Cough Suppressant and Pharmacologic

Protussive Therapy
ACCP Evidence-Based Clinical Practice Guidelines
Donald C. Bolser, PhD

Background: Cough-suppressant therapy, previously termed nonspecific antitussive therapy,

incorporates the use of pharmacologic agents with mucolytic effects and/or inhibitory effects on
the cough reflex itself. The intent of this type of therapy is to reduce the frequency and/or
intensity of coughing on a short-term basis.
Methods: Data for this review were obtained from several National Library of Medicine (PubMed)
searches (from 1960 to 2004), which were performed between May and September 2004, of the
literature published in the English language, limited to human studies, using combinations of the
search terms “cough,” “double-blind placebo-controlled,” “antitussive,” “mucolytic,” “cough
clearance,” “common cold,” “protussive,” “guaifenesin,” “glycerol,” and “zinc.”
Results: Mucolytic agents are not consistently effective in ameliorating cough in patients with
bronchitis, although they may be of benefit to this population in other ways. Peripheral and
central antitussive agents can be useful in patients with chronic bronchitis, but can have little
efficacy in patients with cough due to upper respiratory infection. Some protussive agents are
effective in increasing cough clearance, but their long-term effectiveness has not been estab-
lished. DNase is not effective as a protussive agent in patients with cystic fibrosis. Inhaled
mannitol is acutely effective in this patient population, but its therapeutic potential must be
investigated further.
Conclusions: These findings suggest that suppressant therapy is most effective when used for the
short-term reduction of coughing. Relatively few drugs are effective as cough suppressants.
(CHEST 2006; 129:238S–249S)

Key words: antitussive; cough; cough suppressant; nonopioid; opioid; protussive

Abbreviation: URI ⫽ upper respiratory infection

I ncough-suppressant
this section, the evidence supporting the use of
drugs in the treatment of
sensory receptors is accumulated mucus, and agents
that alter mucociliary factors (eg, mucus volume,
chronic cough is reviewed. Therapies are systemati- production, consistency, or ciliary activity) are con-
cally addressed in relation to their effects on ana- sidered as a separate category in this section. The
tomically defined elements of the nervous and mus- excitability of the sensory receptors themselves can
cular systems responsible for coughing. More be modified by drugs, and compounds that suppress
specifically, cough is produced when sensory recep- cough by this mechanism are defined as peripheral
tors in the airways (ie, the afferent limb of the cough antitussive agents. Airway sensory afferents control
reflex) are excited by mechanical and/or chemical the excitability of neural elements in the brainstem
stimuli. A common mechanical stimulus for these that produce cough, and drugs that act at this level of
the CNS are classified as centrally acting antitussive
Reproduction of this article is prohibited without written permission agents. The brainstem cough-generation system
from the American College of Chest Physicians (www.chestjournal. transmits excitatory information to spinal motoneu-
org/misc/reprints.shtml). rons innervating respiratory muscles. Drugs that may
Correspondence to: Donald C. Bolser, PhD, Department of
Physiological Sciences, University of Florida, Gainesville, FL act on this efferent limb of the cough reflex pathway
32610-0144; e-mail: bolserd@mail.vetmed.ufl.edu and paralytic agents that block the neuromuscular

238S Diagnosis and Management of Cough: ACCP Guidelines

junction are considered as separate categories in this National Library of Medicine (PubMed) searches
document. Finally, the scope of this section includes (from 1960 to 2004), which were performed between
those drugs that have protussive effects (ie, any drug May and September 2004, of literature published in
that may increase cough clearance) in patients with the English language, limited to human studies,
disorders in which thickened or accumulated mucus using combinations of the search terms “cough,”
contributes to morbidity. “double-blind placebo controlled,” “antitussive,”
In the previous evidence-based guideline, these “mucolytic,” “cough clearance,” “common cold,”
types of cough therapy were termed nonspecific, to “protussive,” “guaifenesin,” “glycerol,” and “zinc.”
differentiate them from therapy-specific for a partic-
ular disease/disorder. We have changed that termi-
nology to suppressant therapy. Many of the drugs Drugs That Affect Mucociliary Factors
that fall into this category bind to specific pharma-
cologic receptors, and have effects on well-identified This topic was not addressed separately in the
elements of the CNS and peripheral nervous sys- previous evidence-based guideline.1 In disorders
tems. They are intended to reduce coughing regard- that have associated mucus hypersecretion, cough is
less of etiology. As such, it is considered most elicited to enhance the clearance of accumulated
appropriate to term them as suppressants. secretions. One pharmacologic approach to treating
These types of drugs are intended to be used when these disorders is to alter the mucociliary factors. As
the excitability and/or intensity of cough is elevated described by Irwin et al,2 there are several mecha-
over what is required to defend the airways. Their nisms by which this may occur, as follows: (1) the
actions presumably return a hyperresponsive cough drug could be an expectorant, increasing mucus
reflex to its normal state. There is no evidence that volume; (2) the drug may suppress mucus produc-
cough-suppressant therapy can prevent coughing. tion; (3) mucus consistency may be altered; and (4)
An important point to note is that, unlike specific ciliary function may be enhanced. These mecha-
therapy, these drugs do not resolve the underlying nisms need not be mutually exclusive. For example,
pathophysiology that is responsible for the coughing. it is unlikely that expectorants will alter mucus
The classification of drugs as suppressant or non- volume without also affecting its consistency. Anti-
specific is based largely on their ability to suppress histamines also may act to reduce coughing by the
cough in animal models in which there is no under- suppression of mucus production in URI.
lying airway pathophysiology. Furthermore, many of Relatively few drugs have been shown to suppress
these drugs decrease cough sensitivity in healthy cough by an action on mucociliary factors, and none
humans who are challenged with inhaled irritants. of them consistently. Table 1 summarizes the effects
The recommendations of the committee are re- of putative mucociliary drugs on cough. Of these,
stricted to the efficacy of these drugs in double- inhalation of ipratropium bromide has been shown to
blind, placebo-controlled studies in humans with suppress subjective measures of cough in patients
airway pathology. While the focus of this section is with URI3 or chronic bronchitis.4 However, ox-
on studies published since the last consensus docu- itropium bromide did not alter subjective measures
ment, other older double-blind, placebo-controlled of coughing in subjects with URI.5 Interestingly,
studies that were not included in the previous report tiotropium does not suppress cough in patients with
have been added. This section also refers to other COPD, although cough was a outcome measure in
studies in humans and animals in which the results this study.6 It should be noted that other studies
shed light on mechanistic issues related to the evaluating the effects of tiotropium have not mea-
actions of these drugs. sured cough. The reasons for the inconsistent effects
Because of the strong track record of success of of anticholinergic agents in disorders in which mucus
specific therapy,1 suppressant therapies are neces- production should contribute to cough are not clear.
sary only in specific situations. In particular, their use The previous guideline1 supported the use of inhaled
is typically on a short-term basis for symptomatic ipratropium bromide for cough suppression in bron-
relief of cough. As noted in our previous evidence- chitis. The results of these more recent studies on
based guideline,1 the use of these drugs is most inhaled anticholinergic agents in bronchitis have
appropriate when (1) the etiology of cough is un- caused us to maintain a recommendation that is
known (precluding the use of specific therapy), (2) focused on inhaled ipratropium bromide for relief of
specific therapy requires a period of time before it cough due to URI or chronic bronchitis.
can become effective,1 or (3) specific therapy will be The inconsistent actions of inhaled anticholinergic
ineffective, such as in patients with inoperable lung agents on cough due to URI also are relevant to the
cancer. proposed mechanism of action of older, CNS pene-
Data for this review were obtained from several trant, H1 antihistamines in the suppression of cough

www.chestjournal.org CHEST / 129 / 1 / JANUARY, 2006 SUPPLEMENT 239S

 Table 1—Summary of Studies on the Effects of Mucociliary Drugs on Cough

Patients,
Drug Study/Year No. Age,* yr Population Dosing Results

Guaifenesin Robinson et al /1977

9 239 Mean, 38.1 (range URI 200 mg po qid ⫻ 3 d Improved cough severity
vs placebo not reported) and frequency
(p ⬍ 0.001)
Guaifenesin Kuhn et al11/1982 65 18–30 URI 30 mL (20 mg/mL) No significant effect on
vs placebo po q 6 h ⫻ 2.5 d cough frequency and
severity
Guaifenesin Parvez et al10/1996 60 18–77 Bronchiectasis, 400 mg po qid ⫻ 14 d Reduction in cough intensity
vs placebo COPD (p ⬍ 0.05)
Guaifenesin Thomson et al / 12 7 64 ⫾ 2 Chronic bronchitis 600 mg po sd No effect on cough
vs placebo 1973 frequency
Iodinated Petty14/1990 361 29–83 Chronic bronchitis 60 mg po qid ⫻ 56 d Cough frequency and
glycerol severity reduced
vs placebo (p ⬍ 0.05)
Iodinated Repsher13/1993 32 Mean, 53.7 (range Chronic bronchitis 60 mg po qid ⫻ 5 wk Reduction in cough severity
glycerol not reported) (p ⬍ 0.025)
vs placebo
Iodinated Rubin et al15/1996 26 Not reported Chronic bronchitis 60 mg qid ⫻ 16 wk No effect on cough
glycerol symptoms
vs placebo
Ipratropium Ghafouri et al4/1984 23 27–72 Chronic bronchitis 40 ␮g inhaled qid Reduction in cough
vs placebo ⫻ 49 d frequency and severity
(p ⬍ 0.05)
Ipratropium Holmes et al3/1992 14 47 ⫾ 12 URI 80 ␮g inhaled qid Reduction in cough
vs placebo ⫻ 21 d (p ⬍ 0.05)
Oxitropium Lowry et al /1994
5 56 18–60 URI 200 ␮g inhaled tid No effect on cough
vs placebo ⫻ 10 d
Tiotropium Casaburi et al6/2000 470 65 ⫾ 9 COPD 18 ␮g dry powder qd No effect on cough
vs placebo 13 wk
Bromhexine Mossberg et al17/ 12 39–70 Asthma, chronic 4–8 mg IV sd No effect on cough
vs placebo 1981 bronchitis clearance
Bromhexine Olivieri et al18/1991 88 52 ⫾ 15 Bronchiectasis 30 mg po tid ⫻ 15 d No effect on cough
vs placebo symptoms; reduction in
sputum volume
(p ⬍ 0.01)
Bromhexine Thompson and 14 39–70 Chronic bronchitis, 16 mg bid po ⫻ 21 d No effect on cough
vs placebo Reeve19/1972 asthma, COPD
Bromhexine Valenti and 237 Bromhexine group, COPD 30 mg po bid ⫻ 14 d Significant reduction in
vs placebo Marenco20/1989 53 ⫾ 13; placebo cough (p ⬍ 0.001) and
group, 54 ⫾ 11 sputum volume
(p ⬍ 0.01)
Carbocysteine Edwards et al22/ 82 35–60 Chronic bronchitis 2.25 or 3 g tid ⫻ 10 d No significant effect on
vs placebo 1976 cough frequency or
severity; reduction in
sputum viscosity
(p ⬍ 0.02)
Carbocysteine Thomson et al21/ 16 64 ⫾ 9 Chronic bronchitis, 4 g qid ⫻ 4–7 d No significant effect on
vs placebo 1975 emphysema cough frequency
Acetylcysteine/ Hirsch et al24/1970 12 Not reported Chronic bronchitis 10% aerosol tid ⫻ 5 wk No effect on cough
isoproterenol
vs placebo
Acetylcysteine Dueholm et al23/ 65 Men, 53 ⫾ 2; Chronic bronchitis 4 mg inhaled bid Significantly greater
vs placebo 1992 women, 54 ⫾ 2 ⫻ 16 wk coughing than placebo
(p ⬍ 0.05)
Acetylcysteine Jackson et al25/1984 121 Mean, 63 Chronic bronchitis 200 mg po tid ⫻ 12 wk No difference on cough
vs placebo severity
Mercaptoethane Clarke et al26/1979 11 63 ⫾ 8 Chronic bronchitis 10% aerosol tid ⫻ 3 d No effect on cough
sulphonate frequency
vs placebo
Mercaptoethane Hirsch et al24/1970 12 Not reported Chronic bronchitis 10% aerosol tid ⫻ 5 wk No effect on cough
sulphonate/
isoproterenol
vs placebo
Hypertonic Pavia et al27/1978 7 61 ⫾ 10 Chronic bronchitis 7.1% saline solution No effect on cough
saline inhaled sd frequency
vs placebo
*Values are given as mean ⫾ SD or range, unless otherwise indicated.

due to upper respiratory infection (URI). It is widely onists because they have greater anticholinergic ac-
accepted that first-generation antihistamines appear tivity. The therapeutic effect of cholinergic blockade
to be more effective in the suppression of URI- by the systemic administration of sedating antihista-
induced cough than nonsedating H1-receptor antag- mines is likely to be restricted to the nasal airways.

240S Diagnosis and Management of Cough: ACCP Guidelines

This concept is supported by the inconsistent action objective measures of sputum viscosity after carbo-
of inhaled anticholinergic agents on cough (ie, it is cysteine treatment. There were no significant
unlikely that systemically administered sedating an- changes in the subjective indexes of cough frequency
tihistamines are acting in the lower airways). A or severity, but patients reported significantly better
related point is that only 7% of inhaled ipratropium ease of expectoration while receiving therapy with
bromide is systemically absorbed, and there is little carbocysteine.
evidence for the anticholinergic activity of this drug Other drugs such as acetylcysteine,23–25 mercapto-
in nonpulmonary tissues when it is delivered in this ethane sulfonate,24,26 and hypertonic saline solu-
manner.7 Presumably, a systemically administered tion27 have been found to be inactive against cough
and selective anticholinergic agent would have the in subjects with chronic bronchitis. Bromhexine,
same efficacy on cough due to URI as the sedating mercaptoethane sulfonate, and carbocysteine are not
antihistamine agents. However, a primary difference approved for use in the United States.
between first-generation and second-generation an- In sum, these findings suggest an important con-
tihistamines is central penetration. It is equally plau- clusion regarding the actions of mucociliary agents
sible that first-generation antihistamines are more on cough. While cough is important in the clearance
effective in the suppression of URI-induced cough of mucus from the airways, its frequency and inten-
because they act on H1 histaminergic and/or M1 sity can be independent of mucus properties in
muscarinic receptors located in the CNS. Indeed, patients with chronic bronchitis. It is important to
Muether and Gwaltney8 have proposed this exact note that this conclusion is specific to cough and
mechanism to explain the greater effectiveness of does not lessen the potential benefit of therapy with
first-generation antihistamines over that of second- mucolytic agents in patients with chronic bronchitis
generation antihistamines in blocking sneezing asso- on other outcomes. In essence, the data suggest that
ciated with natural or induced colds. While these two other therapeutic modalities may be more useful to
potential mechanisms are not mutually exclusive, it manage cough in patients with chronic bronchitis.
will be a challenge to sort out their relative roles in
future studies.
The expectorant guaifenesin decreased subjective Recommendations
measures of cough due to URI,9 and subjective and
objectives indexes of cough due to bronchiectasis.10 1. In patients with chronic bronchitis, agents
However, two other studies11,12 found no effect of that have been shown to alter mucus character-
this drug on cough due to chronic bronchitis. An- istics are not recommended for cough suppres-
other expectorant, iodinated glycerol, has been sion. Level of evidence, good; benefit, none; grade
found to be active in reducing subjective assessments of recommendation, D
of cough frequency and severity in patients with 2. In patients with cough due to URI or
chronic bronchitis in two studies.13,14 However, an- chronic bronchitis, the only inhaled anticholin-
other study15 found no significant benefit of iodin- ergic agent that is recommended for cough
ated glycerol on coughing in stable patients with suppression is ipratropium bromide. Level of
chronic bronchitis. This drug has since been re- evidence, fair; benefit, substantial; grade of recom-
moved from the US market because of carcinogenic- mendation, A
ity concerns.16 Bromhexine has been tested in pa-
tients with chronic bronchitis or bronchiectasis in
several studies employing both subjective and objec- Drugs That Affect the Afferent Limb of
tive indexes of cough. While this drug decreased the Cough Reflex
sputum volume or thickness, it was inactive to
modify cough in three studies17–19 and active in only The classification of antitussive drugs as peripheral
one study.20 The latter study consisted of a much or central is based largely on preclinical studies.
larger patient population than those in the other Peripherally acting suppressants lack the sedation
studies, so it is possible that the effect of bromhexine potential that is often associated with centrally acting
on cough is small and requires a much larger group drugs, such as opioids, because they do not penetrate
to be detected. Carbocysteine was inactive in one the CNS to an appreciable extent. It should be
study21 to alter the clearance of secretions or cough noted, however, that one centrally acting drug, dex-
frequency in a small population of patients with tromethorphan, is not sedating, so a central action
chronic bronchitis and with or without radiologic does not guarantee sedation potential as a side-effect
evidence of emphysema. Another larger study22 of of cough suppression.
patients with chronic bronchitis producing at least 25 Peripherally active drugs are thought to act wholly
mL of sputum daily showed significant reductions in on the sensory elements that contribute to cough.

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While the most widely accepted mechanism of action dropropizine and moguisteine, are recom-
for this class of drugs is thought to be the frank mended for the short-term symptomatic relief
suppression of pulmonary afferent activity,28 one of coughing. Level of evidence, good; benefit,
prominent drug, levodropropizine, acts at least in substantial; grade of recommendation, A
part by the activation of C-fiber sensory afferents 4. In patients with cough due to URI, periph-
that reflexively inhibit cough.29 One drug, carami- eral cough suppressants have limited efficacy
phen, has been considered as a centrally acting drug. and are not recommended for this use. Level of
However, according to a preclinical study,30 this drug evidence, good; benefit, none; grade of recommen-
should be classified as a peripherally acting drug. dation, D
There are apparently no other published studies on
the site of action of this drug, and the US Food and
Drugs That Affect the Central
Drug Administration has removed this drug from the
Mechanism for Cough
US market as an antitussive agent.31
The current review expands on the previous one1 This class of compounds is thought to act at one or
for peripheral drugs by citing several more studies on more sites in the CNS to suppress cough. The
levodropropizine and adding moguisteine to this list particular CNS elements that are sensitive to these
of drugs (Table 2). Levodropropizine is very active drugs are unknown. Based on preclinical experi-
(approximately 75% suppression) in reducing cough ments,37 the brainstem is thought to be the main
in patients with chronic or acute bronchitis.32 This region where antitussive agents act by a mechanism
drug also is as effective as dihydrocodeine in sup- in which the motor control of cough is inhibited.
pressing cough due to lung cancer,33 although that However, the production of cough can be associated
study was not placebo-controlled. Moguisteine has with sensation, termed the urge to cough, indicating
been shown to be active in treating cough due to that sensory information associated with cough af-
COPD.34 This drug also can suppress cough due to fects suprapontine sites in the brain.38 Furthermore,
URI, although the effect was restricted to cough at cough can be voluntarily suppressed, indicating a
night and the magnitude of suppression was limit- prominent role for cortical pathways in its control.39
ed.35 Moguisteine and levodropropizine are not ap- It is possible that some centrally acting drugs affect
proved for use in the United States. the excitability of cough by interacting with suprap-
Cough due to lung cancer is also sensitive to ontine pathways that mediate sensation or the vol-
peripherally acting suppressant drugs (reviewed else- untary suppression of this behavior. This issue has
where in the guidelines). A placebo-controlled trial36 been addressed by Hutchings and Eccles,40 who
of inhaled sodium cromoglycate demonstrated sig- showed that the voluntary suppression of cough was
nificant suppression of cough in patients with lung not altered by codeine or the opioid antagonist
cancer, presumably due to the suppression of medi- naltrexone in healthy subjects. Their work suggests
ator release. that endogenous opioids do not mediate the volun-
tary suppression of cough. Further work is necessary
Recommendations to address the role of these novel mechanisms in the
actions of cough suppressants in patients with airway
3. In patients with chronic or acute bronchi- disease.
tis, peripheral cough suppressants, such as levo- The most common patient population covered in
Table 2—Summary of Studies on the Actions of Peripheral Cough Suppressants

Age
Patients, Range,
Drug Study/Year No. yr Population Dosing Results

Levodropropizine vs Allegra and Bossi /1988

32 194 15–79 Acute and chronic 1–10 mL po Reduced cough severity,
placebo bronchitis tid ⫻ 3 d reduced cough frequency
by 72% (p ⬍ 0.05)
Moguisteine vs placebo Aversa et al34/1993 87 18–75 COPD (n ⫽ 44), 200 mg po Reduced cough frequency
pulmonary neoplasm tid ⫻ 4 d 42% (p ⬍ 0.03)
(n ⫽ 7), pulmonary
fibrosis (n ⫽ 6),
unknown (n ⫽ 13),
other (n ⫽ 3)
Moguisteine vs placebo Adams et al35/1993 108 18–69 URI 200 mg po Significant difference in
tid ⫻ 3 d nighttime cough severity
(p ⬍ 0.05)

242S Diagnosis and Management of Cough: ACCP Guidelines

the previous review was patients with chronic bron- of subjects to demonstrate a significant effect. Pavesi
chitis, and a variety of centrally active drugs were et al48 conducted a metaanalysis of six separate
deemed to be effective in patients with this disorder. studies of ⬎ 700 subjects, while Parvez et al10 stud-
Studies on patients with chronic bronchitis appear in ied ⬎ 300 subjects. However, it is unclear the extent
the current review, but there also are a number of to which the metaanalysis of Pavesi et al48 over-
studies on patients with URI. The effects of these lapped with the population reported by Parvez et
drugs on cough are summarized in Table 3. Pi- al.10 The reports of Lee et al46 and Tukiainen et al47
pazethate is not approved for use in the United studied 43 and 108 subjects, respectively.
States. The current review reveals that not all sup- The limited activity of these drugs against cough
pressant drugs are effective, especially in cough due due to URI is not predictable based on our current
to URI. Codeine and dextromethorphan (but not understanding of the physiology and pharmacology
pipazethate) are active in cough due to chronic of the cough reflex. Indeed, the fact that codeine can
bronchitis/COPD,41– 43 suppressing cough counts by have a differential effect on cough based on specific
40 to 60%. However, the antitussive effects of pathology suggests that the central mechanisms for
codeine in patients with chronic bronchitis were cough can differ significantly between disorders. In
established in small patient populations.41– 43 Fur- essence, cough may have the same mechanical func-
thermore, there have been no double-blind placebo- tion in different disorders, but the CNS mechanism
controlled studies of the effects of codeine on cough responsible for its production may have a different
due to acute bronchitis, although it is reasonable to neural organization, analogous to remodeling. This
presume that this drug is effective under these neural remodeling (also called plasticity) may alter
circumstances. There have been several studies that the sensitivity of the central cough mechanism to
have indicated a lack of efficacy of codeine and various pharmacologic agents.
dextromethorphan44 – 47 in cough due to URI. Oth- Centrally acting opioid cough suppressants, such
ers10,48 have reported the suppression of cough due as hydrocodone and dihydrocodeine, have also been
to URI by these drugs. As suggested by Pavesi et al,48 shown to be effective in patients with cough due to
the reason for this discrepancy for dextromethor- lung cancer (reviewed elsewhere in this guideline).
phan may be related to the limited efficacy (⬍ 20% However, the evidence for these effects was obtained
suppression) of this drug, requiring larger numbers from studies that were not placebo-controlled.

Table 3—Summary of Studies on the Actions of Central Cough Suppressants*

Patients,
Drug Study/Year No. Age† Population Dosing Results

Codeine vs placebo Aylward et al41/1984 8 54–65 Chronic bronchitis 7.5–30 mg po ⫻ 1 d sd Reduced cough counts by 40% at 30
mg (p ⬍ 0.05), no effect of lower
doses
Codeine vs placebo Freestone and 82 18–46 URI, LRI 50 mg po qd ⫻ 2 d No difference in cough frequency,
Eccles44/1997 severity, or cough sound pressure
differences
Codeine vs placebo Sevelius and 10 65 ⫾ 7 Chronic bronchitis 30 mg po tid ⫻ 1 d Cough frequency reduced 47%
Colmore42/1966 (p ⬍ 0.01)
Codeine vs placebo Sevelius et al43/1971 12 55–72 COPD 7.5–60 mg po ⫻ 1 d Reduced cough counts by 60%
(p ⬍ 0.004)
Dextromethorphan Lee et al46/2000 43 18–46 URI 30 mg po ⫻ 1 d No difference in cough frequency,
vs placebo severity, or cough sound pressure
differences
Dextromethorphan Pavesi et al48/2001 710 18–69 URI 30 mg po ⫻ 1 d Cough frequency significantly
vs placebo reduced at 1 h (p ⬍ 0.003), cough
intensity not reduced
Dextromethorphan Tukainen et al47/ 108 Mean, 38 (range URI 30 mg po tid ⫻ 4 d No significant difference in cough
vs placebo 1986 not reported) frequency or severity
Dextromethorphan Aylward et al41/1984 8 54–65 Chronic bronchitis 7.5–60 mg po ⫻ 1 d sd Reduced cough counts by 50% at 60
vs placebo mg (p ⬍ 0.05), 28% at 30 mg, no
effect of 7.5 and 15 mg
Dextromethorphan Korppi et al45/1991 78 1–10 RI 7.5 or 15 mg in 5 or 10 No significant difference in cough
vs placebo mL tid ⫻ 3 d frequency or severity
Dextromethorphan Parvez et al10/1996 451 18–69 URI 30 mg po ⫻ 1 d sd Reduction in cough counts 19–36%
vs placebo (p ⬍ 0.05), reduction in cough
effort 41% (p ⬍ 0.05)
Pipazethate vs Sevelius and 10 65 ⫾ 7 Chronic bronchitis 5 mL po ⫻ 1 d No significant difference in cough
placebo Colmore42/1966 frequency
*LR ⫽ lower respiratory tract infection; RI ⫽ respiratory infection.
†Values are given as range or mean ⫾ SD, unless otherwise indicated.

www.chestjournal.org CHEST / 129 / 1 / JANUARY, 2006 SUPPLEMENT 243S

 Recommendations thus to facilitate intubation. The depolarizing agent,
succinylcholine, is most commonly used for this
5. In patients with chronic bronchitis, central application but has a significant side effect profile.54
cough suppressants, such as codeine and dex- Newer non-depolarizing agents have fewer side ef-
tromethorphan, are recommended for the fects but do not possess the rapid onset and recovery
short-term symptomatic relief of coughing. associated with succinylcholine.54 –56 Erhan et al,56 in
Level of evidence, fair; benefit, intermediate; grade a double-blind study, showed that anesthetics, espe-
of recommendation, B cially propofol, can provide adequate cough suppres-
6. In patients with cough due to URI, cen- sion for intubation in the absence of neuromuscular
tral cough suppressants have limited efficacy blockade. However, a single-blind study57 found
for symptomatic relief and are not recom- treatment with a neuromuscular blocker (atra-
mended for this use. Level of evidence, good; curium) plus propofol to be more effective than
benefit, none; grade of recommendation, D propofol alone in suppressing cough induced by
intubation. The increased efficacy of neuromuscular
Drugs That Affect the Efferent Limb of blocking agents in combination with anesthetics in
Cough Reflex suppressing cough accounts for their use during
intubation.
In this context, the efferent limb of the cough
reflex is defined as a spinal action of the drug. While
this definition appears to overlap with that of cen-
trally acting drugs, it bears specific attention here. As Recommendation
defined above, our current definition of centrally
8. In patients requiring intubation during
acting antitussive drugs is restricted to those acting
general anesthesia, the use of neuromuscular
in the brainstem and/or at suprapontine sites. A drug
blocking agents is recommended to suppress
that selectively suppressed the excitability of spinal
coughing. Level of evidence, good; benefit, sub-
pathways to abdominal muscle motoneurons would
stantial; grade of recommendation, A
be expected to ameliorate intense expiratory efforts
associated with repetitive coughing and would rep-
resent a useful adjunct to existing specific therapies.
Of the drugs known to have central actions to inhibit Other Drugs
cough, baclofen may be an example of a drug with
Table 4 summarizes studies on the effects of zinc
this mechanism of action. It is well-known that this
acetate or zinc gluconate on the common cold,58 – 66
drug is a muscle relaxant with a spinal action.49
and two studies63,67 evaluated cough with subjective
Baclofen is a centrally acting cough suppressant in
measures. Mixed results were obtained, with some
animals50 and suppresses irritant-induced cough in
studies58,59,61,63,67 indicating a positive effect of zinc
humans.51,52 Furthermore, this drug did suppress
preparations on the common cold and oth-
subjective measures of angiotensin-converting en-
ers60,62,64 – 66 suggesting no benefit. Two metaanaly-
zyme inhibitor-induced cough in an open-label
ses68,69 of these studies have been performed, and
study.53 However, this drug has not yet been tested
both concluded that there was insufficient evidence
for activity in double-blind placebo-controlled stud-
to support the use of zinc preparations in the
ies of pathologic cough. The utility of this drug or
treatment of the common cold. Various explanations
others that may have solely a spinal action in the
for the divergent results of these studies have been
treatment of cough due to airway disease awaits
proposed including widely variant dosages, inade-
further study.
quate blinding, and bioavailability issues.70 Further-
more, zinc therapy can be associated with a signifi-
Recommendation cant side-effect profile, in particular bad taste and
7. In patients with chronic or acute cough nausea.70 Of these two preparations, only zinc ace-
requiring symptomatic relief, drugs that affect tate is approved for use in the United States.
the efferent limb of the cough reflex are not Albuterol has been evaluated in two studies of
recommended. Level of evidence, low; benefit, none; acute (ie, ⬍ 4 weeks) cough71,72 (Table 4). Cough
grade of recommendation, D was evaluated by subjective measurements in both
studies. Bernard et al71 studied nonasthmatic chil-
Drugs That Affect the Skeletal Muscles dren in whom the exact cause of cough was not
determined, but cough resolved within 7 days in
Neuromuscular blocking agents have been used in both the placebo and treatment groups. Littenberg
conjunction with anesthetics to suppress cough and et al72 studied adults with either bronchitis or cough

244S Diagnosis and Management of Cough: ACCP Guidelines

 Table 4 —Influence of Other Drugs on Cough

Drug Study/Year Patients, No. Age,* yr Population Dosing Results

Zinc acetate vs Prasad et al67/2000 50 37 ⫾ 11 Common cold 42.96 mg po q2–3 h Reduction in duration of coughing
placebo during the day by 3 d (p ⬍ 0.001)
Zinc gluconate vs Mossad et al63/1996 100 38 ⫾ 8 Common cold 13.3 mg po q2 h during Reduction in duration of coughing
placebo the day by 2.5 d (p ⬍ 0.04)
Zinc gluconate vs Eby et al59/1984 65 11–63 Common cold 46 mg po loading dose, Higher percent of subject
placebo then q2 h while asymptomatic after 7 d
awake for maximum (p ⬍ 0.0005)
9d
Zinc gluconate vs Smith et al64/1989 110 ⬎ 18 Common cold 23 mg po q2 h while No effect on duration of symptoms,
placebo awake for 7 d 8% reduction in symptom severity
(p ⬎ 0.02)
Zinc gluconate vs Godfrey et al61/1992 73 18–40 Common cold 23.7 mg po q2 h while Significantly shorter duration of
placebo awake for 7 d symptoms (p ⬍ 0.025)
Zinc gluconate vs Weismann et al66/ 130 18–65 Common cold 4.5 mg po q1.5 h for No effect on symptom duration or
placebo 1990 10 d severity
Zinc gluconate vs Al-Nakib et al58/ 12 18–50 Rhinovirus-induced 23 mg po q2 h while Reduction in clinical symptom score
placebo 1987 cold awake for 6 d on days 4 and 5 postchallenge
(p ⬍ 0.05)
Zinc gluconate vs Farr et al60/1987 32 (part 1); 21 ⫾ 1 Rhinovirus-induced 23 mg po q2 h while No effect on severity or duration of
placebo 45 (part 2) cold awake for 5 d in part symptoms
1 and 8 d in part 2
Zinc gluconate vs Macknin et al62/ 249 6–16 Common cold 10 mg po q2–3 h while No effect on duration of symptoms
placebo 1998 awake for 2 d
Zinc gluconate, zinc Turner and 273 (part 1); 18–65 Rhinovirus induced 5 or 11.5 mg zinc Significantly shorter duration of
acetate vs Cetnarowski65/ 281 (part 2) (part 1); common acetate, 13.3 zinc symptoms by zinc gluconate in
placebo 2000 cold (part 2) gluconate q2–3 h part 1 (p ⬍ 0.035), no effect in
while awake for 14 d part 2 of either formulation
Albuterol vs placebo Bernard et al71/1999 59 1–10 Nonasthmatic, 0.1 mg/kg po tid ⫻ 7 d No effect on cough
otherwise
undetermined
Albuterol vs placebo Littenberg et al72/ 104 19–74 Nonasthmatic, 4 mg po tid ⫻ 7 d No difference in cough severity
1996 nonpneumonia,
non-COPD,
otherwise
undetermined
*Values are given as the mean ⫾ SD or range.

of undetermined origin. Albuterol had no significant not recommended. Level of evidence, good; ben-
effect on coughing in either study. efit, none; grade of recommendation, D
Over the counter, non-prescription medications 10. In patients with acute cough due to the
are commonly used to treat acute cough and other common cold, over the counter combination
symptoms associated with the common cold. The cold medications, with the exception of an older
combination medications contain antitussives, expec- antihistamine-decongestant, are not recom-
torants, sympathomimetics, and/or antihistamines; mended until randomized controlled trials
many are carried in a demulcent vehicle. Unfortu- prove that they are effective cough suppres-
nately, with the exception of an older antihistamine- sants. Level of evidence, fair; benefit, none; grade of
decongestant combination,73 many have never been recommendation, D
shown to be effective, many have never been studied 11. In patients with acute or chronic cough
in combination, and some drugs in the combination not due to asthma, albuterol is not recom-
products are indicated only for other conditions. mended. Level of evidence, good; benefit, none;
Fortunately, one is not limited to having to take one grade of recommendation, D
of these combination medications because there are
available effective cough suppressant medications
that work in a variety of different ways. For further Pharmacologic Protussive Therapy
information, readers are encouraged to refer to
section on Cough and the Common Cold in this Protussive therapy is intended to enhance cough
guideline. effectiveness to promote the clearance of airway
secretions. The most common disorders in which this
type of therapy is indicated include cystic fibrosis,
Recommendations bronchiectasis, pneumonia, and postoperative atel-
ectasis.2 In these disorders, mechanical methods to
9. In patients with acute cough due to the loosen mucus or pharmacologic tools that increase
common cold, preparations containing zinc are cough clearance may be useful to increase the

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effectiveness of coughing. Mechanical protussive was also shown to be effective in combination with
procedures are covered in another section of this chest physiotherapy and postural drainage in patients
guideline. These approaches require the cough mo- with bronchiectasis.
tor control system to be competent. It should be The current guideline includes two new studies
noted that there are several prominent disorders in that investigated the effects of recombinant DNase
which cough is impaired and the resultant accumu- on cough clearance75 and mucociliary clearance76 in
lation of secretions contributes significantly to mor- subjects with cystic fibrosis (Table 5). Both studies
bidity. Cough can be impaired after stroke or spinal also recorded subjective measures of spontaneous
injury. The impairment of cough after stroke can cough. Neither study demonstrated a significant
contribute to aspiration, and this topic has been action of recombinant DNase over placebo, although
reviewed elsewhere in this guideline. Therapeutic Robinson et al75 suggested that their study may have
approaches to the impairment of cough after spinal been underpowered given the large intersubject
injury have been restricted to mechanical methodol- variability that they encountered.
ogies intended to harvest accumulated secretions A double-blind placebo-controlled study77 showed
(eg, suctioning of the airway in tracheostomized that the inhalation of dry-powder mannitol increased
patients) or to enhance cough airflows.74 There are cough clearance in patients with cystic fibrosis (Ta-
currently no pharmacologic therapies for the en- ble 5). In this study, mannitol was as effective as
hancement of cough in disorders in which the motor hypertonic saline solution in increasing mucociliary
system for this behavior is impaired. clearance. The long-term effectiveness and safety of
mannitol must be confirmed before it should be
considered as a treatment for cystic fibrosis patients.
Recommendation
Recommendations
12. In patients with neuromuscular impair-
ment, protussive pharmacologic agents are in- 13. In patients with bronchitis, hypertonic
effective and should not be prescribed. Level of saline solution and erdosteine are recom-
evidence, good; benefit, none; grade of recommen- mended on a short-term basis to increase cough
dation, D clearance. Level of evidence, good; benefit, sub-
stantial; grade of recommendation, A
14. In adult patients with cystic fibrosis,
Pharmacologic Enhancement of Cough amiloride is recommended to increase cough
Clearance clearance. Level of evidence, good; benefit, sub-
stantial; grade of recommendation, A
The previous evidence-based guideline1 cited ran- 15. In adult patients with cystic fibrosis,
domized, double-blind, placebo-controlled studies while recombinant DNase does improve spi-
showing that hypertonic saline solution and erdoste- rometry it is not recommended to increase
ine (which is not approved for use in the United cough clearance. Level of evidence, good; benefit,
States) were effective agents for increasing cough none; grade of recommendation, D
clearance in patients with bronchitis, and that amilo-
ride was effective for this function in patients with Conclusions
cystic fibrosis. Ineffective agents (in bronchitic pa-
tients) included carbocysteine, mercaptoethane sul- Relatively few drugs are effective for the nonspe-
fonate, bromhexine, and guaifenesin. Terbutaline cific suppression of cough. Our current recommen-

Table 5—Influence of Protussive Drugs on Cough or Cough Clearance

Patients,
Drug Study/Year No. Age,* yr Population Dosing Results

DNase vs placebo Laube et al /1996

75 20 18–44 Cystic fibrosis 2.5 mg inhaled bid ⫻ 6 d No effect on cough
frequency
DNase vs placebo Robinson et al74/2000 13 25 ⫾ 5 Cystic fibrosis 2.5 mg inhaled qd ⫻ 7 d No effect on cough
clearance
Mannitol vs placebo Robinson et al76/1999 12 30 ⫾ 9 Cystic fibrosis 300 mg dry powder sd Increase in cough
clearance (p ⬍ 0.01)
*Values are given as the range or mean ⫾ SD.

246S Diagnosis and Management of Cough: ACCP Guidelines

dations largely confirm and extend the findings of
the previous panel.1 Most notably, the current guide- 4. In patients with cough due to URI,
lines expand on the previous consensus by recom- peripheral cough suppressants have limited
efficacy and are not recommended for this
mending that the use of suppressants be guided by
use. Level of evidence, good; benefit, none;
the physician’s specific knowledge of the disorder
grade of recommendation, D
that is eliciting cough.
5. In patients with chronic bronchitis,
The previous guideline1 identified a number of
central cough suppressants, such as codeine
different drugs as effective cough suppressants, par- and dextromethorphan, are recommended
ticularly in patients with chronic bronchitis. These for the short-term symptomatic relief of
drugs included codeine, dextromethorphan, ipratro- coughing. Level of evidence, fair; benefit, in-
pium bromide, and diphenhydramine. The previous termediate; grade of recommendation, B
guideline also included the following several drugs 6. In patients with cough due to URI, cen-
that are not available in the United States: carami- tral cough suppressants have limited efficacy
phen; levodropropizine; the acetylsalicylic acid pro- for symptomatic relief and are not recom-
drug guaimesal; the phosphodiesterase inhibitor and mended for this use. Level of evidence, good;
antidopaminergic agent glaucine; and the analgesic benefit, none; grade of recommendation, D
viminol. The current recommendations have been 7. In patients with chronic or acute cough
revised to narrow recommended inhaled anticholin- requiring symptomatic relief, drugs that af-
ergic agents to a single drug, ipratropium bromide, fect the efferent limb of the cough reflex
for cough due to URI or bronchitis. The current are not recommended. Level of evidence, low;
guideline supports the use of codeine only in chronic benefit, none; grade of recommendation, D
bronchitis and not in cough due to URI. The previ- 8. In patients requiring intubation during
ous guideline also recommended naproxen and dex- general anesthesia, the use of neuromuscu-
brompheniramine/pseudoephedrine for cough due lar blocking agents is recommended to sup-
to colds. press coughing. Level of evidence, good; ben-
Protussive agents that were recommended previ- efit, substantial; grade of recommendation, A
ously were relatively few in number, and the present 9. In patients with acute cough due to the
guideline is essentially unchanged in this regard, common cold, preparations containing zinc
with the exception that recommendations regarding are not recommended. Level of evidence,
cystic fibrosis have been limited to adult patients. good; benefit, none; grade of recommendation,
See Chang and Glomb (these guidelines)78 on eval- D
uating cough in pediatric patients for specific recom- 10. In patients with acute cough due to
mendations regarding that group. the common cold, over the counter com-
bination cold medications, with the excep-
tion of an older antihistamine-deconges-
Summary of Recommendations tant, are not recommended until
randomized controlled trials prove that
1. In patients with chronic bronchitis,
they are effective cough suppressants.
agents that have been shown to alter mucus
Level of evidence, fair; benefit, none; grade of
characteristics are not recommended for
reccommendation: D
cough suppression. Level of evidence, good;
11. In patients with acute or chronic
benefit, none; grade of recommendation, D
cough not due to asthma, albuterol is not
2. In patients with cough due to URI or
recommended. Level of evidence, good; bene-
chronic bronchitis, the only inhaled anti-
fit, none; grade of recommendation, D
cholinergic agent that is recommended for
12. In patients with neuromuscular im-
cough suppression is ipratropium bromide.
pairment, protussive pharmacologic agents
Level of evidence, fair; benefit, substantial;
are ineffective and should not be pre-
grade of recommendation, A
scribed. Level of evidence, good; benefit, none;
3. In patients with chronic or acute bron-
grade of recommendation, D
chitis, peripheral cough suppressants, such
13. In patients with bronchitis, hyper-
as levodropropizine and moguisteine, are
tonic saline solution and erdosteine are rec-
recommended for the short-term symptom-
atic relief of coughing. Level of evidence, ommended on a short-term basis to increase
good; benefit, substantial; grade of recommen- cough clearance. Level of evidence, good;
dation, A benefit, substantial; grade of recommendation, A

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 17 Mossberg B, Philipson K, Strandberg K, et al. Clearance by
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