Older-Generation Antihistamines and Cough Due to Upper Airway Cough Syndrome (UACS): Efficacy and Mechanism

Abstract

Older-generation H1 antihistamines are recommended in empiric protocols for the treatment of cough due to upper airway cough syndrome (UACS). Data from double-blind placebo-controlled trials that support the use of older-generation antihistamines in UACS are limited to a single study of cough due to the common cold. However, several empiric trials strongly support efficacy of older-generation antihistamines in patients with chronic cough. Data from a variety of studies support the concept that newer-generation H1 antihistamines are not useful in the treatment of cough due to UACS. The mechanism of action of older-generation H1 antihistamines has been proposed to be anticholinergic activity, but the rank order potency of these drugs as muscarinic receptor antagonists is not consistent with this hypothesis. Actions of these drugs on histamine H1 and/or nonhistaminergic receptors in the central nervous system remain a possible explanation for their effects on cough due to UACS. The effects of older H1 antihistamines may also be molecule specific, rather than attributable to the entire class of compounds. Additional studies should be performed to document the activity of these drugs in double-blind placebo-controlled trials.

Introduction

Upper respiratory tract disorders are the most common causes of chronic and acute cough in humans [1–3]. It has recently been proposed that the host of upper respiratory disorders that frequently cause cough be collectively described as upper airway cough syndrome (UACS) [1]. This designation reflects the considerable uncertainty with regard to diagnosis and etiology of disorders involving the upper airway that induce cough [1]. The pathogenesis of these disorders leading to coughing may involve multiple mechanisms, including the mechanical action of secretions on laryngeal and pharyngeal afferents [4], enhanced excitability of sensory afferents causing increased cough responsiveness [5], and/or enhanced excitability of central pathways that produce cough [1, 6, 7]. Current recommendations for the treatment of cough due to UACS include older-generation antihistamines [1]. Newer-generation nonsedating antihistamines are thought to be ineffective in treating chronic cough [1]. The purpose of this review is to examine the evidence for the efficacy of sedating antihistamines and their proposed mechanism in the suppression of cough due to UACS.

Evidence for the Efficacy of Antihistamines in Chronic Cough Due to UACS

Evidence from double-blind placebo-controlled studies in humans with upper respiratory disorders supporting the efficacy of sedating antihistamines is limited. Only one study [8] has demonstrated efficacy of a sedating antihistamine (dexbrompheniramine) in cough due to UACS. One other study [9] showed no effect of diphenhydramine on cough due to UACS. In that same study, dextromethorphan significantly inhibited cough relative to placebo, although the magnitude of the effect was relatively low [9].

In contrast to the limited evidence from double-blind placebo-controlled studies, empiric evidence supports the use of sedating antihistamines for the treatment of cough due to UACS [1]. This evidence is derived largely from published success rates in the treatment of patients with chronic cough due to a variety of causes [10–17]. Older-generation antihistamines are recommended when UACS is suspected as a cause of the patient’s coughing [1, 2, 8, 12]. A therapeutic effect of the older-generation antihistamine is considered as evidence that UACS is involved in the production of cough in a given patient.

It is clear that newer-generation nonsedating antihistamines are ineffective in the treatment of cough in UACS based on empiric evidence, double-blind placebo-controlled studies in patients with upper airway pathology, and irritant challenge studies [7, 18–22].

The objective evidence supporting the use of older-generation sedating antihistamines in the treatment of cough due to UACS is not strong. More placebo-controlled double-blind studies are required to fully test the hypothesis that these compounds are effective. An alternate hypothesis that is consistent with the current data is that selected older antihistamines are effective rather than the entire class of drugs. As such, the activities of older-generation antihistamines to inhibit cough in patients with UACS may be unrelated to their binding affinities at histamine H1 receptors.

Possible Mechanisms by Which Older Antihistamines Could Inhibit Cough in UACS

Table 1 lists possible mechanisms by which antihistamines could inhibit pathologic cough. Although listed here for completeness, the peripheral direct mechanism is unlikely to be responsible for cough suppression by this class of compounds because nonsedating antihistamines do not inhibit coughing. Furthermore, the peripheral indirect mechanism is unlikely to be a major contributor to the antitussive effects of antihistamines for the same reason.

Table 1.

Summary of possible mechanisms by which antihistamines could suppress cough due to UACS

Mechanism	Description
Peripheral direct	Histamine receptors on sensory afferents may promote the production of cough
Peripheral indirect	Nasal mucus secretion induced by histamine receptors promotes cough by a mechanical action on pharyngeal or laryngeal mechanoreceptors that elicit cough Nasal mucus secretion induced by cholinergic mechanisms produces cough by a mechanical action on pharyngeal or laryngeal mechanoreceptors that elicit cough
Central direct	Histamine H1 receptors in the central nervous system may directly promote the production of cough. Access to these receptors would require a centrally penetrant H1 antihistamine Centrally penetrant H1 antihistamines may bind to nonhistaminergic receptors in the central nervous system that control cough excitability
Central indirect	Histamine H1 receptors in the central nervous system may regulate nasal mucus secretion. Access to these receptors would require a centrally penetrant H1 antihistamine Centrally penetrant antihistamines may bind to nonhistaminergic receptors that regulate mucus secretion Centrally penetrant antihistamines induce sedation that could result in a reduction in cough excitability

The proposed mechanism for antitussive effects of older-generation antihistamines is the peripheral indirect mechanism involving cholinergic mechanisms [1]. Consistent with this hypothesis is the fact that some antihistamines can have anticholinergic actions [23]. However, an examination of the rank order potency of selected antihistamines for binding to muscarinic receptors does not support this hypothesis. The pA2 values for diphenhydramine, chlorpheniramine, and loratadine for shifting the dose response to carbachol in guinea pig tissue are similar [23]. Given that loratadine is a nonsedating antihistamine and that diphenhydramine and chlorpheniramine are sedating antihistamines that penetrate the central nervous system, these data do not support greater anticholinergic activity for all of the sedating drugs relative to the nonsedating antihistamines. It is clear that promethazine is the most potent anticholinergic agent of the antihistamines, although the nonsedating drug desloratadine has a similar pA2 value [23].

The older antihistamines penetrate the central nervous system [24]. As such, these drugs could have a variety of effects that may result in cough suppression. Elements of the central nervous mechanisms for coughing due to UACS could require histamine H1 receptors. An older antihistamine would be effective in blocking this action while a newer, peripheral antihistamine would be ineffective. At present, the only evidence supporting the concept that central histaminergic pathways are important in the production of pathologic cough in humans are studies showing efficacy of older antihistamines as antitussives [8, 25]. However, these molecules can have other activities at nonhistamine receptors. For example, some antihistamines bind to sigma receptors, which have been shown to be involved in cough suppression in animal models [26]. Therefore, centrally acting antihistamines may have non-specific effects to suppress cough.

The central nervous system can play a prominent role in regulating mucus secretion in the airways [27, 28]. Antihistamines may also have indirect effects that suppress cough by acting on central pathways that alter mucus secretion. This indirect action could involve either central histamine or nonhistamine receptors. Alternatively, the well-known sedating actions of some older antihistamines could be involved in cough suppression. This possibility is unlikely as sedation is not anesthesia or sleep. A study in the guinea pig [29] showed that there was no relationship between the minimum effective antitussive dose of a variety of peripheral and centrally acting antihistamines and their ability to potentiate the loss [28] of righting reflex induced by pentobarbital. That study supported the concept that the sedative and antitussive potentials for antihistamines are unrelated. Furthermore, Lilienfield et al. [25] showed that the cough-suppressant effect of diphenhydramine in patients with lower airway disease was unrelated to the sedative effects of this drug.

Further studies are needed to document the cough-suppressant effects of older antihistamines in UACS. There are a variety of mechanisms, both specific and nonspecific, that could account for these molecules suppressing cough in humans. The mechanisms responsible for cough suppression by older antihistamines may not be attributable to the entire class of molecules but may be more relevant to nonspecific effects of selected molecules within the class. Determination of whether these effects can be attributed to the older antihistamines as a class or solely to specific molecules is likely to be a challenging process.