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Cough Suppressant and Pharmacologic Protussive Therapy : ACCP Evidence-Based Clinical Practice Guidelines FREE TO VIEW

Donald C. Bolser, PhD
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Correspondence to: Donald C. Bolser, PhD, Department of Physiological Sciences, University of Florida, Gainesville, FL 32610-0144; e-mail: bolserd@mail.vetmed.ufl.edu



Chest. 2006;129(1_suppl):238S-249S. doi:10.1378/chest.129.1_suppl.238S
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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 established. 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.

In this section, the evidence supporting the use of cough-suppressant drugs in the treatment of chronic cough is reviewed. Therapies are systematically addressed in relation to their effects on anatomically defined elements of the nervous and muscular systems responsible for coughing. More specifically, cough is produced when sensory receptors in the airways (ie, the afferent limb of the cough reflex) are excited by mechanical and/or chemical stimuli. A common mechanical stimulus for these sensory receptors is accumulated mucus, and agents that alter mucociliary factors (eg, mucus volume, production, consistency, or ciliary activity) are considered as a separate category in this section. The excitability of the sensory receptors themselves can be modified by drugs, and compounds that suppress cough by this mechanism are defined as peripheral antitussive agents. Airway sensory afferents control the excitability of neural elements in the brainstem that produce cough, and drugs that act at this level of the CNS are classified as centrally acting antitussive agents. The brainstem cough-generation system transmits excitatory information to spinal motoneurons innervating respiratory muscles. Drugs that may act on this efferent limb of the cough reflex pathway and paralytic agents that block the neuromuscular junction are considered as separate categories in this document. Finally, the scope of this section includes those drugs that have protussive effects (ie, any drug that may increase cough clearance) in patients with disorders in which thickened or accumulated mucus contributes to morbidity.

In the previous evidence-based guideline, these types of cough therapy were termed nonspecific, to differentiate them from therapy-specific for a particular disease/disorder. We have changed that terminology to suppressant therapy. Many of the drugs that fall into this category bind to specific pharmacologic receptors, and have effects on well-identified elements of the CNS and peripheral nervous systems. They are intended to reduce coughing regardless of etiology. As such, it is considered most appropriate to term them as suppressants.

These types of drugs are intended to be used when the excitability and/or intensity of cough is elevated over what is required to defend the airways. Their actions presumably return a hyperresponsive cough reflex to its normal state. There is no evidence that cough-suppressant therapy can prevent coughing. An important point to note is that, unlike specific therapy, these drugs do not resolve the underlying pathophysiology that is responsible for the coughing.

The classification of drugs as suppressant or nonspecific is based largely on their ability to suppress cough in animal models in which there is no underlying airway pathophysiology. Furthermore, many of these drugs decrease cough sensitivity in healthy humans who are challenged with inhaled irritants. The recommendations of the committee are restricted to the efficacy of these drugs in double-blind, placebo-controlled studies in humans with airway pathology. While the focus of this section is on studies published since the last consensus document, other older double-blind, placebo-controlled studies that were not included in the previous report have been added. This section also refers to other studies in humans and animals in which the results shed light on mechanistic issues related to the actions of these drugs.

Because of the strong track record of success of specific therapy,1 suppressant therapies are necessary only in specific situations. In particular, their use is typically on a short-term basis for symptomatic relief of cough. As noted in our previous evidence-based guideline,1 the use of these drugs is most appropriate when (1) the etiology of cough is unknown (precluding the use of specific therapy), (2) specific therapy requires a period of time before it can become effective,1 or (3) specific therapy will be ineffective, such as in patients with inoperable lung cancer.

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 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.”

This topic was not addressed separately in the previous evidence-based guideline.1In disorders that have associated mucus hypersecretion, cough is elicited to enhance the clearance of accumulated secretions. One pharmacologic approach to treating these disorders is to alter the mucociliary factors. As described by Irwin et al,2 there are several mechanisms by which this may occur, as follows: (1) the drug could be an expectorant, increasing mucus volume; (2) the drug may suppress mucus production; (3) mucus consistency may be altered; and (4) ciliary function may be enhanced. These mechanisms need not be mutually exclusive. For example, it is unlikely that expectorants will alter mucus volume without also affecting its consistency. Antihistamines also may act to reduce coughing by the suppression of mucus production in URI.

Relatively few drugs have been shown to suppress cough by an action on mucociliary factors, and none of them consistently. Table 1 summarizes the effects of putative mucociliary drugs on cough. Of these, inhalation of ipratropium bromide has been shown to suppress subjective measures of cough in patients with URI3or chronic bronchitis.4However, oxitropium bromide did not alter subjective measures of coughing in subjects with URI.5Interestingly, tiotropium does not suppress cough in patients with COPD, although cough was a outcome measure in this study.6 It should be noted that other studies evaluating the effects of tiotropium have not measured cough. The reasons for the inconsistent effects of anticholinergic agents in disorders in which mucus production should contribute to cough are not clear. The previous guideline1 supported the use of inhaled ipratropium bromide for cough suppression in bronchitis. The results of these more recent studies on inhaled anticholinergic agents in bronchitis have caused us to maintain a recommendation that is focused on inhaled ipratropium bromide for relief of cough due to URI or chronic bronchitis.

The inconsistent actions of inhaled anticholinergic agents on cough due to URI also are relevant to the proposed mechanism of action of older, CNS penetrant, H1 antihistamines in the suppression of cough due to upper respiratory infection (URI). It is widely accepted that first-generation antihistamines appear to be more effective in the suppression of URI-induced cough than nonsedating H1-receptor antagonists because they have greater anticholinergic activity. The therapeutic effect of cholinergic blockade by the systemic administration of sedating antihistamines is likely to be restricted to the nasal airways. This concept is supported by the inconsistent action of inhaled anticholinergic agents on cough (ie, it is unlikely that systemically administered sedating antihistamines are acting in the lower airways). A related point is that only 7% of inhaled ipratropium bromide is systemically absorbed, and there is little evidence for the anticholinergic activity of this drug in nonpulmonary tissues when it is delivered in this manner.7Presumably, a systemically administered and selective anticholinergic agent would have the same efficacy on cough due to URI as the sedating antihistamine agents. However, a primary difference between first-generation and second-generation antihistamines is central penetration. It is equally plausible that first-generation antihistamines are more effective in the suppression of URI-induced cough because they act on H1 histaminergic and/or M1 muscarinic receptors located in the CNS. Indeed, Muether and Gwaltney8 have proposed this exact mechanism to explain the greater effectiveness of first-generation antihistamines over that of second-generation antihistamines in blocking sneezing associated with natural or induced colds. While these two potential mechanisms are not mutually exclusive, it will be a challenge to sort out their relative roles in future studies.

The expectorant guaifenesin decreased subjective measures of cough due to URI,9and subjective and objectives indexes of cough due to bronchiectasis.10However, two other studies1112 found no effect of this drug on cough due to chronic bronchitis. Another expectorant, iodinated glycerol, has been found to be active in reducing subjective assessments of cough frequency and severity in patients with chronic bronchitis in two studies.1314 However, another study15found no significant benefit of iodinated glycerol on coughing in stable patients with chronic bronchitis. This drug has since been removed from the US market because of carcinogenicity concerns.16Bromhexine has been tested in patients with chronic bronchitis or bronchiectasis in several studies employing both subjective and objective indexes of cough. While this drug decreased sputum volume or thickness, it was inactive to modify cough in three studies1719 and active in only one study.20The latter study consisted of a much larger patient population than those in the other studies, so it is possible that the effect of bromhexine on cough is small and requires a much larger group to be detected. Carbocysteine was inactive in one study21to alter the clearance of secretions or cough frequency in a small population of patients with chronic bronchitis and with or without radiologic evidence of emphysema. Another larger study22 of patients with chronic bronchitis producing at least 25 mL of sputum daily showed significant reductions in objective measures of sputum viscosity after carbocysteine treatment. There were no significant changes in the subjective indexes of cough frequency or severity, but patients reported significantly better ease of expectoration while receiving therapy with carbocysteine.

Other drugs such as acetylcysteine,2325 mercaptoethane sulfonate,24,26and hypertonic saline solution27 have been found to be inactive against cough in subjects with chronic bronchitis. Bromhexine, mercaptoethane sulfonate, and carbocysteine are not approved for use in the United States.

In sum, these findings suggest an important conclusion regarding the actions of mucociliary agents on cough. While cough is important in the clearance of mucus from the airways, its frequency and intensity can be independent of mucus properties in patients with chronic bronchitis. It is important to note that this conclusion is specific to cough and does not lessen the potential benefit of therapy with mucolytic agents in patients with chronic bronchitis on other outcomes. In essence, the data suggest that other therapeutic modalities may be more useful to manage cough in patients with chronic bronchitis.

1. In patients with chronic bronchitis, agents that have been shown to alter mucus characteristics are not recommended for cough suppression. Level of evidence, good; benefit, none; grade of recommendation, D

2. In patients with cough due to URI or chronic bronchitis, the only inhaled anticholinergic agent that is recommended for cough suppression is ipratropium bromide. Level of evidence, fair; benefit, substantial; grade of recommendation, A

The classification of antitussive drugs as peripheral or central is based largely on preclinical studies. Peripherally acting suppressants lack the sedation potential that is often associated with centrally acting drugs, such as opioids, because they do not penetrate the CNS to an appreciable extent. It should be noted, however, that one centrally acting drug, dextromethorphan, is not sedating, so a central action does not guarantee sedation potential as a side-effect of cough suppression.

Peripherally active drugs are thought to act wholly on the sensory elements that contribute to cough. While the most widely accepted mechanism of action for this class of drugs is thought to be the frank suppression of pulmonary afferent activity,28one prominent drug, levodropropizine, acts at least in part by the activation of C-fiber sensory afferents that reflexively inhibit cough.29One drug, caramiphen, has been considered as a centrally acting drug. However, according to a preclinical study,30this drug should be classified as a peripherally acting drug. There are apparently no other published studies on the site of action of this drug, and the US Food and Drug Administration has removed this drug from the US market as an antitussive agent.31

The current review expands on the previous one1 for peripheral drugs by citing several more studies on levodropropizine and adding moguisteine to this list of drugs (Table 2 ). Levodropropizine is very active (approximately 75% suppression) in reducing cough in patients with chronic or acute bronchitis.,32This drug also is as effective as dihydrocodeine in suppressing cough due to lung cancer,33although that study was not placebo-controlled. Moguisteine has been shown to be active in treating cough due to COPD.34This drug also can suppress cough due to URI, although the effect was restricted to cough at night and the magnitude of suppression was limited.35 Moguisteine and levodropropizine are not approved for use in the United States.

Cough due to lung cancer is also sensitive to peripherally acting suppressant drugs (reviewed elsewhere in the guidelines). A placebo-controlled trial36 of inhaled sodium cromoglycate demonstrated significant suppression of cough in patients with lung cancer, presumably due to the suppression of mediator release.

3. In patients with chronic or acute bronchitis, peripheral cough suppressants, such as levodropropizine and moguisteine, are recommended for the short-term symptomatic relief of coughing. Level of evidence, good; benefit, substantial; grade of recommendation, A

4. In patients with cough due to URI, peripheral cough suppressants have limited efficacy and are not recommended for this use. Level of evidence, good; benefit, none; grade of recommendation, D

This class of compounds is thought to act at one or more sites in the CNS to suppress cough. The particular CNS elements that are sensitive to these drugs are unknown. Based on preclinical experiments,37the brainstem is thought to be the main region where antitussive agents act by a mechanism in which the motor control of cough is inhibited. However, the production of cough can be associated with sensation, termed the urge to cough, indicating that sensory information associated with cough affects suprapontine sites in the brain.38 Furthermore, cough can be voluntarily suppressed, indicating a prominent role for cortical pathways in its control.39It is possible that some centrally acting drugs affect the excitability of cough by interacting with suprapontine pathways that mediate sensation or the voluntary suppression of this behavior. This issue has been addressed by Hutchings and Eccles,40 who showed that the voluntary suppression of cough was not altered by codeine or the opioid antagonist naltrexone in healthy subjects. Their work suggests that endogenous opioids do not mediate the voluntary suppression of cough. Further work is necessary to address the role of these novel mechanisms in the actions of cough suppressants in patients with airway disease.

The most common patient population covered in the previous review was patients with chronic bronchitis, and a variety of centrally active drugs were deemed to be effective in patients with this disorder. Studies on patients with chronic bronchitis appear in the current review, but there also are a number of studies on patients with URI. The effects of these drugs on cough are summarized in Table 3 . Pipazethate is not approved for use in the United States. The current review reveals that not all suppressant drugs are effective, especially in cough due to URI. Codeine and dextromethorphan (but not pipazethate) are active in cough due to chronic bronchitis/COPD,4143 suppressing cough counts by 40 to 60%. However, the antitussive effects of codeine in patients with chronic bronchitis were established in small patient populations.4143 Furthermore, there have been no double-blind placebo-controlled studies of the effects of codeine on cough due to acute bronchitis, although it is reasonable to presume that this drug is effective under these circumstances. There have been several studies that have indicated a lack of efficacy of codeine and dextromethorphan4447 in cough due to URI. Others10,48 have reported the suppression of cough due to URI by these drugs. As suggested by Pavesi et al,48 the reason for this discrepancy for dextromethorphan may be related to the limited efficacy (< 20% suppression) of this drug, requiring larger numbers of subjects to demonstrate a significant effect. Pavesi et al48 conducted a metaanalysis of six separate studies of > 700 subjects, while Parvez et al10 studied > 300 subjects. However, it is unclear the extent to which the metaanalysis of Pavesi et al48 overlapped with the population reported by Parvez et al.10 The reports of Lee et al46and Tukiainen et al47 studied 43 and 108 subjects, respectively.

The limited activity of these drugs against cough due to URI is not predictable based on our current understanding of the physiology and pharmacology of the cough reflex. Indeed, the fact that codeine can have a differential effect on cough based on specific pathology suggests that the central mechanisms for cough can differ significantly between disorders. In essence, cough may have the same mechanical function in different disorders, but the CNS mechanism responsible for its production may have a different neural organization, analogous to remodeling. This neural remodeling (also called plasticity) may alter the sensitivity of the central cough mechanism to various pharmacologic agents.

Centrally acting opioid cough suppressants, such as hydrocodone and dihydrocodeine, have also been shown to be effective in patients with cough due to lung cancer (reviewed elsewhere in this guideline). However, the evidence for these effects was obtained from studies that were not placebo-controlled.

5. In patients with chronic bronchitis, central cough suppressants, such as codeine and dextromethorphan, are recommended for the short-term symptomatic relief of coughing. Level of evidence, fair; benefit, intermediate; grade of recommendation, B

6. In patients with cough due to URI, central cough suppressants have limited efficacy for symptomatic relief and are not recommended for this use. Level of evidence, good; benefit, none; grade of recommendation, D

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 centrally acting drugs, it bears specific attention here. As defined above, our current definition of centrally acting antitussive drugs is restricted to those acting in the brainstem and/or at suprapontine sites. A drug that selectively suppressed the excitability of spinal pathways to abdominal muscle motoneurons would be expected to ameliorate intense expiratory efforts associated with repetitive coughing and would represent a useful adjunct to existing specific therapies. Of the drugs known to have central actions to inhibit cough, baclofen may be an example of a drug with this mechanism of action. It is well-known that this drug is a muscle relaxant with a spinal action.49Baclofen is a centrally acting cough suppressant in animals50and suppresses irritant-induced cough in humans.5152 Furthermore, this drug did suppress subjective measures of angiotensin-converting enzyme inhibitor-induced cough in an open-label study.53 However, this drug has not yet been tested for activity in double-blind placebo-controlled studies of pathologic cough. The utility of this drug or others that may have solely a spinal action in the treatment of cough due to airway disease awaits further study.

7. In patients with chronic or acute cough requiring symptomatic relief, drugs that affect the efferent limb of the cough reflex are not recommended. Level of evidence, low; benefit, none; grade of recommendation, D

Neuromuscular blocking agents have been used in conjunction with anesthetics to suppress cough and thus to facilitate intubation. The depolarizing agent, succinylcholine, is most commonly used for this application but has a significant side effect profile.54 Newer non-depolarizing agents have fewer side effects but do not possess the rapid onset and recovery associated with succinylcholine.5456 Erhan et al,56in a double-blind study, showed that anesthetics, especially propofol, can provide adequate cough suppression for intubation in the absence of neuromuscular blockade. However, a single-blind study57 found treatment with a neuromuscular blocker (atracurium) plus propofol to be more effective than propofol alone in suppressing cough induced by intubation. The increased efficacy of neuromuscular blocking agents in combination with anesthetics in suppressing cough accounts for their use during intubation.

8. In patients requiring intubation during general anesthesia, the use of neuromuscular blocking agents is recommended to suppress coughing. Level of evidence, good; benefit, substantial; grade of recommendation, A

Table 4 summarizes studies on the effects of zinc acetate or zinc gluconate on the common cold,5866 and two studies63,67 evaluated cough with subjective measures. Mixed results were obtained, with some studies5859,61,63,67 indicating a positive effect of zinc preparations on the common cold and others60,62,6466 suggesting no benefit. Two metaanalyses6869 of these studies have been performed, and both concluded that there was insufficient evidence to support the use of zinc preparations in the treatment of the common cold. Various explanations for the divergent results of these studies have been proposed including widely variant dosages, inadequate blinding, and bioavailability issues.70 Furthermore, zinc therapy can be associated with a significant side-effect profile, in particular bad taste and nausea.70 Of these two preparations, only zinc acetate is approved for use in the United States.

Albuterol has been evaluated in two studies of acute (ie, < 4 weeks) cough7172(Table 4). Cough was evaluated by subjective measurements in both studies. Bernard et al71studied nonasthmatic children in whom the exact cause of cough was not determined, but cough resolved within 7 days in both the placebo and treatment groups. Littenberg et al72 studied adults with either bronchitis or cough of undetermined origin. Albuterol had no significant effect on coughing in either study.

Over the counter, non-prescription medications are commonly used to treat acute cough and other symptoms associated with the common cold. The combination medications contain antitussives, expectorants, sympathomimetics, and/or antihistamines; many are carried in a demulcent vehicle. Unfortunately, with the exception of an older antihistamine-decongestant combination,73 many have never been shown to be effective, many have never been studied in combination, and some drugs in the combination products are indicated only for other conditions. Fortunately, one is not limited to having to take one of these combination medications because there are available effective cough suppressant medications that work in a variety of different ways. For further information, readers are encouraged to refer to section on Cough and the Common Cold in this guideline.

9. In patients with acute cough due to the common cold, preparations containing zinc are not recommended. Level of evidence, good; benefit, none; grade of recommendation, D

10. In patients with acute cough due to the common cold, over the counter combination cold medications, with the exception of an older antihistamine-decongestant, are not recommended until randomized controlled trials prove that they are effective cough suppressants. Level of evidence, fair; benefit, none; grade of recommendation, D

11. In patients with acute or chronic cough not due to asthma, albuterol is not recommended. Level of evidence, good; benefit, none; grade of recommendation, D

Protussive therapy is intended to enhance cough effectiveness to promote the clearance of airway secretions. The most common disorders in which this type of therapy is indicated include cystic fibrosis, bronchiectasis, pneumonia, and postoperative atelectasis.2 In these disorders, mechanical methods to loosen mucus or pharmacologic tools that increase cough clearance may be useful to increase the effectiveness of coughing. Mechanical protussive procedures are covered in another section of this guideline. These approaches require the cough motor control system to be competent. It should be noted that there are several prominent disorders in which cough is impaired and the resultant accumulation of secretions contributes significantly to morbidity. Cough can be impaired after stroke or spinal injury. The impairment of cough after stroke can contribute to aspiration, and this topic has been reviewed elsewhere in this guideline. Therapeutic approaches to the impairment of cough after spinal injury have been restricted to mechanical methodologies intended to harvest accumulated secretions (eg, suctioning of the airway in tracheostomized patients) or to enhance cough airflows.,74 There are currently no pharmacologic therapies for the enhancement of cough in disorders in which the motor system for this behavior is impaired.

12. In patients with neuromuscular impairment, protussive pharmacologic agents are ineffective and should not be prescribed. Level of evidence, good; benefit, none; grade of recommendation, D

The previous evidence-based guideline1 cited randomized, double-blind, placebo-controlled studies showing that hypertonic saline solution and erdosteine (which is not approved for use in the United States) were effective agents for increasing cough clearance in patients with bronchitis, and that amiloride was effective for this function in patients with cystic fibrosis. Ineffective agents (in bronchitic patients) included carbocysteine, mercaptoethane sulfonate, bromhexine, and guaifenesin. Terbutaline was also shown to be effective in combination with chest physiotherapy and postural drainage in patients with bronchiectasis.

The current guideline includes two new studies that investigated the effects of recombinant DNase on cough clearance75and mucociliary clearance76 in subjects with cystic fibrosis (Table 5 ). Both studies also recorded subjective measures of spontaneous cough. Neither study demonstrated a significant action of recombinant DNase over placebo, although Robinson et al,75 suggested that their study may have been underpowered given the large intersubject variability that they encountered.

A double-blind placebo-controlled study77 showed that the inhalation of dry-powder mannitol increased cough clearance in patients with cystic fibrosis (Table 5). In this study, mannitol was as effective as hypertonic saline solution in increasing mucociliary clearance. The long-term effectiveness and safety of mannitol must be confirmed before it should be considered as a treatment for cystic fibrosis patients.

13. In patients with bronchitis, hypertonic saline solution and erdosteine are recommended on a short-term basis to increase cough clearance. Level of evidence, good; benefit, substantial; grade of recommendation, A

14. In adult patients with cystic fibrosis, amiloride is recommended to increase cough clearance. Level of evidence, good; benefit, substantial; grade of recommendation, A

15. In adult patients with cystic fibrosis, while recombinant DNase does improve spirometry it is not recommended to increase cough clearance. Level of evidence, good; benefit, none; grade of recommendation, D

Relatively few drugs are effective for the nonspecific suppression of cough. Our current recommendations largely confirm and extend the findings of the previous panel.1 Most notably, the current guidelines expand on the previous consensus by recommending that the use of suppressants be guided by the physician’s specific knowledge of the disorder that is eliciting cough.

The previous guideline1 identified a number of different drugs as effective cough suppressants, particularly in patients with chronic bronchitis. These drugs included codeine, dextromethorphan, ipratropium bromide, and diphenhydramine. The previous guideline also included the following several drugs that are not available in the United States: caramiphen; levodropropizine; the acetylsalicylic acid prodrug guaimesal; the phosphodiesterase inhibitor and antidopaminergic agent glaucine; and the analgesic viminol. The current recommendations have been revised to narrow recommended inhaled anticholinergic agents to a single drug, ipratropium bromide, for cough due to URI or bronchitis. The current guideline supports the use of codeine only in chronic bronchitis and not in cough due to URI. The previous guideline also recommended naproxen and dexbrompheniramine/pseudoephedrine for cough due to colds.

Protussive agents that were recommended previously were relatively few in number, and the present guideline is essentially unchanged in this regard, with the exception that recommendations regarding cystic fibrosis have been limited to adult patients. See Chang and Glomb (these guidelines)78 on evaluating cough in pediatric patients for specific recommendations regarding that group.

1. In patients with chronic bronchitis, agents that have been shown to alter mucus characteristics are not recommended for cough suppression. Level of evidence, good; benefit, none; grade of recommendation, D

2. In patients with cough due to URI or chronic bronchitis, the only inhaled anticholinergic agent that is recommended for cough suppression is ipratropium bromide. Level of evidence, fair; benefit, substantial; grade of recommendation, A

3. In patients with chronic or acute bronchitis, peripheral cough suppressants, such as levodropropizine and moguisteine, are recommended for the short-term symptomatic relief of coughing. Level of evidence, good; benefit, substantial; grade of recommendation, A

4. In patients with cough due to URI, peripheral cough suppressants have limited efficacy and are not recommended for this use. Level of evidence, good; benefit, none; grade of recommendation, D

5. In patients with chronic bronchitis, central cough suppressants, such as codeine and dextromethorphan, are recommended for the short-term symptomatic relief of coughing. Level of evidence, fair; benefit, intermediate; grade of recommendation, B

6. In patients with cough due to URI, central cough suppressants have limited efficacy for symptomatic relief and are not recommended for this use. Level of evidence, good; benefit, none; grade of recommendation, D

7. In patients with chronic or acute cough requiring symptomatic relief, drugs that affect the efferent limb of the cough reflex are not recommended. Level of evidence, low; benefit, none; grade of recommendation, D

8. In patients requiring intubation during general anesthesia, the use of neuromuscular blocking agents is recommended to suppress coughing. Level of evidence, good; benefit, substantial; grade of recommendation, A

9. In patients with acute cough due to the common cold, preparations containing zinc are not recommended. Level of evidence, good; benefit, none; grade of recommendation, D

10. In patients with acute cough due to the common cold, over the counter combination cold medications, with the exception of an older antihistamine-decongestant, are not recommended until randomized controlled trials prove that they are effective cough suppressants. Level of evidence, fair; benefit, none; grade of reccommendation: D

11. In patients with acute or chronic cough not due to asthma, albuterol is not recommended. Level of evidence, good; benefit, none; grade of recommendation, D

12. In patients with neuromuscular impairment, protussive pharmacologic agents are ineffective and should not be prescribed. Level of evidence, good; benefit, none; grade of recommendation, D

13. In patients with bronchitis, hypertonic saline solution and erdosteine are recommended on a short-term basis to increase cough clearance. Level of evidence, good; benefit, substantial; grade of recommendation, A

14. In adult patients with cystic fibrosis, amiloride is recommended to increase cough clearance. Level of evidence, good; benefit, substantial; grade of recommendation, A

15. In adult patients with cystic fibrosis, while recombinant DNase does improve spirometry it is not recommended to increase cough clearance. Level of evidence, good; benefit, none; grade of recommendation, D

Abbreviation: URI = upper respiratory infection

Table Graphic Jump Location
Table 1. Summary of Studies on the Effects of Mucociliary Drugs on Cough
* 

Values are given as mean ± SD or range, unless otherwise indicated.

Table Graphic Jump Location
Table 2. Summary of Studies on the Actions of Peripheral Cough Suppressants
Table Graphic Jump Location
Table 3. Summary of Studies on the Actions of Central Cough Suppressants*
* 

LR = lower respiratory tract infection; RI = respiratory infection.

 

Values are given as range or mean ± SD, unless otherwise indicated.

Table Graphic Jump Location
Table 4. Influence of Other Drugs on Cough
* 

Values are given as the mean ± SD or range.

Table Graphic Jump Location
Table 5. Influence of Protussive Drugs on Cough or Cough Clearance
* 

Values are given as the range or mean ± SD.

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Rubin, BK, Ramirez, O, Ohar, JA Iodinated glycerol has no effect on pulmonary function, symptom score, or sputum properties in patients with stable chronic bronchitis.Chest1996;109,348-352
 
Drug products withdrawn or removed from the market for reasons of safety or effectiveness.Federal Register March 81999;64,10947
 
Mossberg, B, Philipson, K, Strandberg, K, et al Clearance by voluntary coughing and its relationship to subjective assessment and effect of intravenous bromhexine.Eur J Respir Dis1981;62,173-179
 
Olivieri, D, Ciaccia, A, Marangio, E, et al Role of bromhexine in exacerbations of bronchiectasis: double-blind randomized multicenter study versus placebo.Respiration1991;58,117-121
 
Thompson, KJ, Reeve, J A clinical trial of bromhexine.N Z Med J1972;76,73-76
 
Valenti, S, Marenco, G Italian multicenter study on the treatment of chronic obstructive lung disease with bromhexine: a double-blind placebo-controlled trial.Respiration1989;56,11-15
 
Thomson, ML, Pavia, D, Jones, CJ, et al No demonstrable effect of S-carboxymethylcysteine on clearance of secretions from the human lung.Thorax1975;30,669-673
 
Edwards, G, Steel, AE, Scott, JK, et al S-Carboxymethylcysteine in the fluidification of sputum and treatment of chronic airway obstruction.Chest1976;70,506-513
 
Dueholm, M, Neilsen, C, Thorshauge, H, et al N-acetylcysteine by metered dose inhaler in the treatment of chronic bronchitis: a multi-centre study.Respir Med1992;86,89-92
 
Hirsch, SR, Viernes, PF, Kory, RC Clinical and physiological evaluation of mucolytic agents nebulized with soproterenol: 10 per cent N-acetylcysteine verus 10 per cent 2-mercaptoethane sulphonate.Thorax1970;25,737-743
 
Jackson, IM, Barnes, J, Cooksey, P Efficacy and tolerability of oral acetylcysteine (Fabrol) in chronic bronchitis: a double-blind placebo controlled study.J Int Med Res1984;12,198-206
 
Clarke, S, Lopez-Vidriero, MT, Pavia, D, et al The effect of sodium 2-mercaptoethane sulphonate and hypertonic saline aerosols on bronchial clearance in chronic bronchitis.Br J Clin Pharmacol1979;7,39-44
 
Pavia, D, Thomson, ML, Clarke, SW Enhanced clearance of secretions from the human lung after the administration of hypertonic saline aerosol.Am Rev Respir Dis1978;117,199-203
 
Shams, H, Daffonchio, L, Scheid, P Effects of levodropropizine on vagal afferent C-fibres in the cat.Br J Pharmacol1996;117,853-858
 
Lavezzo, A, Melillo, G, Clavenna, G, et al Peripheral site of action of levodropropizine in experimentally-induced cough: role of sensory neuropeptides.Pulm Pharmacol1992;5,143-147
 
Bolser, D, DeGennaro, FC, Chapman, RW, et al Central and peripheral sites of action of antitussive drugs in the cat. Trouth, C Millis, RM eds.Ventral brainstem mechanisms and control of respiration and blood pressure1995,95-102 Marcel Dekker. New York, NY:
 
Oral prescription drugs offered for relief of symptoms of cough, cold, or allergy; drug efficacy study implementation; caramiphen edisylate; final actions on supplemental new drug applications.Federal Register June 282000;65,42017
 
Allegra, L, Bossi, R Clinical trials with the new antitussive levodropizine in adult bronchitic patients.Drug Res1988;38,1163-1166
 
Luporini, G, Barni, S, Marchi, E, et al Efficacy and safety of levodropropizine and dihydrocodeine on nonproductive cough in primary and metastatic lung cancer.Eur Respir J1998;12,97-101
 
Aversa, A, Cazzola, M, Clini, V, et al Clinical trial of the efficacy and safety of moguisteine in patients with cough associated with chronic respiratory diseases.Drugs Exp Clin Res1993;19,273-279
 
Adams, R, Hosie, J, James, I, et al Antitussive activity and tolerability of moguisteine in patients with acute cough: a randomized double-blind placebo-controlled study.Adv Ther1993;10,263-271
 
Moroni, M, Porta, C, Gualtieri, G, et al Inhaled sodium cromoglycate to treat cough in advanced lung cancer patients.Br J Cancer1996;74,309-311
 
Chou, D, Wang, SC Studies on the localization of the central cough mechanism: site of action of antitussive drugs.J Pharmacol Exp Ther1975;194,499-505
 
Davenport, P, Sapienza, CM, Bolser, DC Psychophysical assessment of the urge-to-cough.Eur Respir Rev2002;85,249-253
 
Hutchings, HA, Eccles, R, Smith, AP, et al Voluntary cough suppression as an indication of symptom severity in upper respiratory tract infections.Eur Respir J1993;6,1449-1454
 
Hutchings, HA, Eccles, R The opioid agonist codeine and antagonist naltrexone do not affect voluntary suppression of capsaicin induced cough in healthy subjects.Eur Respir J1994;7,715-719
 
Aylward, M, Maddock, J, Davies, DE, et al Dextromethorphan and codeine: comparison of plasma kinetics and antitussive effects.Eur J Respir Dis1984;65,283-291
 
Sevelius, H, Colmore, JP Objective assessment of antitussive agents in patients with chronic cough.J New Drugs1966;6,216-223
 
Sevelius, H, McCoy, JF, Colmore, JP Dose response to codeine in patients with chronic cough.Clin Pharmacol Ther1971;12,449-455
 
Freestone, C, Eccles, R Assessment of the antitussive efficacy of codeine in cough associated with common cold.J Pharm Pharmacol1997;49,1045-1049
 
Korppi, M, Laurikainen, K, Pietikainen, M, et al Antitussives in the treatment of acute transient cough in children.Acta Paediatr Scand1991;80,969-971
 
Lee, PCL, Jawad, MS, Eccles, R Antitussive efficacy of dextromethorphan in cough associated with acute upper respiratory tract infection.J Pharm Pharmacol2000;52,1137-1142
 
Tukiainen, H, Karttunen, P, Silvasti, M, et al The treatment of acute transient cough: a placebo-controlled comparison of dextromethorphan and dextromethorphan-β2-sympathomimetic combination.Eur J Respir Dis1986;69,95-99
 
Pavesi, L, Subburaj, S, Porter-Shaw, K Application and validation of a computerized cough acquisition system for objective monitoring of acute cough: a meta-analysis.Chest2001;120,1121-1128
 
Penn, RD Intrathecal baclofen for spasticity of spinal origin: seven years of experience.J Neurosurg1992;77,236-240
 
Bolser, D, DeGennaro, FC, O’Reilly, S, et al Peripheral and central sites of action of GABA-B agonists to inhibit the cough reflex in the cat and guinea pig.Br J Pharmacol1994;113,1344-1348
 
Dicpinigaitis, P, Dobkin, JB Antitussive effect of the GABA-agonist baclofen.Chest1997;111,996-999
 
Dicpinigaitis, P, Dobkin, JB, Rauf, K, et al Inhibition of capsaicin-induced cough by the γ-aminobutyric acid agonist baclofen.J Clin Pharmacol1998;38,364-367
 
Dicpinigaitis, P Use of baclofen to suppress cough induced by angiotensin-converting enzyme inhibitors.Ann Pharmacother1997;30,1242-1245
 
Bevan, D Neuromuscular blocking agents: onset and intubation.J Clin Anesth1997;9,36s-39s
 
Sparr, HJ, Beaufort, TM, Fuchs-Buder, T Newer neuromuscular blocking agents: how do they compare with established agents?Drugs2001;61,919-942
 
Erhan, E, Ugur, G, Gunusen, I, et al Propofol—not thiopental or etomidate—with remifentanil provides adequate intubating conditions in the absence of neuromuscular blockade.Can J Anaesth2003;50,108-115
 
Lieutaud, T, Billard, V, Khalaf, H, et al Muscle relaxation and increasing doses of propofol improve intubating conditions.Can J Anaesth2003;50,121-126
 
Al-Nakib, WHP, Barrow, I, Batstone, G, et al Prophylaxis and treatment of rhinovirus colds with zinc gluconate lozenges.J Antimicrob Chemother1987;20,893-901
 
Eby, GA, Davis, DR, Halcomb, WW Reduction in duration of common colds by zinc gluconate lozenges in a double-blind study.Antimicrob Agents Chemother1984;25,20-24
 
Farr, B, Conner, EM, Betts, RF, et al Two randomized controlled trials of zinc gluconate lozenge therapy of experimentally induced rhinovirus colds.Antimicrob Agents Chemother1987;31,1183-1187
 
Godfrey, JC, Conant Sloane, B, Smith, DS, et al Zinc gluconate and the common cold: a controlled clinical study.J Int Med Res1992;20,234-246
 
Macknin, ML, Piedmonte, M, Calendine, C, et al Zinc gluconate lozenges for treating the common cold in children: a randomized controlled trial.JAMA1998;279,1962-1967
 
Mossad, SB, Macknin, ML, Medendorp, SV, et al Zinc gluconate lozenges for treating the common cold: a randomized, double-blind, placebo-controlled study.Ann Intern Med1996;125,81-88
 
Smith, DS, Helzner, EC, Nuttall, CE, Jr, et al Failure of zinc gluconate in treatment of acute upper respiratory tract infections.Antimicrob Agents Chemother1989;33,646-648
 
Turner, RB, Cetnarowski, WE Effect of treatment with zinc gluconate or zinc acetate on experimental and natural colds.Clin Infect Dis2000;31,1202-1208
 
Weismann, K, Jakobsen, JP, Weismann, JE, et al Zinc gluconate lozenges for common cold: a double-blind clinical trial.Dan Med Bull1990;37,279-281
 
Prasad, AS, Fitzgerald, JT, Bao, B, et al Duration of symptoms and plasma cytokine levels in patients with the common cold treated with zinc acetate: a randomized, double-blind, placebo-controlled trial.Ann Intern Med2000;133,245-252
 
Jackson, JL, Peterson, C, Lesho, E A meta-analysis of zinc salts lozenges and the common cold.Arch Intern Med1997;157,2373-2376
 
Jackson, JL, Lesho, E, Peterson, C Zinc and the common cold: a meta-analysis revisited.J Nutr2000;130,1512S-1515S
 
Garland, ML, Hagmeyer, KO The role of zinc lozenges in the treatment of the common cold.Ann Pharmacother1998;32,63-69
 
Bernard, D, Goepp, JG, Duggan, AK, et al Is oral albuterol effective for acute cough in non-asthmatic children?Acta Paediatr1999;88,465-467
 
Littenberg, B, Wheeler, M, Smith, DS A randomized controlled trial of oral albuterol in acute cough.J Fam Pract1996;42,49-53
 
Curley, FJ, Irwin, RS, Pratter, MR, et al Cough and the common cold.Am Rev Respir Dis1988;138,305-311
 
Jaeger, RJ, Turba, RM, Yarkony, GM, et al Cough in spinal cord injured patients: comparison of three methods to produce cough.Arch Phys Med Rehabil1993;74,1358-1361
 
Robinson, M, Hemming, AL, Moriarty, C, et al Effect of a short course of rhDNase on cough and mucociliary clearance in patients with cystic fibrosis.Pediatr Pulmonol2000;30,16-24
 
Laube, BL, Auci, RM, Shields, DE, et al Effect of rhDNase on airflow obstruction and mucociliary clearance in cystic fibrosis.Am J Respir Crit Care Med1996;153,752-760
 
Robinson, M, Daviskas, E, Eberl, S, et al The effect of inhaled mannitol on bronchial mucus clearance in cystic fibrosis patients: a pilot study.Eur Respir J1999;14,678-685
 
Chang, AB, Glomb, WB Guidelines for evaluating chronic cough in pediatrics: ACCP evidence based clinical practice guidelines.Chest2006;129(suppl),260S-283S
 

Figures

Tables

Table Graphic Jump Location
Table 1. Summary of Studies on the Effects of Mucociliary Drugs on Cough
* 

Values are given as mean ± SD or range, unless otherwise indicated.

Table Graphic Jump Location
Table 2. Summary of Studies on the Actions of Peripheral Cough Suppressants
Table Graphic Jump Location
Table 3. Summary of Studies on the Actions of Central Cough Suppressants*
* 

LR = lower respiratory tract infection; RI = respiratory infection.

 

Values are given as range or mean ± SD, unless otherwise indicated.

Table Graphic Jump Location
Table 4. Influence of Other Drugs on Cough
* 

Values are given as the mean ± SD or range.

Table Graphic Jump Location
Table 5. Influence of Protussive Drugs on Cough or Cough Clearance
* 

Values are given as the range or mean ± SD.

References

Irwin, RS, Boulet, LP, Cloutier, MM, et al (1998) Managing cough as a defense mechanism and as a symptom: a consensus panel report of the American College of Chest Physicians.Chest114(suppl),133S-181S
 
Irwin, RS, Curley, FJ, Bennett, FM Appropriate use of antitussives and protussives: a practical review.Drugs1993;46,80-91
 
Holmes, PW, Barter, CE, Pierce, RJ Chronic persistent cough: use of ipratropium bromide in undiagnosed cases following upper respiratory tract infection.Respir Med1992;86,425-429
 
Ghafouri, MA, Patil, KD, Kass, I Sputum changes associated with the use of ipratropium bromide.Chest1984;86,387-393
 
Lowry, R, Wood, A, Higenbottam, T The effect of anticholinergic bronchodilator therapy on cough during upper respiratory tract infections.Br J Clin Pharmacol1994;37,187-191
 
Casaburi, R, Briggs, DD, Donohue, JF, et al The spirometric efficacy of once-daily dosing with tiotropium in stable COPD.Chest2000;118,1294-1302
 
Ensing, K, de Zeeuw, RA, Nossent, GD, et al Pharmacokinetics of ipratropium bromide after single dose inhalation and oral and intravenous administration.Eur J Clin Pharmacol1989;36,189-194
 
Muether, PS, Gwaltney, JM, Jr Variant effect of first- and second-generation antihistamines as clues to their mechanism of action on the sneeze reflex in the common cold.Clin Infect Dis2001;33,1483-1488
 
Robinson, R, Cummings, WB, Deffenbaugh, ER Effectiveness of guaifenesin as an expectorant: a cooperative double-blind study.Curr Ther Res1977;22,284-296
 
Parvez, L, Vaidya, M, Sakhardande, A, et al Evaluation of antitussive agents in man.Pulm Pharmacol1996;9,299-308
 
Kuhn, JJ, Hendley, JO, Adams, KF, et al Antitussive effect of guaifenesin in young adults with natural colds: objective and subjective assessment.Chest1982;82,713-718
 
Thomson, ML, Pavia, D, McNicol, MW A preliminary study of the effect of guaiphenesin on mucociliary clearance from the human lung.Thorax1973;28,742-747
 
Repsher, LH Treatment of stable chronic bronchitis with iodinated glycerol: a double-blind, placebo-controlled trial.J Clin Pharmacol1993;33,856-860
 
Petty, TL The National Mucolytic Study: results of a randomized, double-blind, placebo-controlled study of iodinated glycerol in chronic obstructive bronchitis.Chest1990;97,75-83
 
Rubin, BK, Ramirez, O, Ohar, JA Iodinated glycerol has no effect on pulmonary function, symptom score, or sputum properties in patients with stable chronic bronchitis.Chest1996;109,348-352
 
Drug products withdrawn or removed from the market for reasons of safety or effectiveness.Federal Register March 81999;64,10947
 
Mossberg, B, Philipson, K, Strandberg, K, et al Clearance by voluntary coughing and its relationship to subjective assessment and effect of intravenous bromhexine.Eur J Respir Dis1981;62,173-179
 
Olivieri, D, Ciaccia, A, Marangio, E, et al Role of bromhexine in exacerbations of bronchiectasis: double-blind randomized multicenter study versus placebo.Respiration1991;58,117-121
 
Thompson, KJ, Reeve, J A clinical trial of bromhexine.N Z Med J1972;76,73-76
 
Valenti, S, Marenco, G Italian multicenter study on the treatment of chronic obstructive lung disease with bromhexine: a double-blind placebo-controlled trial.Respiration1989;56,11-15
 
Thomson, ML, Pavia, D, Jones, CJ, et al No demonstrable effect of S-carboxymethylcysteine on clearance of secretions from the human lung.Thorax1975;30,669-673
 
Edwards, G, Steel, AE, Scott, JK, et al S-Carboxymethylcysteine in the fluidification of sputum and treatment of chronic airway obstruction.Chest1976;70,506-513
 
Dueholm, M, Neilsen, C, Thorshauge, H, et al N-acetylcysteine by metered dose inhaler in the treatment of chronic bronchitis: a multi-centre study.Respir Med1992;86,89-92
 
Hirsch, SR, Viernes, PF, Kory, RC Clinical and physiological evaluation of mucolytic agents nebulized with soproterenol: 10 per cent N-acetylcysteine verus 10 per cent 2-mercaptoethane sulphonate.Thorax1970;25,737-743
 
Jackson, IM, Barnes, J, Cooksey, P Efficacy and tolerability of oral acetylcysteine (Fabrol) in chronic bronchitis: a double-blind placebo controlled study.J Int Med Res1984;12,198-206
 
Clarke, S, Lopez-Vidriero, MT, Pavia, D, et al The effect of sodium 2-mercaptoethane sulphonate and hypertonic saline aerosols on bronchial clearance in chronic bronchitis.Br J Clin Pharmacol1979;7,39-44
 
Pavia, D, Thomson, ML, Clarke, SW Enhanced clearance of secretions from the human lung after the administration of hypertonic saline aerosol.Am Rev Respir Dis1978;117,199-203
 
Shams, H, Daffonchio, L, Scheid, P Effects of levodropropizine on vagal afferent C-fibres in the cat.Br J Pharmacol1996;117,853-858
 
Lavezzo, A, Melillo, G, Clavenna, G, et al Peripheral site of action of levodropropizine in experimentally-induced cough: role of sensory neuropeptides.Pulm Pharmacol1992;5,143-147
 
Bolser, D, DeGennaro, FC, Chapman, RW, et al Central and peripheral sites of action of antitussive drugs in the cat. Trouth, C Millis, RM eds.Ventral brainstem mechanisms and control of respiration and blood pressure1995,95-102 Marcel Dekker. New York, NY:
 
Oral prescription drugs offered for relief of symptoms of cough, cold, or allergy; drug efficacy study implementation; caramiphen edisylate; final actions on supplemental new drug applications.Federal Register June 282000;65,42017
 
Allegra, L, Bossi, R Clinical trials with the new antitussive levodropizine in adult bronchitic patients.Drug Res1988;38,1163-1166
 
Luporini, G, Barni, S, Marchi, E, et al Efficacy and safety of levodropropizine and dihydrocodeine on nonproductive cough in primary and metastatic lung cancer.Eur Respir J1998;12,97-101
 
Aversa, A, Cazzola, M, Clini, V, et al Clinical trial of the efficacy and safety of moguisteine in patients with cough associated with chronic respiratory diseases.Drugs Exp Clin Res1993;19,273-279
 
Adams, R, Hosie, J, James, I, et al Antitussive activity and tolerability of moguisteine in patients with acute cough: a randomized double-blind placebo-controlled study.Adv Ther1993;10,263-271
 
Moroni, M, Porta, C, Gualtieri, G, et al Inhaled sodium cromoglycate to treat cough in advanced lung cancer patients.Br J Cancer1996;74,309-311
 
Chou, D, Wang, SC Studies on the localization of the central cough mechanism: site of action of antitussive drugs.J Pharmacol Exp Ther1975;194,499-505
 
Davenport, P, Sapienza, CM, Bolser, DC Psychophysical assessment of the urge-to-cough.Eur Respir Rev2002;85,249-253
 
Hutchings, HA, Eccles, R, Smith, AP, et al Voluntary cough suppression as an indication of symptom severity in upper respiratory tract infections.Eur Respir J1993;6,1449-1454
 
Hutchings, HA, Eccles, R The opioid agonist codeine and antagonist naltrexone do not affect voluntary suppression of capsaicin induced cough in healthy subjects.Eur Respir J1994;7,715-719
 
Aylward, M, Maddock, J, Davies, DE, et al Dextromethorphan and codeine: comparison of plasma kinetics and antitussive effects.Eur J Respir Dis1984;65,283-291
 
Sevelius, H, Colmore, JP Objective assessment of antitussive agents in patients with chronic cough.J New Drugs1966;6,216-223
 
Sevelius, H, McCoy, JF, Colmore, JP Dose response to codeine in patients with chronic cough.Clin Pharmacol Ther1971;12,449-455
 
Freestone, C, Eccles, R Assessment of the antitussive efficacy of codeine in cough associated with common cold.J Pharm Pharmacol1997;49,1045-1049
 
Korppi, M, Laurikainen, K, Pietikainen, M, et al Antitussives in the treatment of acute transient cough in children.Acta Paediatr Scand1991;80,969-971
 
Lee, PCL, Jawad, MS, Eccles, R Antitussive efficacy of dextromethorphan in cough associated with acute upper respiratory tract infection.J Pharm Pharmacol2000;52,1137-1142
 
Tukiainen, H, Karttunen, P, Silvasti, M, et al The treatment of acute transient cough: a placebo-controlled comparison of dextromethorphan and dextromethorphan-β2-sympathomimetic combination.Eur J Respir Dis1986;69,95-99
 
Pavesi, L, Subburaj, S, Porter-Shaw, K Application and validation of a computerized cough acquisition system for objective monitoring of acute cough: a meta-analysis.Chest2001;120,1121-1128
 
Penn, RD Intrathecal baclofen for spasticity of spinal origin: seven years of experience.J Neurosurg1992;77,236-240
 
Bolser, D, DeGennaro, FC, O’Reilly, S, et al Peripheral and central sites of action of GABA-B agonists to inhibit the cough reflex in the cat and guinea pig.Br J Pharmacol1994;113,1344-1348
 
Dicpinigaitis, P, Dobkin, JB Antitussive effect of the GABA-agonist baclofen.Chest1997;111,996-999
 
Dicpinigaitis, P, Dobkin, JB, Rauf, K, et al Inhibition of capsaicin-induced cough by the γ-aminobutyric acid agonist baclofen.J Clin Pharmacol1998;38,364-367
 
Dicpinigaitis, P Use of baclofen to suppress cough induced by angiotensin-converting enzyme inhibitors.Ann Pharmacother1997;30,1242-1245
 
Bevan, D Neuromuscular blocking agents: onset and intubation.J Clin Anesth1997;9,36s-39s
 
Sparr, HJ, Beaufort, TM, Fuchs-Buder, T Newer neuromuscular blocking agents: how do they compare with established agents?Drugs2001;61,919-942
 
Erhan, E, Ugur, G, Gunusen, I, et al Propofol—not thiopental or etomidate—with remifentanil provides adequate intubating conditions in the absence of neuromuscular blockade.Can J Anaesth2003;50,108-115
 
Lieutaud, T, Billard, V, Khalaf, H, et al Muscle relaxation and increasing doses of propofol improve intubating conditions.Can J Anaesth2003;50,121-126
 
Al-Nakib, WHP, Barrow, I, Batstone, G, et al Prophylaxis and treatment of rhinovirus colds with zinc gluconate lozenges.J Antimicrob Chemother1987;20,893-901
 
Eby, GA, Davis, DR, Halcomb, WW Reduction in duration of common colds by zinc gluconate lozenges in a double-blind study.Antimicrob Agents Chemother1984;25,20-24
 
Farr, B, Conner, EM, Betts, RF, et al Two randomized controlled trials of zinc gluconate lozenge therapy of experimentally induced rhinovirus colds.Antimicrob Agents Chemother1987;31,1183-1187
 
Godfrey, JC, Conant Sloane, B, Smith, DS, et al Zinc gluconate and the common cold: a controlled clinical study.J Int Med Res1992;20,234-246
 
Macknin, ML, Piedmonte, M, Calendine, C, et al Zinc gluconate lozenges for treating the common cold in children: a randomized controlled trial.JAMA1998;279,1962-1967
 
Mossad, SB, Macknin, ML, Medendorp, SV, et al Zinc gluconate lozenges for treating the common cold: a randomized, double-blind, placebo-controlled study.Ann Intern Med1996;125,81-88
 
Smith, DS, Helzner, EC, Nuttall, CE, Jr, et al Failure of zinc gluconate in treatment of acute upper respiratory tract infections.Antimicrob Agents Chemother1989;33,646-648
 
Turner, RB, Cetnarowski, WE Effect of treatment with zinc gluconate or zinc acetate on experimental and natural colds.Clin Infect Dis2000;31,1202-1208
 
Weismann, K, Jakobsen, JP, Weismann, JE, et al Zinc gluconate lozenges for common cold: a double-blind clinical trial.Dan Med Bull1990;37,279-281
 
Prasad, AS, Fitzgerald, JT, Bao, B, et al Duration of symptoms and plasma cytokine levels in patients with the common cold treated with zinc acetate: a randomized, double-blind, placebo-controlled trial.Ann Intern Med2000;133,245-252
 
Jackson, JL, Peterson, C, Lesho, E A meta-analysis of zinc salts lozenges and the common cold.Arch Intern Med1997;157,2373-2376
 
Jackson, JL, Lesho, E, Peterson, C Zinc and the common cold: a meta-analysis revisited.J Nutr2000;130,1512S-1515S
 
Garland, ML, Hagmeyer, KO The role of zinc lozenges in the treatment of the common cold.Ann Pharmacother1998;32,63-69
 
Bernard, D, Goepp, JG, Duggan, AK, et al Is oral albuterol effective for acute cough in non-asthmatic children?Acta Paediatr1999;88,465-467
 
Littenberg, B, Wheeler, M, Smith, DS A randomized controlled trial of oral albuterol in acute cough.J Fam Pract1996;42,49-53
 
Curley, FJ, Irwin, RS, Pratter, MR, et al Cough and the common cold.Am Rev Respir Dis1988;138,305-311
 
Jaeger, RJ, Turba, RM, Yarkony, GM, et al Cough in spinal cord injured patients: comparison of three methods to produce cough.Arch Phys Med Rehabil1993;74,1358-1361
 
Robinson, M, Hemming, AL, Moriarty, C, et al Effect of a short course of rhDNase on cough and mucociliary clearance in patients with cystic fibrosis.Pediatr Pulmonol2000;30,16-24
 
Laube, BL, Auci, RM, Shields, DE, et al Effect of rhDNase on airflow obstruction and mucociliary clearance in cystic fibrosis.Am J Respir Crit Care Med1996;153,752-760
 
Robinson, M, Daviskas, E, Eberl, S, et al The effect of inhaled mannitol on bronchial mucus clearance in cystic fibrosis patients: a pilot study.Eur Respir J1999;14,678-685
 
Chang, AB, Glomb, WB Guidelines for evaluating chronic cough in pediatrics: ACCP evidence based clinical practice guidelines.Chest2006;129(suppl),260S-283S
 
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