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Effect of salbutamol on smoking related cough
Pulmonary Pharmacology & Therapeutics 17 (2004) 127–131 www.elsevier.com/locate/ypupt
Effect of salbutamol on smoking related cough Siobhan Mulrennana, Caroline Wrighta, Rachel Thompsona, Peter Goustasb, Alyn Moricea,* a
Division of Academic Medicine, University of Hull, Castle Hill Hospital, Cottingham, East Yorkshire, UK b GlaxoSmithKline, Stockley Park West, Uxbridge, Middlesex, England UK Received 1 July 2003; revised 17 December 2003; accepted 6 January 2004
Abstract Smokers have an increased prevalence of chronic cough and may complain of exacerbation of cough when attempting smoking cessation. We investigated the use of smokers cough as a model for testing anti-tussive agents. The effect of salbutamol was compared with placebo in healthy adult smokers. In a randomised double blind crossover study the effect of 400 mg salbutamol via MDI plus spacer versus placebo was studied. Cough was assessed before and after the first cigarette of the day (received at 20 mintes) and throughout the day. Cough frequency, citric acid cough challenge, change in cough symptoms and peak flow were recorded. Salbutamol reduced the mean cough frequency between 0 and 20 min. A mean of 4.5 compared to 6 on placebo ðp , 0:05Þ: A significant reduction in cough followed cigarette consumption in those on placebo. Mean pre-cigarette 6 compared to 3.9 post-cigarette ðp , 0:02Þ: The citric acid concentration causing two coughs (C2) at 60 min increased on salbutamol. Geometric mean 278.8 compared to 190.4 mM on placebo ðp , 0:03Þ: Cough frequency is reduced in smokers following a cigarette. The reduction in cough frequency and evoked cough after salbutamol suggests that b agonists have modest activity in smoking related cough and that smokers cough represents a sensitive model to test antitussive activity. q 2004 Elsevier Ltd. All rights reserved. Keywords: Cough; Smoking; b Agonists; Anti-tussives
1. Introduction Chronic cigarette smoking leads to a dose related cough and smokers cough is typically productive [1 – 3]. Smoking is associated with airway inflammation manifested as an increase in macrophages and cells expressing interleukin and adhesion molecule receptors. The consequence of this inflammation is an increase in non-specific bronchial hyperresponsiveness, even in subjects with normal lung function [2]. This airway inflammation mimics many of the pathological features seen in disease states characterised by chronic cough. We hypothesised that smoking related cough could provide a useful model to test anti-tussive activity which would be of relevance in clinical practice. b Agonists have a marked bronchoprotective effect on non-specific bronchial hyperresponsiveness but have little * Corresponding author. Tel.: þ 44-1482-624067; fax: þ 44-1482624068. E-mail address: [email protected] (A. Morice). 1094-5539/$ - see front matter q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.pupt.2004.01.002
or no effect on the cough reflex in healthy individuals. Salbutamol has no effect on induced cough in normal subjects, but does alter cough response in asthmatics [4]. If smokers’ cough does mirror disease related alterations in the cough reflex then salbutamol should have detectable activity in this model. We therefore performed a study to determine the anti-tussive effects of salbutamol in smoking related cough.
2. Methods A two way cross over study was performed to determine the efficacy of salbutamol via inhaler versus placebo on natural (i.e. on waking, before contact with triggers) and evoked (following the first cigarette) cough in habituated smokers. The primary efficacy endpoint was a reduction in cough frequency after waking on treatment day 1 over the following periods: 0 –10, 10 –20, 20 –40, and 40 – 60 min.
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The secondary efficacy endpoints were a reduction in cough frequency on treatment days 2 –5, nocturnal disturbance due to cough, change in cough symptoms (severity, chest tightness, expectoration volume, global symptom score), lung function recorded by peak flow measurements and cough threshold elevation measured as a response to citric acid challenge. Subjects (71) were screened following recruitment by external advertisement. Healthy male and female smokers (44) aged 18–65 years with chronic troublesome cough were randomised. Baseline spirometry was required to demonstrate FEV1 . 80% predicted. Subjects had to smoke 15 cigarettes a day with a greater than 5 pack year smoking history. Morning cough was required on all 5 days of screening diary record card assessment and persistent daily morning cough for a minimum of 3 months prior to entry onto the study. The initial screening to assess suitability for the study involved salbutamol reversibility (,12% with 400 mg via MDI and spacer) and a methacholine challenge (Provocative dose causing a fall in FEV1 of 20% (PD20) ,0.5 mg) to detect undiagnosed asthma [5]. Subjects attended two treatment periods of 5 days separated by a washout period of 2–7 days. They were admitted to the Clinical Trials Unit at Castle Hill Hospital on the night prior to treatment day 1, were randomised and told to continue smoking as normal until midnight when they abstained from cigarettes. On waking the next morning overnight abstinence was confirmed by the use of carbon monoxide monitoring (Smokealyser) [6]. Peak flow was recorded and then subjects received either 400 mg of salbutamol or placebo (propellants and excipients without salbutamol) via a MDI and spacer. Cough frequency was manually recorded from 0 to 10 mintes and 10 –20 min and the data was verified using a voice activated analogue tape recorder. Coughs following a cigarette at 20 min were observed at 20 – 40 and 40 – 60 min. One hour after medication subjects underwent a citric acid cough challenge [7]. Sensitivity of the cough reflex was expressed as C2 measurements (the dose of citric acid causing at least two coughs per inhalation). Subjects were
then allowed to smoke as they wished with the number and time of cigarettes recorded. Cough challenge was then repeated at 2 and 4 h. They then received 200 mg of salbutamol or placebo at midday. Patients went home with their diary card and allotted medication of salbutamol or matched placebo via MDI and spacer. Medication schedule on discharge was Day1:1 evening dose, Day 2: first dose in the morning on waking, second dose at mid-day and third dose in the evening. Days 3, 4 and 5: medication taken as required but no more than three doses in 24 h. Procedures in treatment period 1 mirrored those in treatment 1. Subjects were asked to smoke with the same frequency and at the same points as they did during study day 1 in the Clinical Trials Unit. Following discharge with a diary card subjects were allowed to smoke as they wished. At the end of the treatment they were asked to record any treatment preference. 2.1. Data analysis Results are expressed as arithmetic mean with 95% confidence intervals (CI) for cough frequency and geometric mean for citric acid cough challenge C2. Statistical comparison was by paired t-test. Hypotheses tests were 2 sided and of 5% significance level. The results were analysed on an intention to treat basis. 3. Results Males (31) and females (13) of age range 20–61 years were recruited. Mean FEV1 was 4.1 l (range 2.8–6) and mean pack years 20.4 (range 5–100). At screening mean salbutamol reversibility was 5% and mean PD10 was 0.67 mg. Total cough frequency was reduced from 6 to 4.5 in the first 20 min after salbutamol inhalation (p , 0:05; CI of difference 0.02 and 2.9). There was no statistically significant reduction in total cough frequency at the other time intervals. (Fig. 1 and Tables 1 and 2). On the placebo
Fig. 1. Mean cough frequency in the first hour post-treatment. Cigarette taken at 20 min.
S. Mulrennan et al. / Pulmonary Pharmacology & Therapeutics 17 (2004) 127–131
evening peak flow was 545.5 compared to 554.8 for salbutamol (p , 0:01; CI 2.5-16.1).
Table 1 Cough frequency in first hour following medication Time (min)
0–20 20–40 40–60
Mean cough frequency post-placebo
Mean cough frequency post-salbutamol
p value (95% confidence)
6 3.9 2.5
4.5 3.9 2.6
0.05 (0.02, 2.9) 0.9 (20.9, 0.8) 0.8 (20.8, 0.9)
4. Discussion
* Cigarette given at 20 min. Table 2 Cough frequency day 2 –5 Time
Mean cough Mean cough f value frequency frequency (95% confidence) post-placebo post-salbutamol
Day 2 waking-12p.m. Day 2 12–10p.m. Day 3 waking-12p.m. Day 3 12–10p.m. Day 4 waking-12p.m. Day 4 12–10p.m. Day 5 waking-12p.m. Day 5 12–10p.m.
10.3 12.6 12.0 13.0 11.3 11.9 11.3 13.0
10.8 11.8 12.0 13.1 12.8 12.7 10.5 12.8
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0.7 0.5 0.7 0.9 0.2 0.6 0.7 0.8
(21.8, 2.8) (23.8, 2.1) (24.1, 2.9) (22.9, 2.9) (20.6, 3.4) (21.7, 3.0) (23.7, 2.6) (22.9, 2.1)
day cough frequency 20 min post-cigarette was significantly less than in the 20 min pre-cigarette: 6 versus 3.9 coughs ðp ¼ 0:02; CI0:8 – 3:4Þ: There was no significant difference in cough frequency pre- and post-cigarette in salbutamol subjects. p ¼ 0:2 and CI 2 0:4 and 1.8 (Fig. 2). Citric acid cough challenge was significantly increased by salbutamol in the first hour. p ¼ 0:01; CI of the mean difference 17.5 –196.7. Subsequent cough challenge was not significantly different (Fig. 3). No statistically significant difference between placebo and salbutamol was found for mean nocturnal disturbance, cough severity, chest tightness and morning peak flow. There was a small but significant increase in evening peak flow in the salbutamol arm of the study. Placebo mean
Cough is a troublesome symptom in smokers and in those attempting smoking cessation. The cough associated with smoking is multifactorial, related to bronchoconstriction, alteration in cough threshold [8], airway inflammation [9,10], and the fact that smoke is an irritant fume. Salbutamol appears to have anti-tussive properties in asthma due to bronchodilation and reduced bronchial hyperresponsiveness. We hypothesised that it may have a role in the treatment of smoking related cough as short acting b agonists have marked bronchodilator and bronchoprotective properties. Were salbutamol to have an effect this would infer that bronchoconstriction and bronchial hyperresponsiveness are components in the aetiology of smoking related cough and would validate the use of smokers cough as a tool to study the clinical relevance of anti-tussive therapy. In our group of habituated smokers we found that cough frequency in the first 20 min after administration of salbutamol was reduced. This demonstrated that salbutamol reduced cough before the stimulus of a cigarette and b agonists could therefore have a role in smoking cessation. In contrast, after the cigarette salbutamol had no effect on cough frequency. Cough frequency was reduced in the placebo group following the cigarette to levels similar to those seen post-salbutamol. Since we do not have a longer abstention period for comparison it cannot be presumed that this reduction in cough frequency is solely due to the effect of cigarette smoking. It does suggest smokers have a heightened cough frequency early in the morning and our findings are consistent with the theory that smokers ‘need’ a cigarette to reduce cough. Both smoking and salbutamol may reduce cough to basal levels and so b agonists may have little additional anti-tussive effect on cough in those who continue to smoke.
Fig. 2. Mean cough frequency pre- and post-cigarette.
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Fig. 3. Citric acid cough challenge post-treatment.
The cough challenge data are consistent with the observations of cough frequency. C2 concentration for citric acid was increased in the first hour after taking salbutamol. Again the effect was short lived with no significant effect seen on subsequent challenges. Previous studies have demonstrated the association of improvement in cough challenge with diminished cough in disease [11]. The finding of a reduction in cough sensitivity at a time when there was no difference in cough frequency suggests cough challenge may detect small differences in cough reflex sensitivity which are below the level which impact on cough frequency. The reduction in cough frequency and change in cough sensitivity after salbutamol suggests that b agonists may be a useful treatment for smokers attempting abstinence from cigarettes. However, the effect is small and of relatively short duration. It is therefore unlikely to be clinically useful and other more potent and longer acting agents may prove more effective. Our subjects did not have a history of asthma and did not bronchodilate in response to salbutamol to the conventional levels required to support a diagnosis of asthma. Bronchodilation whilst highly predictive of asthma does not exclude the diagnosis. The best diagnostic test for exclusion of asthma is bronchial challenge [12]. Our subjects had a negative methacholine challenge as defined by PD20 , 0.5 mg and a mean PD10 of 0.67 mg. Smokers have been shown to have an increase in non-specific bronchial reactivity which is intermediate between asthma and normal [2]. We suggest our subjects do not have asthma but have an increase in bronchial reactivity that is responsive to salbutamol. This is supported by the small but significant increase in FEV1 seen post-salbutamol at screening and the increase in evening PEFR with salbutamol treatment. Smoking induced cough therefore seems to share some of the characteristics of other conditions causing cough.
In asthma the effect of salbutamol on cough challenge has been studied [4]. Cough response and respiratory resistance fell in asthmatic subjects whereas only respiratory resistance fell in normal subjects. The authors suggested that salbutamol in decreasing airway tone resets the irritant receptors or alters the threshold of airway smooth muscle receptors. The mechanism for bronchial hyperresponsiveness in asthma is unknown but is related to inflammation. Smoking leads to airway inflammation and inflammatory mediators may play a part in the cough associated with smoking. The effect of smoking on airway inflammation would seem to be the same in current smokers and in ex smokers with symptoms of chronic bronchitis [9]. Both these groups have an increase in some inflammatory cells and markers compared to non-smokers and this inflammation may persist after smoking cessation. The mechanism leading to inflammation in smoking may be via free radical production and consequent oxidative stress. Lipid peroxidation occurs in oxidative stress [13] and causes an increase in Prostaglandin F 2a (PGF2a) levels. This may be a local marker of airway inflammation. Pratico et al. [14] showed that the levels of urinary PGF2a III isomer is raised in patients with COPD and levels increase with exacerbations. It has also been shown that smokers show an increase in F2-isoprostane in blood and urine [15]. The effect of PGF2a on capsaicin induced cough and its modulation by beta 2 adrenergic and anti-cholinergic drugs has been studied [16]. Capsaicin induced cough increased after inhalation of PGF 2a. Salbutamol reduced cough after inhalation of PGF 2a and after the augmentation of capsaicin induced cough by PGF2a. We suggest that salbutamol’s activity in reducing the cough associated with smoking cessation is by acting as a functional antagonist of inflammatory mediators such as PGF2a. Nicotine could have a direct pharmacological effect on airway inflammation. Wang et al. have recently shown that macrophages possess a nicotinic receptor consisting of a monomer of the a7 subunit which on binding acetylcholine
S. Mulrennan et al. / Pulmonary Pharmacology & Therapeutics 17 (2004) 127–131
released by the vagus nerve inhibits cytokine release [17]. Nicotine may mimic acetylcholine at this receptor and reduce airway inflammation in smokers by inhibiting macrophage cytokine production. However, such a mechanism may be more important in the long-term effects of smoking on cough rather than short-term anti-tussive activity. We have used chronic cough in cigarette smokers to test salbutamol as an anti-tussive agent. The cough associated with cigarette smoking is multifactorial and mimics many of the features present in patients with both acute and chronic cough syndromes. Unlike acute cough due to respiratory tract infection the time course of the smoking cough model is relatively constant as demonstrated by the reproducibility of the reported cough over the 5-day observation period. In chronic cough the effect of treatment depends on the underlying pathological process. Unlike conventional methods of testing anti-tussives our methodology allows extrapolation to other diseases of similar pathology. We believe that smoking related cough is a useful model for testing the effectiveness of anti-tussive therapies.
Acknowledgements Funded by an unrestricted grant from GlaxoSmithKline.
References [1] Janson C, Chinn S, Jarvis D, et al. Determinants of cough in young adults participating in the European Community Respiratory Health Survey. Eur Respir J 1991;18:647–54. [2] Gerrard JW, Cockcroft DW, Mink JT, et al. Increased nonspecific bronchial reactivity in cigarette smokers with normal lung function. Am Rev Respir Dis 1980;122:577 –81.
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[3] Cullinan P. Persistent cough and sputum: prevalence and clinical characteristics in south east England. Resp Med 1992;86:143– 9. [4] Pounsford JC, Birch MJ, Saunders KB. Effect of bronchodilators on the cough response to inhaled citric acid in normal and asthmatic subjects. Thorax 1985;40:662 –7. [5] Crapo RO, Casaburi R, Coates AL, et al. Guidelines for methacholine and exercise challenge testing-1999. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999. Am J Respir Crit Care Med 2000;161:309 –29. [6] Middleton ET, Morice AH. Breath carbon monoxide as an indication of smoking habit. Chest 2000;117:758–63. [7] Morice AH, Kastelik JA, Thompson R. Cough challenge in the assessment of cough reflex. Br J Clin Pharmacol 2001;52:365 –75. [8] Wong CH, Morice AH. Cough threshold in patients with chronic obstructive pulmonary disease. Thorax 1999;54:62–4. [9] Turato G, Di Stefano A, Maestrelli P, et al. Effect of smoking cessation on airway inflammation in chronic bronchitis. Am J Respir Crit Care Med 1995;152:1262–7. [10] Wright JL, Hobson JE, Wiggs B, et al. Airway inflammation and peribronchiolar attachments in the lungs of nonsmokers, current and ex-smokers. Lung 1988;166:277– 86. [11] O’Connell F, Thomas VE, Pride NB, et al. Capsaicin cough sensitivity decreases with successful treatment of chronic cough. Am J Respir Crit Care Med 1994;150:374–80. [12] Hunter CJ, Brightling CE, Woltmann G, et al. A comparison of the validity of different diagnostic tests in adults with asthma. Chest 2002; 121:1051–7. [13] Rokach J, Khanapure SP, Hwang SW, et al. Nomenclature of isoprostanes: a proposal. Prostaglandins 1997;54:853–73. [14] Pratico D, Basili S, Vieri M, et al. Chronic obstructive pulmonary disease is associated with an increase in urinary levels of isoprostane F2alpha-III, an index of oxidant stress. Am J Respir Crit Care Med 1998;158:1709–14. [15] Morrow JD, Frei B, Longmire AW, et al. Increase in circulating products of lipid peroxidation (F2-isoprostanes) in smokers. Smoking as a cause of oxidative damage. N Engl J Med 1995;332:1198– 203. [16] Nichol G, Nix A, Barnes PJ, et al. Prostaglandin F2 alpha enhancement of capsaicin induced cough in man: modulation by beta 2 adrenergic and anticholinergic drugs. Thorax 1990;45:694 –8. [17] Wang H, Yu M, Ochani M, et al. Nicotinic acetylcholine receptor a7 subunit is an essential regulator of inflammation. Nature 2003;421: 384–8.
Effect of salbutamol on smoking related cough Siobhan Mulrennana, Caroline Wrighta, Rachel Thompsona, Peter Goustasb, Alyn Moricea,* a
Division of Academic Medicine, University of Hull, Castle Hill Hospital, Cottingham, East Yorkshire, UK b GlaxoSmithKline, Stockley Park West, Uxbridge, Middlesex, England UK Received 1 July 2003; revised 17 December 2003; accepted 6 January 2004
Abstract Smokers have an increased prevalence of chronic cough and may complain of exacerbation of cough when attempting smoking cessation. We investigated the use of smokers cough as a model for testing anti-tussive agents. The effect of salbutamol was compared with placebo in healthy adult smokers. In a randomised double blind crossover study the effect of 400 mg salbutamol via MDI plus spacer versus placebo was studied. Cough was assessed before and after the first cigarette of the day (received at 20 mintes) and throughout the day. Cough frequency, citric acid cough challenge, change in cough symptoms and peak flow were recorded. Salbutamol reduced the mean cough frequency between 0 and 20 min. A mean of 4.5 compared to 6 on placebo ðp , 0:05Þ: A significant reduction in cough followed cigarette consumption in those on placebo. Mean pre-cigarette 6 compared to 3.9 post-cigarette ðp , 0:02Þ: The citric acid concentration causing two coughs (C2) at 60 min increased on salbutamol. Geometric mean 278.8 compared to 190.4 mM on placebo ðp , 0:03Þ: Cough frequency is reduced in smokers following a cigarette. The reduction in cough frequency and evoked cough after salbutamol suggests that b agonists have modest activity in smoking related cough and that smokers cough represents a sensitive model to test antitussive activity. q 2004 Elsevier Ltd. All rights reserved. Keywords: Cough; Smoking; b Agonists; Anti-tussives
1. Introduction Chronic cigarette smoking leads to a dose related cough and smokers cough is typically productive [1 – 3]. Smoking is associated with airway inflammation manifested as an increase in macrophages and cells expressing interleukin and adhesion molecule receptors. The consequence of this inflammation is an increase in non-specific bronchial hyperresponsiveness, even in subjects with normal lung function [2]. This airway inflammation mimics many of the pathological features seen in disease states characterised by chronic cough. We hypothesised that smoking related cough could provide a useful model to test anti-tussive activity which would be of relevance in clinical practice. b Agonists have a marked bronchoprotective effect on non-specific bronchial hyperresponsiveness but have little * Corresponding author. Tel.: þ 44-1482-624067; fax: þ 44-1482624068. E-mail address: [email protected] (A. Morice). 1094-5539/$ - see front matter q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.pupt.2004.01.002
or no effect on the cough reflex in healthy individuals. Salbutamol has no effect on induced cough in normal subjects, but does alter cough response in asthmatics [4]. If smokers’ cough does mirror disease related alterations in the cough reflex then salbutamol should have detectable activity in this model. We therefore performed a study to determine the anti-tussive effects of salbutamol in smoking related cough.
2. Methods A two way cross over study was performed to determine the efficacy of salbutamol via inhaler versus placebo on natural (i.e. on waking, before contact with triggers) and evoked (following the first cigarette) cough in habituated smokers. The primary efficacy endpoint was a reduction in cough frequency after waking on treatment day 1 over the following periods: 0 –10, 10 –20, 20 –40, and 40 – 60 min.
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The secondary efficacy endpoints were a reduction in cough frequency on treatment days 2 –5, nocturnal disturbance due to cough, change in cough symptoms (severity, chest tightness, expectoration volume, global symptom score), lung function recorded by peak flow measurements and cough threshold elevation measured as a response to citric acid challenge. Subjects (71) were screened following recruitment by external advertisement. Healthy male and female smokers (44) aged 18–65 years with chronic troublesome cough were randomised. Baseline spirometry was required to demonstrate FEV1 . 80% predicted. Subjects had to smoke 15 cigarettes a day with a greater than 5 pack year smoking history. Morning cough was required on all 5 days of screening diary record card assessment and persistent daily morning cough for a minimum of 3 months prior to entry onto the study. The initial screening to assess suitability for the study involved salbutamol reversibility (,12% with 400 mg via MDI and spacer) and a methacholine challenge (Provocative dose causing a fall in FEV1 of 20% (PD20) ,0.5 mg) to detect undiagnosed asthma [5]. Subjects attended two treatment periods of 5 days separated by a washout period of 2–7 days. They were admitted to the Clinical Trials Unit at Castle Hill Hospital on the night prior to treatment day 1, were randomised and told to continue smoking as normal until midnight when they abstained from cigarettes. On waking the next morning overnight abstinence was confirmed by the use of carbon monoxide monitoring (Smokealyser) [6]. Peak flow was recorded and then subjects received either 400 mg of salbutamol or placebo (propellants and excipients without salbutamol) via a MDI and spacer. Cough frequency was manually recorded from 0 to 10 mintes and 10 –20 min and the data was verified using a voice activated analogue tape recorder. Coughs following a cigarette at 20 min were observed at 20 – 40 and 40 – 60 min. One hour after medication subjects underwent a citric acid cough challenge [7]. Sensitivity of the cough reflex was expressed as C2 measurements (the dose of citric acid causing at least two coughs per inhalation). Subjects were
then allowed to smoke as they wished with the number and time of cigarettes recorded. Cough challenge was then repeated at 2 and 4 h. They then received 200 mg of salbutamol or placebo at midday. Patients went home with their diary card and allotted medication of salbutamol or matched placebo via MDI and spacer. Medication schedule on discharge was Day1:1 evening dose, Day 2: first dose in the morning on waking, second dose at mid-day and third dose in the evening. Days 3, 4 and 5: medication taken as required but no more than three doses in 24 h. Procedures in treatment period 1 mirrored those in treatment 1. Subjects were asked to smoke with the same frequency and at the same points as they did during study day 1 in the Clinical Trials Unit. Following discharge with a diary card subjects were allowed to smoke as they wished. At the end of the treatment they were asked to record any treatment preference. 2.1. Data analysis Results are expressed as arithmetic mean with 95% confidence intervals (CI) for cough frequency and geometric mean for citric acid cough challenge C2. Statistical comparison was by paired t-test. Hypotheses tests were 2 sided and of 5% significance level. The results were analysed on an intention to treat basis. 3. Results Males (31) and females (13) of age range 20–61 years were recruited. Mean FEV1 was 4.1 l (range 2.8–6) and mean pack years 20.4 (range 5–100). At screening mean salbutamol reversibility was 5% and mean PD10 was 0.67 mg. Total cough frequency was reduced from 6 to 4.5 in the first 20 min after salbutamol inhalation (p , 0:05; CI of difference 0.02 and 2.9). There was no statistically significant reduction in total cough frequency at the other time intervals. (Fig. 1 and Tables 1 and 2). On the placebo
Fig. 1. Mean cough frequency in the first hour post-treatment. Cigarette taken at 20 min.
S. Mulrennan et al. / Pulmonary Pharmacology & Therapeutics 17 (2004) 127–131
evening peak flow was 545.5 compared to 554.8 for salbutamol (p , 0:01; CI 2.5-16.1).
Table 1 Cough frequency in first hour following medication Time (min)
0–20 20–40 40–60
Mean cough frequency post-placebo
Mean cough frequency post-salbutamol
p value (95% confidence)
6 3.9 2.5
4.5 3.9 2.6
0.05 (0.02, 2.9) 0.9 (20.9, 0.8) 0.8 (20.8, 0.9)
4. Discussion
* Cigarette given at 20 min. Table 2 Cough frequency day 2 –5 Time
Mean cough Mean cough f value frequency frequency (95% confidence) post-placebo post-salbutamol
Day 2 waking-12p.m. Day 2 12–10p.m. Day 3 waking-12p.m. Day 3 12–10p.m. Day 4 waking-12p.m. Day 4 12–10p.m. Day 5 waking-12p.m. Day 5 12–10p.m.
10.3 12.6 12.0 13.0 11.3 11.9 11.3 13.0
10.8 11.8 12.0 13.1 12.8 12.7 10.5 12.8
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0.7 0.5 0.7 0.9 0.2 0.6 0.7 0.8
(21.8, 2.8) (23.8, 2.1) (24.1, 2.9) (22.9, 2.9) (20.6, 3.4) (21.7, 3.0) (23.7, 2.6) (22.9, 2.1)
day cough frequency 20 min post-cigarette was significantly less than in the 20 min pre-cigarette: 6 versus 3.9 coughs ðp ¼ 0:02; CI0:8 – 3:4Þ: There was no significant difference in cough frequency pre- and post-cigarette in salbutamol subjects. p ¼ 0:2 and CI 2 0:4 and 1.8 (Fig. 2). Citric acid cough challenge was significantly increased by salbutamol in the first hour. p ¼ 0:01; CI of the mean difference 17.5 –196.7. Subsequent cough challenge was not significantly different (Fig. 3). No statistically significant difference between placebo and salbutamol was found for mean nocturnal disturbance, cough severity, chest tightness and morning peak flow. There was a small but significant increase in evening peak flow in the salbutamol arm of the study. Placebo mean
Cough is a troublesome symptom in smokers and in those attempting smoking cessation. The cough associated with smoking is multifactorial, related to bronchoconstriction, alteration in cough threshold [8], airway inflammation [9,10], and the fact that smoke is an irritant fume. Salbutamol appears to have anti-tussive properties in asthma due to bronchodilation and reduced bronchial hyperresponsiveness. We hypothesised that it may have a role in the treatment of smoking related cough as short acting b agonists have marked bronchodilator and bronchoprotective properties. Were salbutamol to have an effect this would infer that bronchoconstriction and bronchial hyperresponsiveness are components in the aetiology of smoking related cough and would validate the use of smokers cough as a tool to study the clinical relevance of anti-tussive therapy. In our group of habituated smokers we found that cough frequency in the first 20 min after administration of salbutamol was reduced. This demonstrated that salbutamol reduced cough before the stimulus of a cigarette and b agonists could therefore have a role in smoking cessation. In contrast, after the cigarette salbutamol had no effect on cough frequency. Cough frequency was reduced in the placebo group following the cigarette to levels similar to those seen post-salbutamol. Since we do not have a longer abstention period for comparison it cannot be presumed that this reduction in cough frequency is solely due to the effect of cigarette smoking. It does suggest smokers have a heightened cough frequency early in the morning and our findings are consistent with the theory that smokers ‘need’ a cigarette to reduce cough. Both smoking and salbutamol may reduce cough to basal levels and so b agonists may have little additional anti-tussive effect on cough in those who continue to smoke.
Fig. 2. Mean cough frequency pre- and post-cigarette.
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Fig. 3. Citric acid cough challenge post-treatment.
The cough challenge data are consistent with the observations of cough frequency. C2 concentration for citric acid was increased in the first hour after taking salbutamol. Again the effect was short lived with no significant effect seen on subsequent challenges. Previous studies have demonstrated the association of improvement in cough challenge with diminished cough in disease [11]. The finding of a reduction in cough sensitivity at a time when there was no difference in cough frequency suggests cough challenge may detect small differences in cough reflex sensitivity which are below the level which impact on cough frequency. The reduction in cough frequency and change in cough sensitivity after salbutamol suggests that b agonists may be a useful treatment for smokers attempting abstinence from cigarettes. However, the effect is small and of relatively short duration. It is therefore unlikely to be clinically useful and other more potent and longer acting agents may prove more effective. Our subjects did not have a history of asthma and did not bronchodilate in response to salbutamol to the conventional levels required to support a diagnosis of asthma. Bronchodilation whilst highly predictive of asthma does not exclude the diagnosis. The best diagnostic test for exclusion of asthma is bronchial challenge [12]. Our subjects had a negative methacholine challenge as defined by PD20 , 0.5 mg and a mean PD10 of 0.67 mg. Smokers have been shown to have an increase in non-specific bronchial reactivity which is intermediate between asthma and normal [2]. We suggest our subjects do not have asthma but have an increase in bronchial reactivity that is responsive to salbutamol. This is supported by the small but significant increase in FEV1 seen post-salbutamol at screening and the increase in evening PEFR with salbutamol treatment. Smoking induced cough therefore seems to share some of the characteristics of other conditions causing cough.
In asthma the effect of salbutamol on cough challenge has been studied [4]. Cough response and respiratory resistance fell in asthmatic subjects whereas only respiratory resistance fell in normal subjects. The authors suggested that salbutamol in decreasing airway tone resets the irritant receptors or alters the threshold of airway smooth muscle receptors. The mechanism for bronchial hyperresponsiveness in asthma is unknown but is related to inflammation. Smoking leads to airway inflammation and inflammatory mediators may play a part in the cough associated with smoking. The effect of smoking on airway inflammation would seem to be the same in current smokers and in ex smokers with symptoms of chronic bronchitis [9]. Both these groups have an increase in some inflammatory cells and markers compared to non-smokers and this inflammation may persist after smoking cessation. The mechanism leading to inflammation in smoking may be via free radical production and consequent oxidative stress. Lipid peroxidation occurs in oxidative stress [13] and causes an increase in Prostaglandin F 2a (PGF2a) levels. This may be a local marker of airway inflammation. Pratico et al. [14] showed that the levels of urinary PGF2a III isomer is raised in patients with COPD and levels increase with exacerbations. It has also been shown that smokers show an increase in F2-isoprostane in blood and urine [15]. The effect of PGF2a on capsaicin induced cough and its modulation by beta 2 adrenergic and anti-cholinergic drugs has been studied [16]. Capsaicin induced cough increased after inhalation of PGF 2a. Salbutamol reduced cough after inhalation of PGF 2a and after the augmentation of capsaicin induced cough by PGF2a. We suggest that salbutamol’s activity in reducing the cough associated with smoking cessation is by acting as a functional antagonist of inflammatory mediators such as PGF2a. Nicotine could have a direct pharmacological effect on airway inflammation. Wang et al. have recently shown that macrophages possess a nicotinic receptor consisting of a monomer of the a7 subunit which on binding acetylcholine
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released by the vagus nerve inhibits cytokine release [17]. Nicotine may mimic acetylcholine at this receptor and reduce airway inflammation in smokers by inhibiting macrophage cytokine production. However, such a mechanism may be more important in the long-term effects of smoking on cough rather than short-term anti-tussive activity. We have used chronic cough in cigarette smokers to test salbutamol as an anti-tussive agent. The cough associated with cigarette smoking is multifactorial and mimics many of the features present in patients with both acute and chronic cough syndromes. Unlike acute cough due to respiratory tract infection the time course of the smoking cough model is relatively constant as demonstrated by the reproducibility of the reported cough over the 5-day observation period. In chronic cough the effect of treatment depends on the underlying pathological process. Unlike conventional methods of testing anti-tussives our methodology allows extrapolation to other diseases of similar pathology. We believe that smoking related cough is a useful model for testing the effectiveness of anti-tussive therapies.
Acknowledgements Funded by an unrestricted grant from GlaxoSmithKline.
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