This review is an update of recent advances in our understanding of cough suppressants and impairment of cough. Low-dose oral morphine has recently been shown to significantly suppress chronic cough, but the side effect profile of this opioid may limit its widespread utility. Several studies have demonstrated a dissociation between the efficacy of antitussives in some metrics of pathologic cough and their effects on cough sensitivity to inhaled irritants. The relevance of widely used inhaled irritants in understanding pathologic cough and its response to antitussives is questionable. A recent advance in the field is the identification and measurement of an index of sensation related to cough: the urge to cough. This measure highlights the potential involvement of suprapontine regions of the brain in the genesis and potential suppression of cough in the awake human. There are no new studies showing that mucolytic agents are of value as monotherapies for chronic cough. However, some of these drugs, presumably because of their antioxidant activity, may be of use as adjunct therapies or in selected patient populations. The term dystussia (impairment of cough) has been coined recently and represents a common and life-threatening problem in patients with neurologic disease. Dystussia is strongly associated with severe dysphagia and the occurrence of both indicates that the patient has a high risk for aspiration. No pharmacologic treatments ae available for dystussia, but scientists and clinicians with experience in studying chronic cough are well qualified to develop methodologies to address the problem of impaired cough.
This review provides an update on advances in the pharmacology of coughing and antitussives. There are a number of informative reviews on recent work in the area of antitussives. These reviews note the limited amount of new information that has become available on the effects of these drugs in humans in the last several years. Furthermore, in double-blind placebo controlled trials in humans with chronic or acute cough, no new drugs been shown to be effective as antitussive agents. This review focuses on some new information on antitussives. The review is expanded to include the potential therapeutic impact of enhancement of cough in patients who suffer from dystussia, or impaired cough.
Antitussives
My previous review, as well as an earlier one by other investigators, noted that, in recent studies, commonly prescribed antitussives, such as codeine and dextromethorphan, had limited or no efficacy relative to placebo in humans with chronic cough. As such, these drugs were not recommended for suppression of cough. Since that time, a comprehensive study of the effect of codeine on chronic cough in patients with chronic obstructive pulmonary disease (COPD) has been published. This report confirmed a lack of efficacy of codeine to suppress cough in this patient group. However, Morice and coworkers have shown a 40% decrease in cough scores in patients treated with an oral formulation of a low (5 mg) dose of morphine. This dosing regime was well tolerated by their patients. Doubling this dose of morphine resulted in a higher frequency of side effects, such as sedation. The use of morphine as an antitussive is likely to be limited by widespread caution regarding the side effect liability of the drug, regardless of how well tolerated this opioid is in any particular study.
The results of this study raise three additional important points:
- 1.
It is possible to observe significant antitussive effects of an orally active opioid in humans with chronic cough. The lack of efficacy of codeine (up to 60 mg by mouth) in recent studies may be related to specific issues with the molecule itself rather than to μ-opioid agonists in general. Indeed, the cough suppressant effects of codeine are not blocked by naloxone in the cat, suggesting that this drug has actions at nonopioid receptors.
- 2.
Although Morice and colleagues showed activity of morphine to suppress cough scores in humans with chronic cough, the drug did not alter the sensitivity of these patients to an inhaled irritant (citric acid). Another study with dextromethorphan in smokers showed significant effects of this drug relative to placebo on cough sensitivity to inhaled citric acid, but there was no difference between active and placebo groups for subjective measures of coughing. These findings call to question the relevance of irritant aerosol challenge in the evaluation of the activity of putative cough suppressants in humans.
- 3.
Antitussive drugs rarely prevent humans from coughing with an antitussive drug. This point should be considered in light of the widely held misconception that new cough suppressants should not be developed because they will eliminate the ability to protect the airway with the cough reflex.
Recent cough research should expand our knowledge of the genesis of this airway protective behavior in humans. Several recent studies have focused in particular on the effects of antitussives on sensory, motor, and mechanical aspects of cough. The production of cough can be associated with significant sensations, termed urge to cough . In dose-response studies with inhaled irritants, these sensations occur in advance of the actual behavior and directly increase in intensity with the number of coughs and dose of irritant. Cough (and presumably the urge to cough) can be suppressed voluntarily, suggesting that there are endogenous neurochemicals in the human that can mediate this effect. Eccles and coworkers showed that voluntary cough suppression is not opioid-mediated in humans. The presence of these sensations associated with the production of coughing indicates that this behavior is not simply an involuntary reflex phenomenon involving only brainstem mechanisms in the human. To be sure, vigorous chronic cough cannot be eliminated solely through voluntary means. However, pharmacologic approaches that address sensory issues involved in the production of cough may yield novel cough suppressants. This argument is subject to the caveat that no information yet exists that demonstrates suppression by antitussives of the urge to cough in humans with chronic cough. In normal subjects, codeine (30 and 60 mg) did not alter cough sensitivity, electromyograms of abdominal muscles, airflows, or sensations associated with capsaicin-induced cough. The role of urge to cough in the action of antitussive drugs in humans awaits specific studies that use effective cough suppressants.
In smokers, nicotine has been thought to have a cough-promoting effect through its excitatory effects on pulmonary afferents. However, recent findings in smokers suggest that nicotine actually has a cough-suppressant effect. Smokers who refrained from smoking for 12 hours had greater levels of anxiety and higher cough responses and urge-to-cough ratings in response to inhalation of capsaicin than those in age-matched nonsmokers. When the smokers were administered nicotine gum during abstinence from smoking, anxiety levels, cough responses, and urge-to-cough ratings were not different from those in the placebo or the nonsmoking group. The investigators concluded that nicotine modulated the central neural state of the smokers, which reduced anxiety, sensations, and cough responses. Regardless of mechanism, nicotine replacement normalized an elevated cough response and acted as a cough suppressant. These results are consistent with other findings showing that spontaneous coughing increases in the subacute period following cessation of smoking. This putative cough suppressant effect of nicotine may account for the ability of smokers to inhale cigarette smoke repeatedly each day without violent coughing. Nicotine penetrates the nervous system readily and the probability of a central action of this drug on the cough reflex in these subjects must be considered high.
In my previous review of this topic, I concluded that mucolytic agents were not recommended to suppress cough in patients with chronic bronchitis. These drugs may have other benefits, such as increased cough clearance and improvement of other symptoms. I further recommended only one anticholinergic agent, ipratropium bromide, for cough suppression. Although new information related to some of these recommendations has appeared in the last several years, it does not appear that sufficient evidence has accumulated to warrant a change in these recommendations. New information has been published on several drugs with mucolytic or anticholinergic activity that have an antitussive effect in patients groups with chronic or acute cough.
N-acetylcysteine was administered in a double-blind clinical trial to patients who had been exposed to sulfur-mustard gas. This drug significantly improved cough, dyspnea, and several components of pulmonary function in these patients. Both the treatment and placebo groups received fluticasone and salmeterol, raising the possibility that N-acetylcysteine had a synergistic effect with these drugs. The investigators suggested that the antioxidant effects of this drug were responsible for its therapeutic effects.
Another antioxidant agent and putative mucolytic agent, erdosteine, when combined with amoxicillin, has recently been shown to be significantly more effective in reducing cough in children with acute lower respiratory illness than this antibiotic and placebo. This was a randomized double-blinded and placebo-controlled study and the combination of erdosteine and amoxicillin reduced visual analog scores for cough by approximately 90% compared with 76% for amoxicillin plus placebo. Note the large placebo effect, which is typical for studies in which cough is an end point. Erdosteine also significantly decreased interleukin 8 (IL-8) in sputum of current smokers with COPD, which is consistent with an anti-inflammatory effect.
These observations are consistent with the potential use of these drugs in combination therapies for the relief of cough in selected patient populations. Mucolytic drugs have not been effective as antitussive agents when used as monotherapies. The extent to which these drugs will be useful for the suppression of cough on a widespread basis is unknown and awaits larger scale clinical trials.
A small-scale double-blind placebo-controlled study was conducted on the effect of the anticholinergic agent tiotropium on cough due to acute upper airway viral infection. Tiotropium significantly inhibited cough sensitivity to capsaicin after the first dose and out to 7 days relative to placebo. The treatment group also had significantly improved spirometry, but this effect was not correlated with cough sensitivity changes, suggesting that bronchodilatation was not responsible for the effect on cough sensitivity. The cough-suppressant activity of tiotropium in this study contrasts with the findings of Casaburi and colleagues, who showed no effect of this drug on cough in patients with COPD. As noted above, Morice and colleagues showed that cough due to inhaled irritants is not an accurate predictor of the activity of antitussive drugs in patients with airway disease. The extent to which tiotropium will suppress spontaneous coughing in patients with acute upper airway viral illness is unknown ( Table 1 ).
| Drug | Mechanism | Outcome |
|---|---|---|
| Codeine | Opioid | No effect on cough due to COPD |
| Morphine | Opioid | 40% decrease in cough in patients with chronic cough refractory to specific therapy; well tolerated but long-term use potentially limited by side effects |
| Dextromethorphan | Nonopioid | Slight but significant decrease in cough due to upper airway disorders; no effect on smoker’s cough |
| N-acetylcysteine | Possible antioxidant effect | Significant cough alleviation in patients with chemical injury to lungs |
| Erdosteine | Possible antioxidant effect | Potentiates cough suppressant effect of antibiotics during airway infection |
| Tiotropium | Unknown | Decreased capsaicin sensitivity; no effect on cough due to COPD |
Enhancement of Cough
Awareness of the significance of dystussia is increasing. While chronic cough is associated with significant morbidity and quality-of-life issues, dystussia is life threatening. Dystussia and atussia represent a breakdown in endogenous mechanisms for airway protection. Airway protection, which is the prevention and/or correction of aspiration ( Table 2 ), is accomplished through the expression of a constellation of different behaviors, which include coughing, swallowing, expiration reflex, laryngeal adduction, and apnea. During the pharyngeal phase of swallowing, aspiration is prevented by closure of the vocal folds, changes in breathing, elevation of the larynx, and movement of the epiglottis to protect the laryngeal orifice. In awake humans, swallowing preferentially occurs during the expiratory phase of breathing, usually resulting in a prolonged expiration and resetting of the breathing cycle. The expiration reflex prevents aspiration by changing breathing pattern and producing a ballisticlike expiratory airflow to “blow” adherent material away from the vocal folds. If aspiration occurs, coughing corrects this problem by producing high-velocity airflows that create shear forces to dislodge and eject material from the airway.
| Term | Definition |
|---|---|
| Airway protection | Prevention and/or correction of aspiration |
| Dystussia | Impaired cough |
| Atussia | Inability to cough |
| Silent aspiration | Aspiration with atussia |
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