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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
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,
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