Why Have I Started Coughing Again After Quitting Smoking 2 Years Ago

Effect of smoking cessation on cough reflex sensitivity

European Respiratory Periodical 2006 28: 786-790; DOI: 10.1183/09031936.06.00007806

Abstract

Recent studies have shown that cigarette smokers take diminished cough reflex sensitivity compared with nonsmokers. The current authors proposed a mechanism of chronic cigarette fume-induced desensitisation of airway cough receptors.

To investigate this hypothesis, cough sensitivity to inhaled capsaicin (C_v) in chronic smokers was measured both while they were actively smoking and 2, 6, 12 and 24 weeks after smoking cessation.

In total, 29 subjects underwent baseline capsaicin challenge while smoking and ii weeks after smoking cessation. Hateful±sem log C₅ vicious from one.86±0.12 to one.60±0.12, demonstrating significant enhancement of cough reflex sensitivity. Of the total, 20, 18 and fourteen subjects successfully abstained from smoking for 6, 12 and 24 weeks, respectively. Mean log C_five values after 12 and 24 weeks of smoking cessation were significantly diminished from baseline. In a control group of smokers, mean log C₅ did non subtract from baseline after half-dozen, 12 and 24 weeks. Overall, the log C₅ profile of the smoking cessation group showed a clear, linearly decreasing trend over time compared with the control group.

Fifty-fifty later many years of smoking, coughing sensitivity is enhanced equally early equally 2 weeks later smoking cessation. Given the importance of an intact cough reflex, these changes may provide clinical benefit.

• Capsaicin
• cigarette smoking
• cough
• nicotine
• tobacco

Cough results from the stimulation of airway sensory receptors whose afferent impulses activate a brainstem cough centre 1. The cough reflex serves a protective function by facilitating the expulsion of mucus from the respiratory tract and past preventing foreign material from entering the airways.

The nowadays authors and others accept recently shown that salubrious cigarette smokers take diminished cough reflex sensitivity compared with healthy nonsmokers ii, 3. It was hypothesised that chronic exposure to tobacco smoke desensitises the cough receptors lying superficially within the airway epithelium. Supporting the present authors' speculation is the demonstrated lower incidence of angiotensin-converting enzyme inhibitor-induced coughing in smokers relative to nonsmokers 4, v, and anecdotal observations that coughing often transiently increases after smoking cessation 6.

Alternatively, it has been proposed that diminished cough reflex sensitivity in smokers is non due to the furnishings of tobacco use, just rather that cigarette smokers comprise a select grouping of individuals with naturally macerated cough reflex sensitivity that allows them to tolerate and enjoy smoking two, 7, viii. In support of this hypothesis were multiple small studies that demonstrated decreased cough reflex sensitivity in persons who enjoyed occasional smoking, compared with regular smokers and nonsmokers 9–eleven.

To further explore the machinery of diminished cough reflex sensitivity in cigarette smokers, the nowadays study was performed to evaluate the event of smoking cessation on the sensitivity of the cough reflex.

METHODS

Subjects

Healthy, active smokers who were planning smoking abeyance were recruited for the study, which was canonical by the Institutional Review Boards of both study sites: Montefiore Medical Center, New York, NY, United states, and Kaunas University of Medicine, Kaunas, Lithuania. A smoker was arbitrarily defined as an private who had smoked at to the lowest degree five cigarettes daily for at least 1 yr. Subjects were without history of pulmonary affliction, or recent (within 4 weeks) symptoms suggestive of respiratory tract infection or seasonal allergies. Subjects were not receiving any medication known to bear on coughing reflex sensitivity.

Upon enrolment, subjects underwent initial capsaicin coughing challenge testing while still actively smoking, to make up one's mind their baseline coughing reflex sensitivity. Subjects then discontinued smoking at a time of their determination. Subjects were allowed to use pharmacological smoking cessation aids, including nicotine replacement (transdermal patches and chewing gum) and bupropion, at their discretion and that of their physicians.

Ten healthy smokers, fulfilling the same criteria, were recruited to serve every bit a control group.

Capsaicin cough challenge

Subjects underwent capsaicin cough challenge at baseline (while nonetheless actively smoking), and again 2, 6, 12 and 24 weeks after successful smoking cessation. Control subjects underwent capsaicin cough challenge at the aforementioned time intervals. Cough challenge testing was performed equally previously described 12. Briefly, solutions of capsaicin (Sigma Chemical Co., St. Louis, MO, The states) were prepared to make a stock solution of 0.01 Chiliad, and were subsequently further diluted with physiological saline solution to yield series doubling concentrations ranging 0.98–1,000 µM. Fresh dilutions were prepared on each 24-hour interval of testing.

Subjects inhaled single breaths (from functional residue chapters to total lung capacity) of capsaicin aerosol administered via a nebuliser (model 646; De Vilbiss Wellness Intendance Inc., Somerset, PA, USA) controlled by a dosimeter (KoKO Digidoser; Ferraris Respiratory, Louisville, CO, USA). The nebulisers used in this study were modified in two ways. First, an inspiratory catamenia regulator valve (RIFR; Ferraris Respiratory) was added. This limited the inspiratory flow rate to 0.v L·southward^-1 regardless of excessive inspiratory force, thereby guaranteeing a consistent and reproducible inspiratory effort with each breath. Secondly, the straw-and-baffle associates of each nebuliser was welded in place, thereby eliminating the variations in nebuliser output that occur when these components are discrete for washing and then reattached with resulting variable distances betwixt the jet orifice and the straw. Under these conditions, the output of the nebulisers used in the current study was 0.02 mL·breath^-1. Single breaths of capsaicin aerosol were administered in lodge of ascending concentration, with inhalations of saline randomly interspersed to increase challenge blindness, until the concentration inducing five or more than coughs (C₅) was reached. Breaths were delivered at 1-min intervals. Subjects were unaware that the finish-bespeak of the study was the number of coughs induced.

Exhaled carbon monoxide measurement

Prior to each coughing claiming, to ostend smoking or nonsmoking status, subjects underwent measurement of exhaled carbon monoxide (CO) using a portable breath CO monitor (Bedfont EC50 Micro Smokerlyzer; Bedfont Scientific Ltd, Rochester, UK). Previous studies with this instrument have demonstrated that a breath CO level of half-dozen ppm serves every bit a cutting-off value that distinguishes smoking from nonsmoking outpatients, with a sensitivity of 94% and a selectivity of 96% 13.

Data assay

In the smoking abeyance grouping, differences in cough reflex sensitivity measurements at dissimilar time periods were evaluated past comparison values for mean log C₅ using a paired t-test for dependent samples. In comparison the profile of log C_five between the smoking cessation and active smoking groups, linear mixed effects models xiv were employed in order to use all available data and to take into account the inside-field of study correlation of log C_five measurements. In all analyses, a two-tailed examination was employed and p-values <0.05 were considered to exist significant.

RESULTS

In total, 29 subjects (18 males, 11 females) were enrolled and, after undergoing baseline cough reflex sensitivity measurement, successfully abstained from smoking for at least ii weeks. Hateful±sem age of the subjects was 28.0±two.0 yrs (range 19–58); mean duration of smoking was 9.5±1.vii yrs (range 1.5–43); and mean value for pack-yrs was 9.8±two.2 yrs (range 1.5–50). The fourth dimension interval from baseline coughing reflex sensitivity measurement while smoking until onset of smoking cessation was v.4±1.6 days (range 1–30 days). All subjects underwent exhaled CO measurements at the fourth dimension of enrolment. Of the 29 subjects, 26 had exhaled CO measurements of ≥half-dozen ppm, supporting agile smoking status 13. The three subjects whose exhaled CO measurements were <6 ppm had all abstained from smoking for at least eight h prior to evaluation, thus probably allowing their exhaled CO levels to diminish. The range of exhaled CO values was 2–34 ppm, with a hateful of xvi.6±ane.vi ppm. Pharmacological smoking cessation aids were used equally follows: nicotine patch and nicotine gum (n = seven); nicotine patch alone (n = 4); nicotine gum alone (north = 4); nicotine gum and bupropion (n = 1); nicotine patch and clonidine patch (n = i); nicotine patch, clonidine patch and bupropion (due north = ane); and no pharmacological smoking cessation aids (n = 11).

Afterwards two weeks of smoking abeyance, at that place was a significant enhancement of cough reflex sensitivity, i.eastward. decrease in C₅. Hateful±sem log C_v fell from a baseline of 1.86±0.12 to 1.sixty±0.12 (p = 0.0004; fig. 1⇓). One doubling-concentration change in C₅ is represented by a 0.iii unit of measurement change in log C₅. Of the 29 subjects, 27 demonstrated exhaled CO levels of ≤6 ppm, confirming their nonsmoking condition. In two subjects, exhaled CO measurements were non performed due to malfunction of the instrument.

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Fig. 1—

Modify in cough reflex sensitivity after smoking abeyance. Baseline measurement reflects cough sensitivity to capsaicin (log C_five) while subjects (n = 29) were actively smoking. Two weeks later on smoking abeyance, mean±sem log C_v decreased from 1.86±0.12 to 1.60±0.12 (p = 0.0004).

Later on 6 weeks, nine subjects had resumed smoking. Of the twenty subjects remaining, mean log C_v after six weeks of smoking cessation was less than that later 2 weeks of smoking abeyance, but the deviation did non reach statistical significance (fig. two⇓). In this grouping of subjects, equally in the entire group, there was a significant decrement in mean log C_v later 2 weeks of smoking cessation (p = 0.01; fig. two⇓). Exhaled CO measurements demonstrated 16 out of xviii subjects to accept levels of ≤6 ppm; two subjects had levels of 7 ppm. In two subjects, measurements were non performed due to malfunction of the musical instrument.

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Fig. 2—

Cough reflex sensitivity (log C₅) in subjects at baseline (0) and at ii, 6, 12 and 24 weeks later on smoking cessation (○), and in control grouping of active smokers (•). Data are reported equally mean±sem for both groups. For the control group, north = ten for all time-points. For the smoking abeyance grouping, n = 29 at baseline and at 2 weeks; northward = 20 at half dozen weeks; due north = 18 at 12 weeks; and northward = 14 at 24 weeks. Attrition in the smoking cessation grouping occurred due to resumption of smoking in some subjects. p = 0.0001.

Later on 12 weeks, 18 subjects continued to abstain from smoking. In these subjects, hateful log C_five continued to autumn subsequently each time interval, but the differences betwixt consecutive measurements did non attain statistical significance. Hateful log C₅ after 12 weeks of smoking cessation was significantly lower than baseline (p = 0.03; fig. ii⇑). Of these subjects, 15 underwent exhaled CO measurement; 14 demonstrated an exhaled CO level of ≤6 ppm, and one subject had a level of 7 ppm. Three subjects did not undergo exhaled CO measurement due to malfunction of the musical instrument.

Past the end of the 24-calendar week written report menstruation, 14 out of the original 29 subjects had connected to abjure from smoking. In this grouping, mean log C_five continued to decrease at each written report interval, although differences between consecutive measurements did not reach statistical significance. Mean log C₅ after 24 weeks of smoking abeyance was significantly lower compared with baseline (p = 0.008; fig. ii⇑). Exhaled CO measurements were ≤6 ppm in 13 out of the fourteen subjects; in ane bailiwick, the level was 7 ppm.

Ten control subjects (vii males, three females) continued to smoke throughout the 24-week study period. For the control group, hateful±sem historic period was 28.5±1.7 yrs; mean duration of smoking was 9.four±i.nine yrs; and mean value for pack-yrs was 6.9±1.8 yrs. There was a small decrement in mean log C₅ later on two weeks that did not reach statistical significance (p = 0.64). The hateful log C_five levels subsequently 6, 12 and 24 weeks were college than baseline, in contrast to the smoking abeyance grouping. The profile of log C_v by smoking status is presented in figure 2⇑. Using a linear mixed-effects model, the difference in the contour of log C_five betwixt the smoking cessation and active smoking (command) groups was statistically significant, i.e. the log C_five profile of the smoking cessation grouping showed a clear, linearly decreasing tendency over time equally compared with the command group (p = 0.0001).

Give-and-take

It has previously been shown that healthy cigarette smokers have a diminished coughing reflex sensitivity relative to nonsmokers 2. Information technology was speculated that the suppression of the cough reflex was due to chronic cigarette smoke-induced desensitisation of airway coughing receptors two. To farther investigate these findings, the present study was performed to evaluate the effect of smoking abeyance on cough reflex sensitivity in subjects who had been chronic smokers. The results from the present written report demonstrate that fifty-fifty afterward many years of cigarette smoking, cough reflex sensitivity is measurably enhanced as early as 2 weeks afterwards smoking cessation. In some subjects, further enhancement of coughing reflex sensitivity connected 6, 12 and 24 weeks after smoking abeyance; however, the major effect appears to have occurred inside the initial 2 weeks after discontinuation of smoking.

The results of the nowadays report support the hypothesis that chronic exposure to cigarette smoke desensitises afferent coughing receptors within the airway epithelium 2, since removal of this noxious stimulus immune the sit-in of increased cough reflex sensitivity. Presumably, rapidly adapting pulmonary stretch receptors and/or C fibres, receptors believed to exist involved in the cough reflex 1, are desensitised, albeit reversibly, past regular and prolonged exposure to cigarette fume. Changes in airway mucus secretion may besides be relevant to present observations. If, for example, mucus secretion decreased afterwards smoking abeyance, a thinner mucus layer may have rendered the airway cough receptors less shielded from the tussive agent capsaicin during the post-smoking abeyance cough-challenge report.

The present data too show that the cough reflex is quite dynamic, since changes in sensitivity to capsaicin were demonstrable as early as 2 weeks after many years, in some cases, of cigarette smoking. Furthermore, these results contradict the alternate hypothesis that cigarette smokers comprise a group of individuals with naturally occurring, diminished cough reflex sensitivity that renders them able to tolerate and enjoy cigarette smoking 7, viii.

Multiple studies have demonstrated that cough reflex sensitivity measurements with inhaled capsaicin are highly reproducible, both in the short and long term 12. However, there is corking interindividual variation in coughing reflex sensitivity among healthy individuals 12. Thus, the ascertainment that the mean log C_five in the electric current command group of agile smokers increased during the grade of the report was unexpected. This tin can be attributed to a take a chance effect (or random variation), given the minor size (northward = 10) of the group. Notwithstanding, the controls served as a articulate contrast to the smoking cessation grouping, whose mean log C₅ steadily decreased, indicating enhancement of cough reflex sensitivity throughout the duration of the study.

It is felt to be unlikely that the pharmacological smoking cessation aids used by some subjects in the present study afflicted information in any significant way. For example, when subjects were separated into those that did and did not use drugs (mainly nicotine replacement) to aid smoking cessation, the bulk of subjects in each group demonstrated an enhancement of cough reflex sensitivity two weeks after discontinuation of smoking. Furthermore, previous studies have shown that inhaled nicotine induces cough in salubrious subjects xv. Therefore, if nicotine were a significant contributor to the degree of cough reflex sensitivity in smokers, one would expect a diminution of cough reflex sensitivity after smoking cessation, whereas the present authors observed the reverse effect.

Another relevant question to consider is the possibility that transdermal nicotine patches could have produced blood levels of nicotine in the nowadays subjects higher than those present during active smoking. If that were the case and if nicotine indeed potentiated the cough reflex 15, and then such an effect could have contributed to the present authors' observation of enhanced coughing reflex sensitivity subsequently smoking cessation. However, previous studies comparing blood nicotine levels during active smoking and later on smoking cessation while using transdermal nicotine replacement accept demonstrated lower or similar nicotine levels with the nicotine patch sixteen–18. But a loftier-dose nicotine patch (44 mg) has been shown to achieve like or higher blood nicotine levels compared with the active smoking period 17, 19. The present report subjects used patches of ≤21 mg. Thus, college blood nicotine levels in the present written report'south postal service-smoking cessation subjects are highly unlikely to have contributed to the results presently observed. Lastly, clonidine has been shown to have no result on capsaicin-induced cough in humans 20.

The suppression of the cough reflex, an important respiratory defence mechanism, may take pregnant clinical ramifications in smokers. Tobacco-smoke-induced inhibition of the cough reflex may contribute to the significantly increased hazard of bacterial and viral respiratory tract infections in cigarette smokers 21. A diminished coughing reflex has been associated with an increased risk of developing aspiration pneumonia in stroke patients 22 and in the elderly 23. Conversely, hypertensive stroke patients treated with angiotensin-converting enzyme inhibitors, agents that enhance cough reflex sensitivity, accept a lower incidence of pneumonia compared with stroke patients treated with other classes of antihypertensive drugs 24, 25. Furthermore, studies using radiolabelled aerosols have shown that immature, good for you smokers with normal pulmonary function are unable to enhance their rate of mucus clearance by cough, suggesting an alteration in the mucociliary apparatus 26.

Given the importance of an intact cough reflex as a vital respiratory defence mechanism, the results of the nowadays study, demonstrating the reversal of chronic, cigarette-smoke-induced suppression of cough reflex sensitivity afterwards smoking cessation, offer yet another reason for smokers to discontinue the use of tobacco.

• Received January 18, 2006.
• Accustomed May 31, 2006.

• © ERS Journals Ltd

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