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Capsaicin cough sensitivity is decreased in smokers
RESPIRATORY MEDICINE (2001) 95, 19–21 doi:10.1053/rmed.2000.0965, available online at http://www.idealibrary.com on
Capsaicin cough sensitivity is decreased in smokers E. MILLQVIST* AND M. BENDE{ *Department of Allergy, Sahlgrenska University Hospital, Go¨teborg and { Department of Otorhinolaryngology, Central Hospital, Sko¨vde, Sweden Although capsaicin provocation has been used to evaluate treatment against cough, which is one of the most common respiratory symptoms, there are still methodological considerations that are not fully known. Capsaicin stimulates the unmyelinated slow C-fibres of the sensory nervous system, which leads to coughing. Smoking often leads to respiratory symptoms with cough and phlegm. The aim of this study was to examine the effect of smoking on capsaicin provocation. Subjectively healthy smokers and non-smokers were challenged with capsaicin in increasing doses. The coughs were counted and irritation of the lower airways was graded on a symptom score. Smokers reacted to provocation with significantly fewer coughs, but there was no difference regarding other symptoms. These results are in agreement with the hypothesis that nicotine inhibits or blocks C-fibres of the sensory nervous system of the lower respiratory tract. Clinically, this may serve to explain increasing airway symptoms that are often seen after cessation of smoking. Key words: cough sensitivity; capsaicin; smoking. RESPIR. MED. (2001) 95, 19–21
Introduction Capsaicin, an ingredient in red pepper, is known to stimulate the unmyelinated slow C-fibres of the sensory nervous system. In fact, the C-fibres are characterized by their sensitivity to the neurotoxin capsaicin (1). In small doses, capsaicin releases neuropeptides from the C-fibre endings, while in high doses it effectively eliminates the neuropeptides. These neuropeptides, including the tachykinins substance P, neurokinin A and calcitonin gene-related peptide (CGRP), are found in vesicles in the C-fibres of the respiratory epithelium. Activation leads to various effects, such as cough, bronchoconstriction and mucous secretion (1). The tachykinins have potent inflammatory effects and are important agents in what is called ‘neurogenic inflammation’. Inhalation of capsaicin has previously been used to induce cough in provocation models and for testing antitussive drugs (2–7). Capsaicin has been used previously in cough provocation to differentiate between patients with sensory hyperreactivity and healthy subjects or patients with asthma (8,9). Patients with sensory hyperreactivity but no asthma or allergy complained of symptoms from the upper and/or lower respiratory tract after having been exposed to chemical agents such as strong scents. It was found that these patients reacted with increased coughing
Received 11 August 2000 and accepted 4 September 2000. Correspondence should be addressed to: Eva Millqvist, MD, PhD, Allergy Centre, Sahlgrenska University Hospital, S-413 45 Gothenburg, Sweden. E-mail: [email protected].
0954-6111/01/010019+03 $35?00/0
# 2001 HARCOURT PUBLISHERS LTD
after capsaicin inhalation and that the effect was reproducible in controlled experiments (8). In the authors’ studies of sensory hyperreactivity, it was found that smokers reacted with less coughing than nonsmokers to provocation with capsaicin. This was astonishing as smoking often leads to chronic bronchitis, with coughing as a major symptom. The authors often meet exsmokers in their practice, who after cessation, show increased symptoms of the respiratory tract. The hypothesis is that nicotine inhibits the receptors of the C-fibres of the sensory nerves in the respiratory epithelium or induces a depletion of neuropeptides, and thus inhibits coughing. To test this hypothesis, the effect of cough provocation with capsaicin in a group of smokers and a group of nonsmokers was compared, all subjects being without respiratory symptoms.
Materials and methods Fifteen regular smokers, 10 women and five men (aged 15– 60 years, mean age 43 years), were recruited for the study. They were compared with 39 non-smoking volunteers, 32 women and seven men (aged 24–57 years, mean age 43 years). The smokers as well as the controls were subjectively healthy and on no regular treatment with any drug. None of the subjects had a history of obstructive pulmonary disease. Smokers were included if they had smoked five or more cigarettes per day for at least 1 year, with an average of 12?5 (+4?6 SD) cigarettes day71. A questionnaire was used to identify smoking habits. # 2001 HARCOURT PUBLISHERS LTD
20 E. MILLQVIST AND M. BENDE Provocation with capsaicin started with inhalation of 1 ml capsaicin (0?4 mM) for 6 min, followed by a 4 min rest, in accordance with a previous study (8). The number of coughs was counted for 10 min from the start of the provocation, and recorded on a tape recorder. Thereafter, the provocations continued in the same way with increasing concentrations of capsaicin, viz. 2 mM and 10 mM in a 1 ml solution. If a subject coughed 70 times with any of the doses, the test was discontinued. The effect parameters were number of coughs and degree of irritation from the lower airways after each dose of capsaicin. The degree of irritation was graded from 0 to 3 (‘no symptoms’ to ‘very irritated’). Student’s t-test was used to compare smokers’ and nonsmokers’ reactions to each concentration. Analysis of variance (ANOVA) was used for a complete comparison of both the cough and the symptoms. The local ethics committee approved the study and all subjects gave informed consent.
between smokers and non-smokers for any concentration, nor was there any overall difference between the groups. In the smokers, there was no relationship between number of cigarettes smoked daily and coughs after capsaicin provocation.
Discussion
Capsaicin induced dose-dependent coughs in all subjects, with a statistically significant difference between smokers and non-smokers for the two highest concentrations (P50?01) (Fig. 1). The mean number of coughs for capsaicin 0?4 mM in smokers was 0?2 (confidence interval 0; 0?4) and in non-smokers, 2?0 (0?8; 12?4). Corresponding values for capsaicin 2 mM were 2?1 (0?5; 3?7) and 9?5 (6?6; 12?4), and for capsaicin 10 mM, 14?3 (8?1; 20?6) and 26?0 (21?2; 30?8). Examination by ANOVA showed a statistically significant difference between smokers and nonsmokers (P50?005). In general, the irritation in the lower airways induced by the capsaicin provocations was minor. With increasing doses of capsaicin, symptoms increased (Fig. 2). Regarding symptoms, there was no statistically significant difference
The present study confirms the authors’ observation that smokers react to capsaicin provocation with less coughing than non-smokers. The difference in coughing between the groups was obvious, but there was no difference regarding symptoms. Respiratory reflexes evoked by nicotine are similar to those produced by capsaicin but it is unclear whether the same type of sensory nerves mediates these reflexes (4). It is possible that nicotine in high doses eliminates the neuropeptides from the C-fibre endings in a similar way that capsaicin does (1). Such a theory may provide an explanation for these results and may also explain the increasing symptoms from the upper and lower airways so often seen in patients who have ceased to smoke. Cough provocation with capsaicin has often been performed on non-smoking subjects (4,7,8). After cough provocation with citric acid, a comparison has been made previously between moderate smokers (10–20 cigarettes day71), occasional smokers (1–5 cigarettes week71) and non-smokers (10). The study showed that moderate smokers tend to cough more than non-smokers; the occasional smokers in the study did not cough at all (10). In another study, cough threshold for citric acid and capsaicin was evaluated in patients with chronic obstructive pulmonary disease (11). These patients were all smokers with a reduced lung function and with limited reversibility on terbutaline. Healthy, non-smoking subjects were used as controls. The results showed that patients with chronic obstructive pulmonary disease had a significantly lower cough threshold to citric acid. However, there was no
FIG. 1. Mean number of coughs (+SEM) in smokers and non-smokers elicited by provocation with three doses of capsaicin. &, Non-smokers; *, smokers. ****P50?0001; ***P50?001; and **P50?01. Examination by ANOVA showed a statistically significant difference (P50?005) between smokers (n ¼ 15) and non-smokers (n ¼ 39).
FIG. 2. Mean symptom score of irritation of the lower airways (+SEM) in smokers and non-smokers elicited by provocation with three doses of capsaicin. &, Nonsmokers; *, smokers. ***P50?001; **P50?01. Analysis by ANOVA showed no statistically significant difference between smokers (n ¼ 15) and non-smokers (n ¼ 39).
Results
DECREASED CAPSAICIN COUGH SENSITIVITY IN SMOKERS 21 difference between groups after capsaicin provocation. Wong and Morice postulated that citric acid and capsaicin stimulate cough through different mechanisms. A lower threshold to citric acid implied an increased sensitivity. These findings are in contrast to the present study in which a decreased sensitivity in smokers was found. Differences in materials and methods used may be one explanation for this discrepancy. The smokers in the present study were not patients and had no history of pulmonary disease. Furthermore, the method of provocation differed. Wong and Morice exposed their subjects to provocation with citric acid immediately followed by capsaicin (11), using increasing doses until patients achieved two coughs. The authors then constructed a log dose–response curve for each test and calculated the cough threshold by linear regression. All subjects were provoked with the same doses and the number of coughs for each dose were counted. Both methods of provocation have been described in the literature; the authors showed a good reproducibility by provoking all subjects with constant doses (8). Cough is one of the most common respiratory symptoms and capsaicin provocation is an established method of studying cough. Therefore, it is important to know more about the effect of smoking on capsaicin provocation. It has previously been found that men are more sensitive to capsaicin than women, and that upper respiratory tract infections increase the sensitivity (5,6). In the present study, lung function was not measured but none of the subjects had a history of any airway symptom or had ever been on any therapy for asthma or bronchitis. Furthermore, in previous studies, provocation with capsaicin did not alter lung function (8,9). The authors conclude that smokers are less sensitive to capsaicin than non-smokers, which supports the hypothesis that nicotine either inhibits the receptors of the C-fibres of the sensory nerves in the respiratory epithelium, or induces a depletion of neuropeptides. Clinically, this may serve to explain increasing airway symptoms that are often seen after cessation of smoking.
Acknowledgements This study was supported by grants from the Va˚rdal Foundation, the Regional Health Care Authority of
West Sweden, the Swedish National Association against Asthma and Allergy Diseases, and the Swedish Heart and Lung Foundation. We are grateful to Ewa Ternesten and Christel Larsson for excellent help with the recordings.
References 1. James DE, Nijkamp FP. Neuro-immune interactions in the lung. Clin Exp Allergy 1999; 29: 1309–1319. 2. Karlsson J-A, Sant’Ambrogio G, Widdicombe J. Afferent neural pathways in cough and reflex bronchoconstriction. J Appl Physiol 1988; 65: 1007–1023. 3. Midgren B, Hansson L, Karlsson J-A, et al. Capsaicininduced cough in humans. Am Rev Respir Dis 1992; 146: 347–351. 4. Hansson L, Choudry NB, Karlsson JA, et al. Inhaled nicotine in humans: effect on the respiratory and cardiovascular systems. J Appl Physiol 1994; 76: 2420–2427. 5. O’Connell F, Thomas VE, Studham JM et al. Capsaicin cough sensitivity increases during upper respiratory infection. Respir Med 1996; 90: 279–286. 6. Fujimura M, Kasahara K, Kamio Y, et al. Female gender as a determinant of cough threshold to inhaled capsaicin. Eur Respir J 1996; 9: 1624–1626. 7. Fujimura M, Kasahara K, Yasui M, et al. Atopy in cough sensitivity to capsaicin and bronchial responsiveness in young females. Eur Respir J 1998; 11: 1060–1063. 8. Millqvist E, Bende M, Lo¨whagen O. Sensory hyperreactivity – a possible mechanism underlying cough and asthma-like symptoms. Allergy 1999; 53: 1208–1212. 9. Millqvist E. Cough provocation with capsaicin is an objective way to test sensory hyperreactivity in patients with asthma-like symptoms. Allergy 2000; 55: 546–550. 10. Pounsford JC, Saunders KB. Cough response to citric acid aerosol in occasional smokers. Br Med J; 293: 1528. 11. Wong CH, Morice AH. Cough threshold in patients with chronic obstructive pulmonary disease. Thorax 1999; 54: 62–64.
Capsaicin cough sensitivity is decreased in smokers E. MILLQVIST* AND M. BENDE{ *Department of Allergy, Sahlgrenska University Hospital, Go¨teborg and { Department of Otorhinolaryngology, Central Hospital, Sko¨vde, Sweden Although capsaicin provocation has been used to evaluate treatment against cough, which is one of the most common respiratory symptoms, there are still methodological considerations that are not fully known. Capsaicin stimulates the unmyelinated slow C-fibres of the sensory nervous system, which leads to coughing. Smoking often leads to respiratory symptoms with cough and phlegm. The aim of this study was to examine the effect of smoking on capsaicin provocation. Subjectively healthy smokers and non-smokers were challenged with capsaicin in increasing doses. The coughs were counted and irritation of the lower airways was graded on a symptom score. Smokers reacted to provocation with significantly fewer coughs, but there was no difference regarding other symptoms. These results are in agreement with the hypothesis that nicotine inhibits or blocks C-fibres of the sensory nervous system of the lower respiratory tract. Clinically, this may serve to explain increasing airway symptoms that are often seen after cessation of smoking. Key words: cough sensitivity; capsaicin; smoking. RESPIR. MED. (2001) 95, 19–21
Introduction Capsaicin, an ingredient in red pepper, is known to stimulate the unmyelinated slow C-fibres of the sensory nervous system. In fact, the C-fibres are characterized by their sensitivity to the neurotoxin capsaicin (1). In small doses, capsaicin releases neuropeptides from the C-fibre endings, while in high doses it effectively eliminates the neuropeptides. These neuropeptides, including the tachykinins substance P, neurokinin A and calcitonin gene-related peptide (CGRP), are found in vesicles in the C-fibres of the respiratory epithelium. Activation leads to various effects, such as cough, bronchoconstriction and mucous secretion (1). The tachykinins have potent inflammatory effects and are important agents in what is called ‘neurogenic inflammation’. Inhalation of capsaicin has previously been used to induce cough in provocation models and for testing antitussive drugs (2–7). Capsaicin has been used previously in cough provocation to differentiate between patients with sensory hyperreactivity and healthy subjects or patients with asthma (8,9). Patients with sensory hyperreactivity but no asthma or allergy complained of symptoms from the upper and/or lower respiratory tract after having been exposed to chemical agents such as strong scents. It was found that these patients reacted with increased coughing
Received 11 August 2000 and accepted 4 September 2000. Correspondence should be addressed to: Eva Millqvist, MD, PhD, Allergy Centre, Sahlgrenska University Hospital, S-413 45 Gothenburg, Sweden. E-mail: [email protected].
0954-6111/01/010019+03 $35?00/0
# 2001 HARCOURT PUBLISHERS LTD
after capsaicin inhalation and that the effect was reproducible in controlled experiments (8). In the authors’ studies of sensory hyperreactivity, it was found that smokers reacted with less coughing than nonsmokers to provocation with capsaicin. This was astonishing as smoking often leads to chronic bronchitis, with coughing as a major symptom. The authors often meet exsmokers in their practice, who after cessation, show increased symptoms of the respiratory tract. The hypothesis is that nicotine inhibits the receptors of the C-fibres of the sensory nerves in the respiratory epithelium or induces a depletion of neuropeptides, and thus inhibits coughing. To test this hypothesis, the effect of cough provocation with capsaicin in a group of smokers and a group of nonsmokers was compared, all subjects being without respiratory symptoms.
Materials and methods Fifteen regular smokers, 10 women and five men (aged 15– 60 years, mean age 43 years), were recruited for the study. They were compared with 39 non-smoking volunteers, 32 women and seven men (aged 24–57 years, mean age 43 years). The smokers as well as the controls were subjectively healthy and on no regular treatment with any drug. None of the subjects had a history of obstructive pulmonary disease. Smokers were included if they had smoked five or more cigarettes per day for at least 1 year, with an average of 12?5 (+4?6 SD) cigarettes day71. A questionnaire was used to identify smoking habits. # 2001 HARCOURT PUBLISHERS LTD
20 E. MILLQVIST AND M. BENDE Provocation with capsaicin started with inhalation of 1 ml capsaicin (0?4 mM) for 6 min, followed by a 4 min rest, in accordance with a previous study (8). The number of coughs was counted for 10 min from the start of the provocation, and recorded on a tape recorder. Thereafter, the provocations continued in the same way with increasing concentrations of capsaicin, viz. 2 mM and 10 mM in a 1 ml solution. If a subject coughed 70 times with any of the doses, the test was discontinued. The effect parameters were number of coughs and degree of irritation from the lower airways after each dose of capsaicin. The degree of irritation was graded from 0 to 3 (‘no symptoms’ to ‘very irritated’). Student’s t-test was used to compare smokers’ and nonsmokers’ reactions to each concentration. Analysis of variance (ANOVA) was used for a complete comparison of both the cough and the symptoms. The local ethics committee approved the study and all subjects gave informed consent.
between smokers and non-smokers for any concentration, nor was there any overall difference between the groups. In the smokers, there was no relationship between number of cigarettes smoked daily and coughs after capsaicin provocation.
Discussion
Capsaicin induced dose-dependent coughs in all subjects, with a statistically significant difference between smokers and non-smokers for the two highest concentrations (P50?01) (Fig. 1). The mean number of coughs for capsaicin 0?4 mM in smokers was 0?2 (confidence interval 0; 0?4) and in non-smokers, 2?0 (0?8; 12?4). Corresponding values for capsaicin 2 mM were 2?1 (0?5; 3?7) and 9?5 (6?6; 12?4), and for capsaicin 10 mM, 14?3 (8?1; 20?6) and 26?0 (21?2; 30?8). Examination by ANOVA showed a statistically significant difference between smokers and nonsmokers (P50?005). In general, the irritation in the lower airways induced by the capsaicin provocations was minor. With increasing doses of capsaicin, symptoms increased (Fig. 2). Regarding symptoms, there was no statistically significant difference
The present study confirms the authors’ observation that smokers react to capsaicin provocation with less coughing than non-smokers. The difference in coughing between the groups was obvious, but there was no difference regarding symptoms. Respiratory reflexes evoked by nicotine are similar to those produced by capsaicin but it is unclear whether the same type of sensory nerves mediates these reflexes (4). It is possible that nicotine in high doses eliminates the neuropeptides from the C-fibre endings in a similar way that capsaicin does (1). Such a theory may provide an explanation for these results and may also explain the increasing symptoms from the upper and lower airways so often seen in patients who have ceased to smoke. Cough provocation with capsaicin has often been performed on non-smoking subjects (4,7,8). After cough provocation with citric acid, a comparison has been made previously between moderate smokers (10–20 cigarettes day71), occasional smokers (1–5 cigarettes week71) and non-smokers (10). The study showed that moderate smokers tend to cough more than non-smokers; the occasional smokers in the study did not cough at all (10). In another study, cough threshold for citric acid and capsaicin was evaluated in patients with chronic obstructive pulmonary disease (11). These patients were all smokers with a reduced lung function and with limited reversibility on terbutaline. Healthy, non-smoking subjects were used as controls. The results showed that patients with chronic obstructive pulmonary disease had a significantly lower cough threshold to citric acid. However, there was no
FIG. 1. Mean number of coughs (+SEM) in smokers and non-smokers elicited by provocation with three doses of capsaicin. &, Non-smokers; *, smokers. ****P50?0001; ***P50?001; and **P50?01. Examination by ANOVA showed a statistically significant difference (P50?005) between smokers (n ¼ 15) and non-smokers (n ¼ 39).
FIG. 2. Mean symptom score of irritation of the lower airways (+SEM) in smokers and non-smokers elicited by provocation with three doses of capsaicin. &, Nonsmokers; *, smokers. ***P50?001; **P50?01. Analysis by ANOVA showed no statistically significant difference between smokers (n ¼ 15) and non-smokers (n ¼ 39).
Results
DECREASED CAPSAICIN COUGH SENSITIVITY IN SMOKERS 21 difference between groups after capsaicin provocation. Wong and Morice postulated that citric acid and capsaicin stimulate cough through different mechanisms. A lower threshold to citric acid implied an increased sensitivity. These findings are in contrast to the present study in which a decreased sensitivity in smokers was found. Differences in materials and methods used may be one explanation for this discrepancy. The smokers in the present study were not patients and had no history of pulmonary disease. Furthermore, the method of provocation differed. Wong and Morice exposed their subjects to provocation with citric acid immediately followed by capsaicin (11), using increasing doses until patients achieved two coughs. The authors then constructed a log dose–response curve for each test and calculated the cough threshold by linear regression. All subjects were provoked with the same doses and the number of coughs for each dose were counted. Both methods of provocation have been described in the literature; the authors showed a good reproducibility by provoking all subjects with constant doses (8). Cough is one of the most common respiratory symptoms and capsaicin provocation is an established method of studying cough. Therefore, it is important to know more about the effect of smoking on capsaicin provocation. It has previously been found that men are more sensitive to capsaicin than women, and that upper respiratory tract infections increase the sensitivity (5,6). In the present study, lung function was not measured but none of the subjects had a history of any airway symptom or had ever been on any therapy for asthma or bronchitis. Furthermore, in previous studies, provocation with capsaicin did not alter lung function (8,9). The authors conclude that smokers are less sensitive to capsaicin than non-smokers, which supports the hypothesis that nicotine either inhibits the receptors of the C-fibres of the sensory nerves in the respiratory epithelium, or induces a depletion of neuropeptides. Clinically, this may serve to explain increasing airway symptoms that are often seen after cessation of smoking.
Acknowledgements This study was supported by grants from the Va˚rdal Foundation, the Regional Health Care Authority of
West Sweden, the Swedish National Association against Asthma and Allergy Diseases, and the Swedish Heart and Lung Foundation. We are grateful to Ewa Ternesten and Christel Larsson for excellent help with the recordings.
References 1. James DE, Nijkamp FP. Neuro-immune interactions in the lung. Clin Exp Allergy 1999; 29: 1309–1319. 2. Karlsson J-A, Sant’Ambrogio G, Widdicombe J. Afferent neural pathways in cough and reflex bronchoconstriction. J Appl Physiol 1988; 65: 1007–1023. 3. Midgren B, Hansson L, Karlsson J-A, et al. Capsaicininduced cough in humans. Am Rev Respir Dis 1992; 146: 347–351. 4. Hansson L, Choudry NB, Karlsson JA, et al. Inhaled nicotine in humans: effect on the respiratory and cardiovascular systems. J Appl Physiol 1994; 76: 2420–2427. 5. O’Connell F, Thomas VE, Studham JM et al. Capsaicin cough sensitivity increases during upper respiratory infection. Respir Med 1996; 90: 279–286. 6. Fujimura M, Kasahara K, Kamio Y, et al. Female gender as a determinant of cough threshold to inhaled capsaicin. Eur Respir J 1996; 9: 1624–1626. 7. Fujimura M, Kasahara K, Yasui M, et al. Atopy in cough sensitivity to capsaicin and bronchial responsiveness in young females. Eur Respir J 1998; 11: 1060–1063. 8. Millqvist E, Bende M, Lo¨whagen O. Sensory hyperreactivity – a possible mechanism underlying cough and asthma-like symptoms. Allergy 1999; 53: 1208–1212. 9. Millqvist E. Cough provocation with capsaicin is an objective way to test sensory hyperreactivity in patients with asthma-like symptoms. Allergy 2000; 55: 546–550. 10. Pounsford JC, Saunders KB. Cough response to citric acid aerosol in occasional smokers. Br Med J; 293: 1528. 11. Wong CH, Morice AH. Cough threshold in patients with chronic obstructive pulmonary disease. Thorax 1999; 54: 62–64.