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CHEST Original Research

SIGNS AND SYMPTOMS OF CHEST DISEASES

Efficacy and Tolerability of Treatments for


Chronic Cough
A Systematic Review and Meta-analysis
William S. Yancy Jr, MD, MHSc; Douglas C. McCrory, MD, MHS;
Remy R. Coeytaux, MD, PhD; Kristine M. Schmit, MD, MPH; Alex R. Kemper, MD, MPH;
Adam Goode, PhD, PT, DPT; Victor Hasselblad, PhD; Brooke L. Heidenfelder, PhD;
and Gillian D. Sanders, PhD

Background: Understanding the comparative effectiveness of treatments for patients with unex-
plained or refractory cough is important to increase awareness of proven therapies and their
potential adverse effects in this unique population.
Methods: We performed a literature search for English-language studies published up to June
2012 that compared symptomatic therapies for chronic cough. Two investigators screened each
abstract and full-text article for inclusion, abstracted data, and rated quality. Meta-analysis with
random-effects models was used to summarize effects of treatments.
Results: We identified 49 studies (3,067 patients) comprising 68 therapeutic comparisons. Of the
studied agents, opioid and certain nonopioid and nonanesthetic antitussives had demonstrated
efficacy for chronic cough in adults. Compared with placebo, effect sizes (standardized mean
differences for cough severity and rate ratios for cough frequency) for opioids were 0.55 (95% CI,
0.38-0.72; P , .0001) and 0.57 (95% CI, 0.36-0.91; P 5 .0260), respectively. For dextromethorphan,
effect sizes were 0.37 (95% CI, 0.19-0.56; P 5 .0008) and 0.40 (95% CI, 0.18-0.85; P 5 .0248), respec-
tively. The overall strength of evidence was limited by inconsistency and imprecision of results and
by small numbers of direct comparisons. Nonpharmacologic therapies and the management of cough
in children were infrequently studied.
Conclusions: Although evidence is limited, opioid and certain nonopioid and nonanesthetic antitus-
sives demonstrated efficacy for treating chronic cough in adults. There is a need for further studies
in patients with unexplained or refractory cough as well as for more systematic study designs,
assessment of patient-centered outcomes, and reporting. CHEST 2013; 144(6):1827–1838

Abbreviations: RR 5 rate ratio; SMD 5 standardized mean difference

Cough is the most common complaint for which


patients seek medical attention in the United States,
Up to 46% of patients with chronic cough do not have
a clear etiology despite a thorough diagnostic investi-
accounting for . 26 million office visits annually.1 gation.13 Patients with such unexplained cough or cough
Chronic cough, defined as lasting . 4 weeks in that is refractory to treatment of underlying etiologies
patients aged , 14 years or for . 8 weeks in patients may receive therapies aimed simply at the symptom of
aged ⱖ 14 years,2,3 is responsible for up to 38% of cough. Symptomatic treatment consists of antitussive
pulmonary-related outpatient visits.4,5 For adult patients therapy to decrease cough frequency and severity or
in whom a specific cause of chronic cough is not easily protussive therapy to improve clearance of mucus.
identified, guidelines published by the American Col- The safety and effectiveness of many of these ther-
lege of Chest Physicians in 2006 recommend an empir- apies is uncertain, however, particularly in the setting
ical approach to diagnosis and treatment.6,7 For children, of chronic cough. The purpose of this review is to
however, there is little consensus regarding the appro- evaluate the comparative effectiveness of treatments
priate approach because data on medication safety for the symptom of chronic cough in adult and pedi-
and effectiveness are few.8-12 atric patients with unexplained or refractory cough.

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Materials and Methods We used random-effects models to quantitatively synthesize
the available evidence (Comprehensive Meta-Analysis version 2
This article summarizes a comparative effectiveness review software; Biostat, Inc). We tested for heterogeneity with graphic
commissioned by the Agency for Healthcare Research and Quality.14 displays and test statistics (Q and I2 statistics). We reported P values
Further details of the topic refinement, literature search, methods, for Q statistics as follows: .15 . P . .05 as some evidence of het-
and conclusions can be found in the full report. erogeneity, .05 . P . .0001 as evidence of heterogeneity, and
P , .0001 as evidence of extreme heterogeneity.
Literature Search and Study Selection We performed a mixed treatment meta-analysis that enabled
us to incorporate data from placebo comparisons and head-to-
We searched MEDLINE, EMBASE, and the Cochrane Data- head comparisons. This model, fitted with the use of SAS PROC
base of Systematic Reviews through June 2012 to identify relevant NLMIXED (SAS Institute Inc), estimated the effect sizes (rela-
published literature. We sought additional articles from reference tive to placebo) for each treatment. For treatments that could not
lists of key primary and review articles, content experts, and the be included in the mixed-treatment meta-analysis, we calculated
US Food and Drug Administration device registration studies and effect sizes from data reported in the studies (raw data, means and
new drug applications. Studies eligible for inclusion were English- variances, or test statistics) to present results in comparable terms.
language, prospective, comparative (vs placebo or active therapy)
assessments of pharmacologic and nonpharmacologic therapies
aimed at treating the symptom of cough in patients with unexplained Results
or refractory chronic cough (persisting 4 weeks if aged , 14 years
or 8 weeks if aged ⱖ 14 years or as stated by study authors). Arti- Figure 1 shows the flow of literature through the
cles were excluded if (1) the therapy was directed at an underlying search and screening process. Forty-three articles
etiology, (2) cough resulted from invasive respiratory tract instru- describing 49 separate studies met the inclusion cri-
mentation, (3) the only outcomes assessed were induced sputum
or bronchoprovocation challenge, (4) the therapy was not commer-
teria (Table 1).15-57 One article15 reported results for
cially available globally or had been withdrawn from the US mar- six separate studies, whereas another37 described results
ket or rejected by the US Food and Drug Administration, or for two separate studies. Only three studies39,50,56 were
(5) the study was a case-control design. performed in children. The majority of studies were
Forms were designed and completed by DistillerSR (Evidence rated fair in quality (n 5 30, 61%), 11 were good in
Partners Incorporated) to standardize the data collection. For eli-
gible studies, an investigator abstracted data and assigned quality
quality, and eight were poor in quality.
ratings. A second investigator reviewed the completed abstraction A total of 3,067 participants were included across
form to check for accuracy and completeness and independently trials. A variety of causes for chronic cough were rep-
assigned quality ratings. Disagreements were resolved by consen- resented, including bronchitis, COPD, asthma, upper
sus or by obtaining a third reviewer’s opinion if consensus could airway cough syndrome, fibrosis, neoplasm, TB, cystic
not be reached.
fibrosis, gastroesophageal reflux disease, and unex-
plained cough. Sample sizes were relatively small, rang-
Data Synthesis and Analysis ing from eight to 214 participants. A variety of therapies
We considered meta-analysis for comparisons where at least were studied; these can be broadly categorized into
three studies reported the same outcome. We considered measures antitussive, protussive, and nonantitussive and nonpro-
of cough severity, regardless of the scale used, to be similar enough tussive therapies. Antitussives were further subcate-
to combine estimating effect sizes as standardized mean differ-
ences (SMDs). Cough frequency data were analyzed with the use
gorized into opioid, anesthetic, and nonopioid and
of the rate ratio (RR) as an effect size measure. nonanesthetic therapies. Patient-centered outcomes
data for all studies are presented in e-Table 1.
Manuscript received February 28, 2013; revision accepted July 8,
2013. Studies Involving Opioid Antitussives
Affiliations: From the Department of Medicine (Drs Yancy,
McCrory, and Sanders), Doctor of Physical Therapy Division We found 29 comparisons within 17 studies involv-
(Drs Coeytaux and Goode), Department of Community and Family ing opioid antitussives. Of 11 comparisons of opioids
Medicine (Dr Schmit), Department of Pediatrics (Dr Kemper),
and Department of Biostatistics & Bioinformatics (Dr Hasselblad), with placebo,18-20,24,33,35,43,44,46,47,57 eight showed opioids
Duke University School of Medicine; Center for Health Services to be more effective for decreasing cough frequency
Research in Primary Care (Drs Yancy and McCrory), Veterans and cough severity and improving quality of life (Leic-
Affairs Medical Center; and Duke Evidence-based Practice Center
(Drs McCrory, Coeytaux, Heidenfelder, and Sanders), Duke Clini- ester Cough Questionnaire).18-20,24,33,35,44,57 No one opi-
cal Research Institute, Durham, NC. oid was superior to another, although codeine had a
Funding/Support: This project was funded by the Agency dose-response improvement in cough severity and fre-
for Healthcare Research and Quality (AHRQ), US Department
of Health and Human Services [Contract 290-2007-10066-I]. quency,44 and viminol was effective at reducing cough
Dr Goode is supported by the AHRQ K-12 Comparative Effec- severity at a higher dose but not at a lower dose.43
tiveness Career Development Award [Grant HS19479-01]. Among studies comparing opioids with other active
Correspondence to: William S. Yancy Jr, MD, MHSc, VA Medical
Center (152), 508 Fulton St, Durham, NC 27705; e-mail: yancy006@ agents, two compared opioids with anesthetic antitus-
mc.duke.edu sives, and neither class of medication showed superi-
© 2013 American College of Chest Physicians. Reproduction ority.25,46 Codeine derivatives were also compared with
of this article is prohibited without written permission from the
American College of Chest Physicians. See online for more details. a variety of nonopioid and nonanesthetic antitussives
DOI: 10.1378/chest.13-0490 with mixed results. Compared with dextromethorphan,

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Figure 1. Literature flow diagram. KQ 5 key question; RCT 5 randomized controlled trial.

codeine was less effective in one study,33 comparable Studies Involving Anesthetic Antitussives
in another,20 and more effective in two, but the latter
Anesthetic antitussives were examined in three
two studies compared standard-dose codeine to low-
studies25,45,46 that included four comparisons. Benzo-
dose dextromethorphan.18,19 Two studies comparing
natate was not superior to placebo in one study.46
codeine with glaucine reported conflicting results.24,27
Chlophedianol and benzonatate were not more effec-
Codeine or dihydrocodeine were similar in effective-
tive than opioids in two studies.25,46 Benzonatate and
ness to moguisteine (one study17), levodropropizine
Becantyl (sodium 2.6 ditertiarybutylnaphthalene mono-
(one study32), and levocloperastine (two studies [one
sulfonate) had similar effects on cough severity in a
article]15).
comparison trial.45
In terms of tolerability, two of 39 patients taking
codeine 30 mg in one study discontinued the medica-
Studies Involving Nonopioid and Nonanesthetic
tion because of adverse effects.17 In one study, mor-
Antitussives
phine resulted in significant rates of constipation and
drowsiness but was not discontinued because of tol- We found 31 comparisons in 21 studies involving
erability issues.35 In another study, the percentage of nonopioid and nonanesthetic antitussives. Ten of the
patients experiencing somnolence while taking dihy- 31 comparisons were with opioids and have been
drocodeine was significantly higher (22%) than in the described previously in these results.
group receiving levodropropizine (8%).32 In two studies, Six studies compared dextromethorphan with pla-
nausea, constipation, and drowsiness were more fre- cebo.18-20,33,38,41 Four of these showed that dextromethor-
quent with codeine than with dextromethorphan.18,19 phan was effective at reducing cough severity, frequency,

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Table 1—Study Characteristics

Comparison and Quality: Intervention Outcomes


Study/Year No. Patients Description Disease vs Comparator Reported
Antibiotic vs placebo
Yousaf et al55/2010 Good: 30 Chronic cough Unexplained cough Erythromycin vs placebo 1, 2, 4,5
Marchant et al56/2012 Good: 50 Chronic cougha NR Amoxicillin vs placebo 1, 2
Anticholinergic
vs placebo
Holmes et al29/1992 Good: 13 Persistent cough Postviral URTI Ipratropium bromide 1, 11
secondary to inhaler vs placebo
prior URTI
Antihistamine vs antihistamine
Lilienfield et al31/1976 Fair: 13 NR NR Diphenhydramine 2, 10
vs diphenhydramine
Antihistamine vs placebo
Reid39/1989 Fair: 189 Chronic recurrent Asthma Ketotifen vs placebo 1, 4
cough or wheeze
with airway
hyperreactivitya
van Asperen et al50/1992 Good: 112 Chronic cough Unexplained cough Ketotifen vs placebo 1
or wheezea
Tanaka et al48/1996 Fair: 17 Chronic cough UACS Loratadine vs placebo 5
Antitussive (anesthetics)
vs antitussive
(anesthetics)
Simon45/1957 Poor: 59 Chronic asthmatic COPD Benzonatate vs linctussal 1
bronchitis or pulmonary (Bencantyl)
emphysema
Antitussive (anesthetics)
vs antitussive (opiates)
Simon46/1960 Poor: 45 Chronic asthmatic Chronic bronchitis, Benzonatate 1, 2, 7
bronchitis or pulmonary pulmonary emphysema vs dihydrocodeinone
emphysema
Diwan et al25/1982 Fair: 60 Chronic cough COPD, chronic Isoaminile citrate 2, 9
bronchitis, TB vs chlophedianol HCl
Antitussive (anesthetics)
vs placebo
Simon46/1960 Poor: 45 Chronic asthmatic Chronic bronchitis, Benzonatate vs placebo 1, 2, 7
bronchitis or pulmonary pulmonary emphysema
emphysema
Antitussive (nonpharmacologic)
vs placebo
Vertigan et al52/2006 Fair: 87 Chronic cough GERD, asthma, UACS, SPEICH-C vs placebo 1, 8
ACE inhibitor cough
Antitussive (opiates)
vs antitussive (opiates)
Sevelius et al44/1971 Fair: 12 Chronic cough COPD Codeine vs codeine 2
secondary to obstructive
emphysema and chronic
bronchitis
Sabot et al43/1977 Fair: 24 Chronic cough NR Viminol p-hydroxybezoate 1
vs viminol
p-hydroxybezoate
Antitussive (opiates)
vs antitussive (other)
Cass and Frederik18/1953 Fair: 69 Persistent cough NR Codeine 1, 9, 10
vs dextromethorphan
Cass et al19/1954 Poor: 65 Persistent cough NR Codeine 1, 9, 10
vs dextromethorphan
Cass and Frederik20/1956 Fair: 63 Persistent cough NR Codeine 1
vs dextromethorphan
Dierckx et al24/1981 Fair: 38 Chronic cough Asthma, chronic bronchitis, Codeine vs glaucine 1, 2
CF, TB
(Continued)

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Table 1—Continued

Comparison and Quality: Intervention Outcomes


Study/Year No. Patients Description Disease vs Comparator Reported
Matthys et al33/1983 Fair : 16 Chronic cough TB, bronchial cancer, Codeine 1, 2, 7
secondary to pulmonary obstructive lung disease vs dextromethorphan
TB, bronchial cancer, or
obstructive lung disease
Gastpar et al27/1984 Poor: 90 Cough secondary to NR Codeine vs glaucine 1, 2
respiratory tract disease
Barnabè et al17/1995 Fair: 113 Dry or slightly productive COPD, unexplained Codeine vs moguisteine 1, 2
cough cough, neoplasm,
pulmonary fibrosis
Luporini et al32/1998 Fair: 124 Persistent, nonproductive Lung cancer Dihydrocodeine rhodanate 1, 3, 8, 10
cough vs levodropropizine
Aliprandi et al15/2004, Fair: 120 Chronic nonproductive COPD, asthma, chronic Codeine 1, 2, 3
study 4 cough secondary to bronchitis vs levocloperastine
chronic bronchitis,
bronchial asthma,
COPD, or medication
Aliprandi et al15/2004, Fair: 60 Chronic nonproductive COPD, chronic bronchitis Codeine 1, 2, 3
study 5 cough secondary to vs levocloperastine
chronic bronchitis,
bronchial asthma,
COPD, or medication
Antitussive (opiates)
vs placebo
Cass and Frederik18/1953 Fair: 69 Persistent cough NR Codeine vs placebo 1, 9, 10
Cass et al19/1954 Poor: 65 Persistent cough NR Codeine vs placebo 1, 9, 10
Cass and Frederik20/1956 Fair: 63 Persistent cough NR Codeine vs placebo 1
Simon46/1960 Poor: 45 Chronic asthmatic Chronic bronchitis, Dihydrocodeinone 1, 2, 7
bronchitis or pulmonary pulmonary emphysema vs placebo
emphysema
Woolf and Rosenberg57/1964 Poor: 10 Chronic cough Chronic bronchitis, Codeine vs placebo 2
emphysema
Sevelius et al44/1971 Fair: 12 Chronic cough secondary COPD Codeine vs placebo 1, 2
to obstructive
emphysema and
chronic bronchitis
Sabot et al43/1977 Fair: 24 Chronic cough NR Viminol p-hydroxybezoate 1
vs placebo
Dierckx et al24/1981 Fair: 38 Chronic cough Asthma, chronic bronchitis, Codeine vs placebo 1, 2
CF, TB
Matthys et al33/1983 Fair: 16 Chronic cough TB, bronchial cancer, Codeine vs placebo 1, 2, 7
secondary to pulmonary obstructive lung disease
TB, bronchial cancer,
or obstructive
lung disease
Smith et al47/2006 Fair: 19 COPD with cough COPD Codeine vs placebo 1, 2, 5, 9, 10
Morice et al35/2007 Poor: 27 Chronic cough Unexplained cough Morphine sulfate 1, 4, 5, 9
vs placebo
Antitussive (other)
vs antitussive (other)
Cass and Frederik20/1956 Fair: 63 Persistent cough NR Dextromethorphan 1
vs dextromethorphan
Rühle et al41/1984 Fair: 24 Chronic cough COPD, asthma, chronic Glaucine 1, 2, 9
bronchitis, TB vs dextromethorphan
Del Donno et al23/1994 Good: 99 Dry or slightly COPD, unexplained cough, Moguisteine
productive cough acute or unspecified vs dextromethorphan
bronchitis, other
respiratory disease
(Continued)

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Table 1—Continued

Comparison and Quality: Intervention Outcomes


Study/Year No. Patients Description Disease vs Comparator Reported
Aliprandi et al15/2004 Poor: 50 Chronic nonproductive COPD, asthma, chronic Levocloperastine 1, 2, 3
study 1 cough secondary to bronchitis vs levodropropizine
chronic bronchitis,
bronchial asthma,
COPD, or medication
Aliprandi15/2004 study 2 Fair: 60 Chronic nonproductive COPD, asthma, chronic Levocloperastine 1, 2, 3
cough secondary to bronchitis vs levodropropizine
chronic bronchitis,
bronchial asthma,
COPD, or medication
Aliprandi et al15/2004 Fair: 40 Chronic nonproductive COPD, asthma, chronic Levocloperastine 1, 2, 3
study 3 cough secondary to bronchitis vs levodropropizine
chronic bronchitis,
bronchial asthma,
COPD, or medication
Aliprandi et al15/2004 Fair: 120 Chronic nonproductive Cough of varying origin, Levocloperastine 1, 2, 3
study 6 cough secondary to ACE inhibitor cough vs dl-cloperastine
chronic bronchitis,
bronchial asthma,
COPD, or medication
Antitussive (other) vs placebo
Cass and Frederik18/1953 Fair: 69 Persistent cough NR Dextromethorphan 1, 9
vs placebo
Cass et al19/1954 Poor: 65 Persistent cough NR Dextromethorphan 1, 9
vs placebo
Cass and Frederik20/1956 Fair: 63 Persistent cough NR Dextromethorphan 1
vs placebo
Vakil et al49/1966 Fair: 70 Chronic cough Chronic bronchitis, TB Pipazethate vs placebo 2
Wójcicki et al54/1975 Good: 32 Cough and nocturnal Chronic bronchitis, Duopect vs placebo 1
paroxysms of coughing CF, TB
Dierckx et al24/1981 Fair: 38 Chronic cough Asthma, chronic bronchitis, Glaucine vs placebo 1, 2
CF, TB
Matthys et al33/1983 Fair: 16 Chronic cough secondary TB, bronchial cancer, Dextromethorphan 1, 2, 7
to pulmonary TB, obstructive lung disease vs placebo
bronchial cancer, or
obstructive lung disease
Rühle et al41/1984 Fair: 24 Chronic cough COPD, asthma, chronic Glaucine vs placebo 1, 2, 9
bronchitis, TB
Rühle et al41/1984 Fair: 24 Chronic cough COPD, asthma, chronic Dextromethorphan 1, 2, 9
bronchitis, TB vs placebo
Aversa et al16/1993 Fair: 73 Chronic lung disease COPD, unexplained Moguisteine vs placebo 2
cough, neoplasm,
pulmonary fibrosis
Ramsay et al38/2008 Good: 42 Chronic cough None Dextromethorphan 1, 4, 5, 9
vs placebo
Mukaida et al36/2011 Fair: 19 Chronic cough secondary COPD Bakumondoto 1, 2
to COPD vs placebo
Antitussive (other)
vs protussive
(expectorants)
Wójcicki et al54/1975 Good: 32 Cough and nocturnal Chronic bronchitis, Duopect vs glycerol 1
paroxysms of coughing CF, TB
Matts34/1977 Fair: 50 Chronic cough Postviral infection Diphenhydramine 7
vs guaifenesin
Bronchodilator
vs bronchodilator
Wei et al53/2010 Fair: 214 Nonproductive or mildly Cough variant asthma, Diprophylline 1, 2, 4
productive cough GERD, nonasthmatic vs methoxyphenamine
eosinophilic bronchitis,
UACS
(Continued)

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Table 1—Continued

Comparison and Quality: Intervention Outcomes


Study/Year No. Patients Description Disease vs Comparator Reported
Corticosteroid vs placebo
Chaudhuri et al21/2004 Fair: 88 Chronic cough GERD, asthma, Fluticasone vs placebo 1
UACS, bronchiectasis,
eosinophilic bronchitis,
bronchitis
Ribeiro et al40/2007 Good: 64 Chronic cough Unexplained cough Beclomethasone 1, 2, 3
vs placebo
Rytilä et al42/2008 Fair: 144 Chronic cough Unexplained cough Mometasone vs placebo 1
Protussive (expectorants)
vs placebo
Wójcicki et al54/1975 Good: 32 Cough and nocturnal Chronic bronchitis, Glycerol vs placebo 1, 2
paroxysms of coughing CF, TB
Parvez et al37/1996, Good: 60 Chronic productive COPD, CF Guaifenesin vs placebo 1, 2
study 1 cough secondary to
bronchopulmonary
disease
Protussive (mucolytic)
vs placebo
Jackson et al30/1984 Poor: 121 Chronic bronchitis Chronic bronchitis N-acetylcysteine 1, 8
vs placebo
Guyatt et al28/1987 Fair: 78 Chronic productive cough Chronic bronchitis Ambroxol vs placebo 1
Dueholm et al26/1992 Fair: 51 Chronic bronchitis Chronic bronchitis N-acetylcysteine 1, 4,1 1
vs placebo
Parvez et al37/1996, study 2 Good: 24 Chronic productive COPD, CF Bromhexine vs placebo 1, 2
cough secondary to
bronchopulmonary
disease
Protussive (mucolytic)
vs protussive (mucolytic)
Clarke et al22/1979 Good: 11 Chronic bronchitis Chronic bronchitis 2-mercaptoethane- 2, 6
sulphonate
vs hypertonic saline
Protussive (nonpharmacologic)
vs protussive
(nonpharmacologic)
van Hengstum et al51/1988 Fair: 8 Chronic bronchitis Chronic bronchitis Positive expiratory 6
pressure mask
vs forced expiration
1 5 cough severity; 2 5 cough frequency/resolution; 3 5 nighttime awakenings; 4 5 functional status; 5 5 tussigenic challenge; 6 5 clearance/reten-
tion; 7 5 patient preference; 8 5 global assessment; 9 5 adverse events; 10 5 drowsiness; 11 5 dyspnea. ACE 5 angiotensin-converting enzyme;
CF 5 cystic fibrosis; GERD 5 gastroesophageal reflux disease; HCl 5 hydrogen chloride; NR 5 not reported; SPEICH-C 5 Speech Pathology
Evaluation and Intervention for Chronic Cough; UACS 5 upper airway cough syndrome; URTI 5 upper respiratory tract infection.
aThree studies included only children.

or both.18-20,33 In one study,38 dextromethorphan was cough severity.54 Compared with placebo, moguisteine
more effective than placebo at reducing cough in reduced cough frequency over 4 days,16 whereas
response to tussigenic challenge but not for cough pipazethate did not.49
severity, sleep disturbance, or cough-specific quality In seven studies (including four separate studies
of life (Leicester Cough Questionnaire). The one study published in Aliprandi et al15), none of the other anti-
finding negative results41 examined a single dose of tussives was found to be superior to another in head-
dextromethorphan vs placebo. to-head comparisons,15,23,41 nor were different doses
Two studies of a single dose of glaucine compared of the same agent.20
with placebo noted improvements in cough frequency
over 4 to 6 h.24,41 A Chinese herbal medicine called
Studies Involving Protussives
bakumondoto reduced cough severity and frequency
compared with no treatment over 8 weeks.36 One study We found 10 comparisons in eight studies (includ-
comparing the combination antitussive and expecto- ing two published in Parvez et al37) involving protus-
rant Duopect (narcotine/glycerol) vs either agent alone sives.22,26,28,30,34,37,54 In one study, guaifenesin reduced
or placebo found that Duopect or narcotine improved cough intensity and improved ease of expectoration

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in a subgroup of patients who produced a high volume the other found ketotifen to be ineffective in children
of sputum.37 In the Duopect study, expectoration was aged 6 to 36 months.50 The third study56 found that
easier and freer in a higher percentage of patients amoxicillin clavulanate resolved cough in 48% of
taking Duopect or glycerol than narcotine or placebo.54 children aged 0.9 to 5.25 years vs 16% for placebo
The combination agent Lotussin (diphenhydramine, (P 5 .0016).
dextromethorphan, ephedrine, guaifenesin) was pre-
ferred by more patients than linctus diphenhydramine.34
Quantitative Synthesis
The following regimens did not improve cough fre-
quency, severity, or quality of life compared with pla- Data from 13 studies were analyzed in a
cebo: oral N-acetylcysteine,30 inhaled N-acetylcysteine,26 mixed-treatment meta-analysis for cough
bromhexine,37 ambroxol,28 or inhaled 2-mercaptoethane severity.17-19,23,26,28,30,33,35,37,38,43,46 Seven studies provided
sulfonate.22 information on opioids,17-19,33,35,43,46 five on dextromethor-
phan,18,19,23,33,38 four on mucolytics,26,28,30,37 and two on
Studies Involving Nonantitussive or Nonprotussive moguisteine.17,23 Eleven studies had a placebo con-
Pharmacotherapies trol18,19,26,28,30,33,35,37,38,43,46 (three of which included both
a placebo arm and an active comparison18,19,33), whereas
We identified two studies examining antihistamines two studies had only active comparisons.17,23 Because
in adults.31,48 One compared two doses of diphenhy- studies used various measures of severity, we con-
dramine with placebo.31 Both doses of diphenhy- verted all results to effect sizes (SMDs). Relative to
dramine were similarly superior to placebo, with the placebo, the following therapies showed a beneficial
higher dose resulting in greater drowsiness. In another effect on cough severity: opioids (SMD, 0.55; 95% CI,
placebo-controlled study,48 loratadine reduced the 0.38-0.72; P , .0001), dextromethorphan (SMD, 0.37;
number of coughs following tussigenic challenge. 95% CI, 0.19-0.56; P 5 .0008), and moguisteine (SMD,
One study examined the antibiotic erythromycin and 0.46; 95% CI, 0.01-0.92; P 5 .0475) (Fig 2). The effect
found no difference in cough severity, cough frequency, of mucolytics was not significant (SMD, 0.09; 95% CI,
cough-specific quality of life, or response to tussigenic 20.18 to 0.36; P 5 .483). For context, effect size values
challenge compared with placebo.55 Another study of 0.20, 0.50, and 0.80 represent small, medium, and
compared inhaled ipratropium bromide with placebo large effects, respectively.58 The studies included in
and found improvements in cough severity and dysp- the meta-analysis showed evidence of heterogeneity
nea associated with cough.29 Another study comparing (P 5 .0152). The evidence was insufficient to determine
two bronchodilators (diprophylline vs methoxyphe- relative benefit among these therapies.
namine) did not find differences in cough frequency or The meta-analysis for cough frequency included
cough-specific quality of life.53 Three studies evaluated seven studies (n 5 700 patients).16,17,23,24,33,44,46 Five pro-
inhaled corticosteroids: Two found that cough severity vided information on opioids, two on dextrometho-
was reduced21 or cough more frequently resolved,40 rphan, and three on moguisteine. Relative to placebo,
and one found no significant improvement in cough codeine (RR, 0.57; 95% CI, 0.36- 0.91; P 5 .0260)
severity42 compared with placebo. and dextromethorphan (RR, 0.40; 95% CI, 0.18-0.85;
P 5 .0248) showed a beneficial effect on cough fre-
Studies Involving Nonpharmacologic Therapies quency. The effect of moguisteine was not significant
Only two studies evaluated nonpharmacologic inter- (RR, 0.60; 95% CI, 0.31-1.17; P 5 .1117) (Fig 3). The
ventions.51,52 The first found that a forced expiratory studies showed significant heterogeneity (P 5 .0231).
technique was more effective than positive expiratory The estimates were too imprecise to determine whether
pressure physiotherapy or no treatment in enhancing codeine or dextromethorphan is superior to the other.
tracheobronchial clearance but did not improve cough
frequency or severity.51 The second study found that
speech pathology management reduced cough and Discussion
limitations on everyday activity due to symptoms rel-
ative to placebo.52 In studies that included an active or placebo com-
parison, we found evidence of relative efficacy for the
reduction of frequency and severity of chronic cough
Studies Involving Children
only for codeine and dextromethorphan. Because of
Three studies addressed the treatment of chronic the small number of head-to-head comparisons and
cough in children. Two of these evaluated the antihis- inconsistency and imprecision of results, however, we
tamine ketotifen vs placebo.39,50 One study found that were unable to draw conclusions about the compara-
ketotifen reduced cough and wheeze in children aged tive effectiveness of these two agents. Tolerability
2 to 6 years taking medication for asthma,39 whereas concerns were found only for opioids.

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sample sizes and short durations of follow-up; (6) lack
of gold standard outcomes to assess efficacy and tol-
erability; (7) inconsistent reporting of comparative
statistical analyses; and (8) a limited number of direct
comparisons between active treatments. In addition,
the literature search may have missed pertinent research,
particularly studies that have not been published.
Future research could improve the state of the lit-
erature in a number of ways. Commonly used defini-
tions for chronic cough and reporting the duration,
etiology, and pertinent comorbid conditions of cough
would help with characterizing the patient population
accurately. Explicitly stating whether the aim of ther-
apy is to treat the symptom of chronic cough or an
underlying etiology would help clinicians to under-
stand how the study results apply to their patients.
Using longer durations of follow-up would help stake-
holders to better estimate the risks and benefits of
medications used for chronic cough. Furthermore,
assessing tolerability of therapies over these durations
would assist in making comparisons among thera-
pies. A combination of objective cough frequency and
patient-oriented outcome measures would provide the
most meaningful information regarding efficacy.

Figure 2. Meta-analysis of data on cough severity (standardized


mean differences).

The applicability of the findings to the United States


is limited because many of the trials we identified
included drugs that are not currently available in the
United States (14 studies, 29%). Although we excluded
drugs that had been withdrawn from the US market
(eg, for safety issues), we retained studies of drugs
marketed elsewhere but never marketed in the United
States in part because such studies may help with the
assessment of the effects of a class of cough treat-
ments. Applicability is also reduced given the age of
much of the evidence; publication dates ranged from
1953 to 2012, with 32 (76%) articles published before
2000. Given the changes in available therapies as well
as the diagnosis and treatment of underlying etiologies,
studies of contemporary therapies are needed.
The findings have limitations related to the existing
literature, including (1) few studies explicitly explor-
ing the target population (patients with unexplained
or refractory chronic cough) or subpopulations (eg,
children); (2) variable definitions of chronic cough;
(3) diverse etiologies that might respond differently to
different therapies; (4) incomplete reporting of patient
characteristics, study design, or outcomes; (5) small Figure 3. Meta-analysis of data on cough frequency (rate ratios).

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Conclusions report and comments on draft versions of the full evidence report.
AHRQ did not directly participate in the literature search; deter-
A wide variety of pharmaceutical agents have been mination of study eligibility criteria; data analysis or interpretation;
used to treat the symptom of chronic cough. However, or preparation, review, or approval of the manuscript for publica-
tion. The authors of this manuscript are responsible for its con-
there were relatively few good-quality studies that tent. Statements in the manuscript should not be construed as
used reliable outcome measurements over pertinent endorsement by the Agency for Healthcare Research and Quality
durations of follow-up. The opioid and certain nono- or the US Department of Health and Human Services.
Other contributions: This material is the result of work partially
pioid and nonanesthetic antitussives most frequently supported with resources and the use of facilities at the VA Medical
demonstrated efficacy for managing the symptom of Center, Durham, NC. The views expressed in this article are those
chronic cough, but there were insufficient data to draw of the authors and do not necessarily reflect the position or policy
of Duke University or the Department of Veterans Affairs. The
conclusions about their relative efficacy. Data on non- authors thank Megan von Isenburg, MSLS, for help with the liter-
pharmacologic therapies are extremely limited, as are ature search and retrieval; the peer reviewers of the full AHRQ
data on the management of chronic cough in children. report for helpful feedback and guidance; R. Julian Irvine, MCM,
for project coordination; and Rebecca Gray, DPhil, for editing and
Overall, the literature regarding patients with unex- manuscript preparation.
plained or refractory chronic cough would be enhanced Additional information: The e-Table can be found in the
by more systematic study design and reporting as well as “Supplemental Materials” area of the online article.
by assessment of both objective and patient-centered
outcomes.
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