q000139:chemically induced / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome
chemical_list: D000996:Antitussive Agents; D002211:Capsaicin
keywords: C2; C5; CC; Capsaicin; Capsaicin dose inducing half-maximal response; Chronic cough; Concentration of capsaicin inducing at least 2 coughs; Concentration of capsaicin inducing at least 5 coughs; E(max); ED(50); FVC; Forced vital capacity; HV; Healthy volunteer; Maximum cough response evoked by any concentration of capsaicin; TRPV1; Transient receptor potential vanilloid 1; challenge; cough; human; model; nonlinear; reflex; response; sensitivity