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.

CONCLUSION:

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: Saifudin Khalid, Robert Murdoch, Amy Newlands, Kevin Smart, Angela Kelsall, Kimberley Holt, Rachel Dockry, Ashley Woodcock, Jaclyn A Smith
• Journal: The Journal of allergy and clinical immunology (J Allergy Clin Immunol) Vol. 134 Issue 1 Pg. 56-62 (Jul 2014) ISSN: 1097-6825 [Electronic] United States
• PMID: 24666696 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

Chemical References

• Antitussive Agents
• Pyrrolidines
• SB 705498
• TRPV Cation Channels
• TRPV1 protein, human
• Urea
• Capsaicin

Topics

• Administration, Inhalation
• Adult
• Aged
• Animals
• Antitussive Agents (therapeutic use)
• Capsaicin
• Chronic Disease
• Cough (chemically induced, drug therapy, genetics, physiopathology)
• Cross-Over Studies
• Double-Blind Method
• Female
• Gene Expression
• Humans
• Male
• Middle Aged
• Pyrrolidines (therapeutic use)
• Quality of Life
• Severity of Illness Index
• TRPV Cation Channels (antagonists & inhibitors, genetics)
• Treatment Outcome
• Urea (analogs & derivatives, therapeutic use)