The Treatment of Cough* A Comprehensive Review RichardS. ln.vin, M.D., F.C.C.P.; and FrederickJ Curley, M.D.
W
(Chat 1991; 99:1411-84)
e have previously critically reviewed the effects of clinically useful drugs on cough that reHected the literature through 1984. 1 The purpose of this communication is to update our current understanding of this subject. The older portions of this review have previously been published . 1 Since cough can serve a variety of functions, the treatment of cough could theoretically vary, depending upon which function one is trying to modify. Among the functions that cough can serve are as an indicator of an underlying illness and as a defense mechanism. As an indicator of an underlying condition, cough is one of the most common reasons people seek medical treatment.2 Although the act of coughing itself has previously been reported to cause a variety of musculoskeletal, pulmonary, cardiovascular, and central nervous system complications,3 we have recently determined that these were not the most common or troublesome reasons for which patients with chronic cough (ie, greater than three weeks' duration) sought medical attention (Table 1). These previously unreported data were prospectively collected, using a questionnaire designed to determine why patients with chronic cough sought medical attention, during a studyt involving 108 consecutive and unselected patients. When considering the two previously stated functions of cough, the treatment of cough can be categorized into therapy that controls, prevents, or eliminates cough (ie, antitussive therapy) and therapy that makes cough more effective (ie, protussive therapy). ANTITUSSIVE THERAPY
When cough performs no useful function and it is an annoyance or its complications represent a real or potential hazard, antitussive therapy is indicated. Antitussive therapy can be categorized as definitive or nonspecific. It is definitive when it eliminates cough. Definitive therapy is directed in a specific way at either the etiology (eg, killing the tubercle bacillus in tuberculosis; smoking cessation in chronic bronchitis) or the presumed operant pathophysiologic mechanism responsible for cough (eg, eliminating the postnasal discharge in allergic rhinitis and chronic sinusitis).5 •From the Division of Pulmonary and Critical Care Medicine, University of Massachusetts Medical School, Worcester. Reprint requests: Dr. lnoin, University of Massachusetts Medical Center; 55 Lake Avenue North, \.\.brcester 01655
Nonspecific therapy is directed at the symptom, rather than the underlying etiology or mechanism; consequently, its aim is to control, rather than to eliminate cough. It is indicated when definitive therapy cannot be given either because the cause of the cough is unknown or because definitive therapy has not had a chance to work or will not work (eg, cancer metastatic to lung).
Definitive Therapy We are aware of seven studies published in the English language which describe series of patients complaining of chronic cough. Even though the ability of different physicians to effectively manage chronic cough varies, 6 all of these studies have substantiated the generally accepted concept in medicine that the optimal approach to the treatment of any symptom (such as cough) is first to determine its cause and then direct therapy specifically at eliminating the etiology or pathophysiologic mechanism . In 1981, Irwin et al6 prospectively evaluated 49 consecutive and unselected adult patients with chronic Table 1-Realona Why .ftmentl with Chronic Cough Seek Medical Attention
Reason Something's wrong Exhaustion Self-conscious Insomnia Life-style change Musculoskeletal pain• Hoarseness Excessive perspiration Urinary incontinencet Dizziness Fear of cancer Headache Fear of AIDS or tuberculosis Retching \bmiting Nausea Anorexia Syncope or near syncope
Frequency, percent
Most Troublesome, percent
98
57
55 45 45 44 43
12 17 10 4
12 3 2
42
39 38 33
32 28
21 18 16 15 5
9
0 11
3
11 4
1 0 0 1
•Musculoskeletal pain was documented by chest x-ray 61m to be due to rib fracture in only one patient. tUrinary incontinence complicated cough only in women and two men who had undergone prior transurethral prostatectomy. CHEST I 99 I 6 I JUNE, 1991
1477
cough and were able to determine the cause of the cough in all and, therefore, to prescribe definitive therapy. Specific therapy was immediately successful in 97 percent of the patients. The only patient who continued to cough had breast carcinoma metastatic to the lung that was refractory to chemotherapy. She was the only patient in this series who received nonspecific therapy (eg, codeine). During follow-up evaluations an average of 19 months later, specific therapy continued to be successful in eliminating cough as a complaint in 90 percent of the patients overall and 97 percent of the patients who followed their plan of treatment as prescribed. Specific therapy depended upon the cause of the cough. In this study, asthma was treated with bronchodilators alone or with a corticosteroid; postnasal drip syndrome due to sinusitis was treated with an antibiotic, a decongestant nasal spray, and an antihistamine-decongestant tablet; postnasal drip due to allergic or perennial nonallergic rhinitis was treated with avoidance of environmental precipitating factor(s) and an H 1-receptor blocker or H 1 blocker-decongestant tablet; gastroesophageal reflux was treated with elevation of the head of the bed, diet modification (eg, high-protein, low-fat antireflux diet; nothing to eat or drink for 2 to 3 hours prior to reclining; 3 meals per day with little or no snacking in between), antacids, and an H 2 blocker; chronic bronchitis was treated solely with cessation of cigarette smoking; sarcoidosis was treated with corticosteroids; and congestive heart failure was treated with digoxin and furosemide. In a retrospective report published in 1982 involving 109 adult patients, Poe et al7 determined the cause in 97 percent. When their data are adjusted for the patients who followed the recommended treatment, cough disappeared spontaneously or in association with specific therapy in at least 93 percent of the patients. In a prospective study published in 1986 involving 38 infants and children under the age of 16 years, Holinger" determined the cause and prescribed successful specific therapy in 87 percent. In 1989, Poe et al 9 reported their second retrospective study involving 139 adult patients. These investigators9 determined the cause of cough in 88 percent and obtained a long-term success rate of 93 percent with specific therapy in those patients who followed the recommended treatment. In 1990, in a prospective study involving 102 adults, Irwin et a1~ determined the cause of cough in 99 percent of the patients and had a success rate of 98 percent with specific therapy. In essentially reduplicating the results of their first study published in 1981, these authors had modified their diagnostic and therapeutic protocols. The major modifications were as follows: 4 · 10 (l) prolonged esophageal pH monitoring was added to the diagnostic testing in order to be able 1478
to assess whether gastroesophageal reflux was causing cough, even when gastroesophageal reflux was silent and barium swallow was normal; 11 (2) intranasal corticosteroids, rather than H 1 blocker-decongestant tablets, were preferentially prescribed for postnasal drip syndromes not due to sinusitis; and (3) oral, rather than inhalational, ~-adrenergic agonists were prescribed for the asthmatic component of cough when the latter was observed to provoke cough in the clinic. In 1989, two studies reported on the treatment of chronic cough due to gastroesophageal reflux. In a prospective study involving nine patients, Irwin et al 11 showed the following: (1) empiric therapy with an H 2 blocker alone may not be adequate; (2) therapy was successful in all patients and included a high-protein, low-fat, anti-reflux diet, eating 3 meals per day without snacking, not eating or drinking except for taking medicines for 2 to 3 hours prior to lying down, elevation of the head of the bed, and metoclopramide or H 2 blockers (or both); and (3) the resolution of cough with specific therapy was gradual, taking an average of 161 days. Fitzgerald et al, 12 in a retrospective study involving 20 patients, reported a 90 percent success rate with specific therapy. A three-month course of medical therapy similar to that used by Irwin et al 11 relieved cough in 14 of the 20 patients. Of the remaining six patients who continued to cough, four were asymptomatic three months after surgical antireflux therapy, one was lost to follow-up, and one refused surgery and remained symptomatic.
Nonspecific Therapy After reviewing the extensive literature on the efficacy of nonspecific antitussive treatment, we concluded the following about evaluating this form of therapy: 1 (1) Although studies on artificially induced cough in animals and healthy subjects were important in order to determine which drugs should be selected for clinical trials, these studies by themselves could not be used to determine effectiveness, since their efficacy has not always been reproducible in patients with pathologic cough. 13 (2) In evaluating antitussive action, it is not only important to assess a change in the frequency of cough, but also a change in intensity (severity). (3) Since objective cough counting can only evaluate cough frequency, while the patients subjective assessment probably integrates both cough frequency and intensity, it is possible for a drug to be considered effective when subjective and objective results deviate. On the basis of these conclusions, we decided to evaluate the literature on antitussive therapy according to the following guidelines: nonspecific antitussives can only be considered clinically useful if they have been shown to decrease significantly cough frequency or intensity (or both) by objective cough counting or standardized questionnaires in randomThe Treatment of Cough (Irwin, Curley}
ized, double-blind placebo-controlled studies in patients with pathologic cough. With few exceptions, only those drugs that have been adequately evaluated according to these guidelines will be mentioned in this review. Nonspecific antitussive drugs can be classified according to how and where they might theoretically control the cough reflex, as shown in the following classification: 1. Alter mumciliary factors irritating cough receptors. 2. Increase the threshold or latency (or both) of the afferent limb. 3. Increase the threshold or latency (or both) of the rough
W
(Chat 1991; 99:1411-84)
e have previously critically reviewed the effects of clinically useful drugs on cough that reHected the literature through 1984. 1 The purpose of this communication is to update our current understanding of this subject. The older portions of this review have previously been published . 1 Since cough can serve a variety of functions, the treatment of cough could theoretically vary, depending upon which function one is trying to modify. Among the functions that cough can serve are as an indicator of an underlying illness and as a defense mechanism. As an indicator of an underlying condition, cough is one of the most common reasons people seek medical treatment.2 Although the act of coughing itself has previously been reported to cause a variety of musculoskeletal, pulmonary, cardiovascular, and central nervous system complications,3 we have recently determined that these were not the most common or troublesome reasons for which patients with chronic cough (ie, greater than three weeks' duration) sought medical attention (Table 1). These previously unreported data were prospectively collected, using a questionnaire designed to determine why patients with chronic cough sought medical attention, during a studyt involving 108 consecutive and unselected patients. When considering the two previously stated functions of cough, the treatment of cough can be categorized into therapy that controls, prevents, or eliminates cough (ie, antitussive therapy) and therapy that makes cough more effective (ie, protussive therapy). ANTITUSSIVE THERAPY
When cough performs no useful function and it is an annoyance or its complications represent a real or potential hazard, antitussive therapy is indicated. Antitussive therapy can be categorized as definitive or nonspecific. It is definitive when it eliminates cough. Definitive therapy is directed in a specific way at either the etiology (eg, killing the tubercle bacillus in tuberculosis; smoking cessation in chronic bronchitis) or the presumed operant pathophysiologic mechanism responsible for cough (eg, eliminating the postnasal discharge in allergic rhinitis and chronic sinusitis).5 •From the Division of Pulmonary and Critical Care Medicine, University of Massachusetts Medical School, Worcester. Reprint requests: Dr. lnoin, University of Massachusetts Medical Center; 55 Lake Avenue North, \.\.brcester 01655
Nonspecific therapy is directed at the symptom, rather than the underlying etiology or mechanism; consequently, its aim is to control, rather than to eliminate cough. It is indicated when definitive therapy cannot be given either because the cause of the cough is unknown or because definitive therapy has not had a chance to work or will not work (eg, cancer metastatic to lung).
Definitive Therapy We are aware of seven studies published in the English language which describe series of patients complaining of chronic cough. Even though the ability of different physicians to effectively manage chronic cough varies, 6 all of these studies have substantiated the generally accepted concept in medicine that the optimal approach to the treatment of any symptom (such as cough) is first to determine its cause and then direct therapy specifically at eliminating the etiology or pathophysiologic mechanism . In 1981, Irwin et al6 prospectively evaluated 49 consecutive and unselected adult patients with chronic Table 1-Realona Why .ftmentl with Chronic Cough Seek Medical Attention
Reason Something's wrong Exhaustion Self-conscious Insomnia Life-style change Musculoskeletal pain• Hoarseness Excessive perspiration Urinary incontinencet Dizziness Fear of cancer Headache Fear of AIDS or tuberculosis Retching \bmiting Nausea Anorexia Syncope or near syncope
Frequency, percent
Most Troublesome, percent
98
57
55 45 45 44 43
12 17 10 4
12 3 2
42
39 38 33
32 28
21 18 16 15 5
9
0 11
3
11 4
1 0 0 1
•Musculoskeletal pain was documented by chest x-ray 61m to be due to rib fracture in only one patient. tUrinary incontinence complicated cough only in women and two men who had undergone prior transurethral prostatectomy. CHEST I 99 I 6 I JUNE, 1991
1477
cough and were able to determine the cause of the cough in all and, therefore, to prescribe definitive therapy. Specific therapy was immediately successful in 97 percent of the patients. The only patient who continued to cough had breast carcinoma metastatic to the lung that was refractory to chemotherapy. She was the only patient in this series who received nonspecific therapy (eg, codeine). During follow-up evaluations an average of 19 months later, specific therapy continued to be successful in eliminating cough as a complaint in 90 percent of the patients overall and 97 percent of the patients who followed their plan of treatment as prescribed. Specific therapy depended upon the cause of the cough. In this study, asthma was treated with bronchodilators alone or with a corticosteroid; postnasal drip syndrome due to sinusitis was treated with an antibiotic, a decongestant nasal spray, and an antihistamine-decongestant tablet; postnasal drip due to allergic or perennial nonallergic rhinitis was treated with avoidance of environmental precipitating factor(s) and an H 1-receptor blocker or H 1 blocker-decongestant tablet; gastroesophageal reflux was treated with elevation of the head of the bed, diet modification (eg, high-protein, low-fat antireflux diet; nothing to eat or drink for 2 to 3 hours prior to reclining; 3 meals per day with little or no snacking in between), antacids, and an H 2 blocker; chronic bronchitis was treated solely with cessation of cigarette smoking; sarcoidosis was treated with corticosteroids; and congestive heart failure was treated with digoxin and furosemide. In a retrospective report published in 1982 involving 109 adult patients, Poe et al7 determined the cause in 97 percent. When their data are adjusted for the patients who followed the recommended treatment, cough disappeared spontaneously or in association with specific therapy in at least 93 percent of the patients. In a prospective study published in 1986 involving 38 infants and children under the age of 16 years, Holinger" determined the cause and prescribed successful specific therapy in 87 percent. In 1989, Poe et al 9 reported their second retrospective study involving 139 adult patients. These investigators9 determined the cause of cough in 88 percent and obtained a long-term success rate of 93 percent with specific therapy in those patients who followed the recommended treatment. In 1990, in a prospective study involving 102 adults, Irwin et a1~ determined the cause of cough in 99 percent of the patients and had a success rate of 98 percent with specific therapy. In essentially reduplicating the results of their first study published in 1981, these authors had modified their diagnostic and therapeutic protocols. The major modifications were as follows: 4 · 10 (l) prolonged esophageal pH monitoring was added to the diagnostic testing in order to be able 1478
to assess whether gastroesophageal reflux was causing cough, even when gastroesophageal reflux was silent and barium swallow was normal; 11 (2) intranasal corticosteroids, rather than H 1 blocker-decongestant tablets, were preferentially prescribed for postnasal drip syndromes not due to sinusitis; and (3) oral, rather than inhalational, ~-adrenergic agonists were prescribed for the asthmatic component of cough when the latter was observed to provoke cough in the clinic. In 1989, two studies reported on the treatment of chronic cough due to gastroesophageal reflux. In a prospective study involving nine patients, Irwin et al 11 showed the following: (1) empiric therapy with an H 2 blocker alone may not be adequate; (2) therapy was successful in all patients and included a high-protein, low-fat, anti-reflux diet, eating 3 meals per day without snacking, not eating or drinking except for taking medicines for 2 to 3 hours prior to lying down, elevation of the head of the bed, and metoclopramide or H 2 blockers (or both); and (3) the resolution of cough with specific therapy was gradual, taking an average of 161 days. Fitzgerald et al, 12 in a retrospective study involving 20 patients, reported a 90 percent success rate with specific therapy. A three-month course of medical therapy similar to that used by Irwin et al 11 relieved cough in 14 of the 20 patients. Of the remaining six patients who continued to cough, four were asymptomatic three months after surgical antireflux therapy, one was lost to follow-up, and one refused surgery and remained symptomatic.
Nonspecific Therapy After reviewing the extensive literature on the efficacy of nonspecific antitussive treatment, we concluded the following about evaluating this form of therapy: 1 (1) Although studies on artificially induced cough in animals and healthy subjects were important in order to determine which drugs should be selected for clinical trials, these studies by themselves could not be used to determine effectiveness, since their efficacy has not always been reproducible in patients with pathologic cough. 13 (2) In evaluating antitussive action, it is not only important to assess a change in the frequency of cough, but also a change in intensity (severity). (3) Since objective cough counting can only evaluate cough frequency, while the patients subjective assessment probably integrates both cough frequency and intensity, it is possible for a drug to be considered effective when subjective and objective results deviate. On the basis of these conclusions, we decided to evaluate the literature on antitussive therapy according to the following guidelines: nonspecific antitussives can only be considered clinically useful if they have been shown to decrease significantly cough frequency or intensity (or both) by objective cough counting or standardized questionnaires in randomThe Treatment of Cough (Irwin, Curley}
ized, double-blind placebo-controlled studies in patients with pathologic cough. With few exceptions, only those drugs that have been adequately evaluated according to these guidelines will be mentioned in this review. Nonspecific antitussive drugs can be classified according to how and where they might theoretically control the cough reflex, as shown in the following classification: 1. Alter mumciliary factors irritating cough receptors. 2. Increase the threshold or latency (or both) of the afferent limb. 3. Increase the threshold or latency (or both) of the rough
