Review: Effect of drugs on human cough reflex sensitivity to inhaled capsaicin

Cough20128:10

DOI: 10.1186/1745-9974-8-10

Received: 25 July 2012

Accepted: 9 October 2012

Published: 12 November 2012

Abstract

Capsaicin, the pungent extract of red peppers, has been used in clinical research for almost three decades. Capsaicin has gained favor as the provocative agent of choice to measure cough reflex sensitivity, as it induces cough in a safe, reproducible, and dose-dependent manner. One of the major uses of capsaicin cough challenge testing has been to evaluate the effect of a pharmacological intervention on the human cough reflex. The current review summarizes the published experience with capsaicin inhalation challenge in the evaluation of drug effects on cough reflex sensitivity. A notable contrast evident between studies demonstrating a drug effect (inhibition of cough reflex sensitivity) and those that do not, is the predominance of healthy volunteers as subjects in the latter. This observation suggests that subjects with pathological cough, rather than normal volunteers, comprise the optimal group in which to evaluate the effect of potential antitussive agents on human cough reflex sensitivity.

Keywords

Cough Capsaicin Antitussive Respiratory tract infection Asthma

Introduction

Capsaicin, the pungent extract of red pepper (capsicum), has gained widespread use as a research tool among clinical investigators, as it induces cough in humans in a safe [1], dose-dependent, and reproducible manner [2, 3]. Capsaicin cough challenge in humans was first described in 1984 [4], and has since been used to evaluate the effect of numerous pharmacological agents on cough reflex sensitivity. Although many drugs have been shown to inhibit induced cough in the laboratory, others have failed to do so, including agents widely regarded as clinically effective antitussives.

Methods

A United States National Library of Medicine (PubMed) search was performed in September, 2012 using the search terms “cough” and “capsaicin” limited to human studies published in English. The abstracts of the 328 articles meeting those search criteria were reviewed and 56 studies were identified in which capsaicin cough challenge was employed to assess the effect of a pharmacological intervention on cough reflex sensitivity. Studies in which a positive drug effect was demonstrated (n = 33) are listed in Table 1[537]; trials in which no effect was noted (n = 30) are summarized in Table 2[4, 10, 12, 1719, 35, 3759]. In seven of these studies, multiple drugs and/or multiple subject groups were evaluated, resulting in both positive and negative results in terms of assessment of drug activity. As the purpose of this review was to assess drug trials in which a potential therapeutic (antitussive) effect of a drug was being evaluated, studies demonstrating enhancement of cough reflex sensitivity by angiotensin-converting enzyme (ACE) inhibitors or other agents were excluded.
Table 1

Drugs shown to inhibit cough reflex sensitivity to capsaicin

1stauthor

Ref. #

Year

Drug

Subject population

Wise P

[5]

2012

menthol

healthy volunteers

Takemura M

[6]

2012

montelukast

cough-variant asthma

Ekstrand Y

[7]

2011

inhaled steroids

asthma

Ishiura Y

[8]

2010

etodolac

sinobronchial syndrome

Ishiura Y

[9]

2009

etodolac

asthma

Dicpinigaitis P

[10]

2009

guaifenesin

viral URI

Davenport P

[11]

2009

nicotine

healthy smokers

Dicpinigaitis P

[12]

2008

tiotropium

viral URI

Ishiura Y

[13]

2008

suplatast

atopic cough

Ferrari M

[14]

2007

omeprazole

asthma + GERD

Usmani O

[15]

2005

theobromine

healthy volunteers

Shioya T

[16]

2004

epinastine

atopic cough

Dicpinigaitis P

[17]

2003

guaifenesin

viral URI

Ishiura Y

[18]

2003

carbocysteine

asthma

Ishiura Y

[19]

2003

seratrodast

chronic bronchitis

Shioya T

[20]

2002

suplatast

cough-variant asthma

Dicpinigaitis P

[21]

2002

zafirlukast

cough-variant asthma

Ceyhan B

[22]

2002

oxolamine

COPD

Dicpinigaitis P

[23]

2000

baclofen

cervical SCI

Brightling C

[24]

2000

budesonide

eosinophilic bronchitis

Dicpinigaitis P

[25]

1998

baclofen

healthy volunteers

Shioya T

[26]

1998

azelastine

asthma

Dicpinigaitis P

[27]

1997

baclofen

healthy volunteers

Shioya T

[28]

1996

azelastine

cough-variant asthma

Fujimura M

[29]

1995

indomethacin

asthma, chronic bronchitis

Hargreaves M

[30]

1995

sodium cromoglycate

ACE-inhibitor cough

Hansson L

[31]

1994

lignocaine

healthy volunteers

Van Wyck M

[32]

1994

glycopyrrolate

ACE-inhibitor cough

Cazzola M

[33]

1993

theophylline

ACE-inhibitor cough

Foster G

[34]

1991

sulindac

healthy volunteers

McEwan J

[35]

1990

sulindac

ACE-inhibitor cough

Choudry N

[36]

1990

lignocaine

healthy volunteers

Fuller R

[37]

1988

codeine,morphine

healthy volunteers

Abbreviations: URI-acute upper respiratory tract infection; GERD-gastroesophageal reflux disease; SCI-spinal cord injury; ACE-angiotensin-converting enzyme.

Table 2

Drugs shown not to inhibit cough reflex sensitivity to capsaicin

1stauthor

Ref. #

Year

Drug

Subject population

Ryan M

[38]

2012

gabapentin

chronic cough

Yousaf N

[39]

2010

erythromycin

chronic cough

Dicpinigaitis P

[10]

2009

benzonatate

viral URI

Dicpinigaitis P

[12]

2008

tiotropium

healthy volunteers

Davenport P

[40]

2007

codeine

healthy volunteers

Dicpinigaitis P

[41]

2003

fexofenadine

healthy volunteers

Dicpinigaitis P

[17]

2003

guaifenesin

healthy volunteers

Ishiura Y

[18]

2003

ambroxol

asthma

Ishiura Y

[19]

2003

pranlukast

chronic bronchitis

Dicpinigaitis P

[42]

2001

celecoxib

asthma

Fujimura M

[43]

2000

mexiletine

healthy volunteers

Dicpinigaitis P

[44]

1999

zafirlukast

asthma without cough

Capon D

[45]

1996

dextromethorphan

healthy volunteers

Hansson L

[46]

1994

nicotine

healthy nonsmokers

Hutchings H

[47]

1994

codeine

healthy volunteers

O’Connell F

[48]

1994

clonidine

healthy volunteers

Fujimura M

[49]

1993

procaterol

asthma, chronic bronchitis

Choudry N

[50]

1993

MAO inhibitors

healthy volunteers

Stone R

[51]

1993

5-HT (serotonin)

healthy volunteers

Fujimura M

[52]

1992

procaterol

healthy volunteers

Ventresca P

[53]

1992

furosemide

healthy volunteers

Karlsson J

[54]

1992

furosemide, HCTZ

healthy volunteers

Studham J

[55]

1992

terfenadine

healthy volunteers

Choudry N

[56]

1991

inhaled mu opioid agonist

healthy volunteers

Smith C

[57]

1991

salbutamol, ipratropium

healthy volunteers

Choudry N

[58]

1991

granisteron (5-HT3)

healthy volunteers

McEwan J

[35]

1990

sulindac

idiopathic cough

Hansson L

[59]

1988

nedocromil

healthy volunteers

Fuller R

[37]

1988

inhaled opiates

healthy volunteers

Collier J

[4]

1984

sodium cromoglycate

healthy volunteers

Abbreviations: URI-acute upper respiratory tract infection; MAO-monoamine oxidase; HCTZ-hydrochlorothiazide.

Discussion

This review has identified 33 studies in which a pharmacological intervention was demonstrated to inhibit cough reflex sensitivity to inhaled capsaicin in a variety of subject populations, thus supporting the role of cough challenge as a useful clinical tool in the evaluation of potential antitussives [3]. A striking difference between the studies showing a positive drug effect (Table 1), and those failing to demonstrate a change in cough reflex sensitivity (Table 2) is the predominant subject populations studied. Of the negative studies, 70% involved evaluation of healthy volunteers. Among the trials displaying a positive drug effect, only 27% evaluated healthy volunteers, while the majority (73%) investigated various forms of pathological cough. Of note, multiple agents were shown to inhibit cough reflex sensitivity in pathological cough, while having no effect in healthy volunteers, including guaifenesin [10, 17] and tiotropium [12] in cough due to acute viral upper respiratory tract infection (URI; common cold). The leukotriene receptor antagonist zafirlukast inhibited capsaicin-induced cough in subjects with cough-variant asthma [21], but not in stable asthmatics without cough and healthy volunteers [44]. Interestingly, gabapentin has recently been shown to improve cough-specific quality of life in patients with refractory chronic cough, without affecting cough reflex sensitivity [38]. This particular study highlights the concept that the optimal approach to the evaluation of a potential antitussive agent should be multifaceted, with cough reflex sensitivity measurement complementing other measures, such as objective cough counting and subjective symptom-based questionnaires.

Conspicuous in their absence from the list of agents having demonstrated the ability to inhibit cough reflex sensitivity to capsaicin during URI are codeine and dextromethorphan, two of the most commonly used agents worldwide for the treatment of cough due to the common cold [60]. The only agents demonstrating the ability to inhibit cough reflex sensitivity to capsaicin in healthy volunteers were theobromine [15], baclofen [25, 27], inhaled lignocaine [31, 36], sulindac [34], systemic opiates [37], menthol [5] and, in healthy smokers, nicotine [11]. Interestingly, this list includes drugs thought to be centrally acting antitussives, as well as agents whose cough-inhibiting properties are presumed to occur through a peripheral mechanism.

Limiting the evaluation of a potential modulator of cough reflex sensitivity to a study group of healthy volunteers, whose cough reflex is not hyperresponsive, may not allow the drug to demonstrate its inhibitory effect. Thus, subjects with pathological cough appear to comprise the optimal study population when evaluating the effects of a potential antitussive agent on cough reflex sensitivity. The particular type of pathological cough best suited for evaluation of a novel antitussive may depend on the specific pharmacological action of the drug, and currently remains a question under vigorous debate.

Declarations

Authors’ Affiliations

(1)
Albert Einstein College of Medicine and Montefiore Medical Center
(2)
Einstein Division/Montefiore Medical Center

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