title: Transient receptor potential vanilloid 1 (TRPV1) antagonism in patients with refractory chronic cough: a double-blind randomized controlled trial.
abstract: BACKGROUND
  Inhalation of capsaicin, the extract of hot chili peppers, induces coughing in both animals and human subjects through activation of transient receptor potential vanilloid 1 (TRPV1) on airway sensory nerves. Therefore the TRPV1 receptor is an attractive target for the development of antitussive agents.
  
  
  OBJECTIVE
  We sought to assess the antitussive effect of TRPV1 antagonism in patients with refractory chronic cough.
  
  
  METHODS
  Twenty-one subjects with refractory chronic cough (>8 weeks) attending a specialist clinic were recruited to a randomized, double-blind, placebo-controlled crossover trial assessing a TRPV1 antagonist (SB-705498). Cough reflex sensitivity to capsaicin (concentration of capsaicin inducing at least 5 coughs) and 24-hour cough frequency were coprimary end points assessed after a single dose of SB-705498 (600 mg) and matched placebo. Cough severity and urge to cough were reported on visual analog scales, and cough-specific quality of life data were also collected.
  
  
  RESULTS
  Treatment with SB-705498 produced a significant improvement in cough reflex sensitivity to capsaicin at 2 hours and a borderline significant improvement at 24 hours compared with placebo (adjusted mean difference of +1.3 doubling doses at 2 hours [95% CI, +0.3 to +2.2; P = .0049] and +0.7 doubling doses at 24 hours [95% CI, +0.0 to +1.5; P = .0259]). However, 24-hour objective cough frequency was not improved compared with placebo. Patient-reported cough severity, urge to cough, and cough-specific quality of life similarly suggested no effect of SB-705498.
  
  
  CONCLUSIONS
  This study raises important questions about both the role of TRVP1-mediated mechanisms in patients with refractory chronic cough and also the predictive value of capsaicin challenge testing in the assessment of novel antitussive agents.
authors.affiliation: Centre for Respiratory and Allergy, University of Manchester, University Hospital of South Manchester, Manchester, United Kingdom.
authors.forename: Saifudin
authors.initials: S
authors.lastname: Khalid
authors.affiliation: GlaxoSmithKline, Stevenage, United Kingdom.
authors.forename: Robert
authors.initials: R
authors.lastname: Murdoch
authors.affiliation: GlaxoSmithKline, Stevenage, United Kingdom.
authors.forename: Amy
authors.initials: A
authors.lastname: Newlands
authors.affiliation: GlaxoSmithKline, Stevenage, United Kingdom.
authors.forename: Kevin
authors.initials: K
authors.lastname: Smart
authors.affiliation: Centre for Respiratory and Allergy, University of Manchester, University Hospital of South Manchester, Manchester, United Kingdom.
authors.forename: Angela
authors.initials: A
authors.lastname: Kelsall
authors.affiliation: Centre for Respiratory and Allergy, University of Manchester, University Hospital of South Manchester, Manchester, United Kingdom.
authors.forename: Kimberley
authors.initials: K
authors.lastname: Holt
authors.affiliation: Centre for Respiratory and Allergy, University of Manchester, University Hospital of South Manchester, Manchester, United Kingdom.
authors.forename: Rachel
authors.initials: R
authors.lastname: Dockry
authors.affiliation: Centre for Respiratory and Allergy, University of Manchester, University Hospital of South Manchester, Manchester, United Kingdom.
authors.forename: Ashley
authors.initials: A
authors.lastname: Woodcock
authors.affiliation: Centre for Respiratory and Allergy, University of Manchester, University Hospital of South Manchester, Manchester, United Kingdom. Electronic address: jacky.smith@manchester.ac.uk.
authors.forename: Jaclyn A
authors.initials: JA
authors.lastname: Smith
mesh_terms: D000280:Administration, Inhalation; D000328:Adult; D000368:Aged; D000818:Animals; D000996:Antitussive Agents / Q000627:therapeutic use*; D002211:Capsaicin; D002908:Chronic Disease; D003371:Cough / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D008875:Middle Aged; D011759:Pyrrolidines / Q000627:therapeutic use*; D011788:Quality of Life; D012720:Severity of Illness Index; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000235:genetics; D016896:Treatment Outcome; D014508:Urea / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D000996:Antitussive Agents; D011759:Pyrrolidines; C512301:SB 705498; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D014508:Urea; D002211:Capsaicin
keywords: Cough; capsaicin; cough sounds; sensory nerves; transient receptor potential vanilloid 1