Antitussive drugs--past, present, and future.

Cough remains a serious unmet clinical problem, both as a symptom of a range of other conditions such as asthma, chronic obstructive pulmonary disease, gastroesophageal reflux, and as a problem in its own right in patients with chronic cough of unknown origin. This article reviews our current understanding of the pathogenesis of cough and the hypertussive state characterizing a number of diseases as well as reviewing the evidence for the different classes of antitussive drug currently in clinical use. For completeness, the review also discusses a number of major drug classes often clinically used to treat cough but that are not generally classified as antitussive drugs. We also reviewed a number of drug classes in various stages of development as antitussive drugs. Perhaps surprising for drugs used to treat such a common symptom, there is a paucity of well-controlled clinical studies documenting evidence for the use of many of the drug classes in use today, particularly those available over the counter. Nonetheless, there has been a considerable increase in our understanding of the cough reflex over the last decade that has led to a number of promising new targets for antitussive drugs being identified and thus giving some hope of new drugs being available in the not too distant future for the treatment of this often debilitating symptom.

Rhinovirus upregulates transient receptor potential channels in a human neuronal cell line: implications for respiratory virus-induced cough reflex sensitivity.

BACKGROUND: The mechanism underlying respiratory virus-induced cough hypersensitivity is unknown. Upregulation of airway neuronal receptors responsible for sensing physical and chemical stimuli is one possibility, and the transient receptor potential (TRP) channel family are potential candidates. We have used an in vitro model of sensory neurons and human rhinovirus (HRV-16) to study the effect of virus infection on TRP expression. METHODS: IMR-32 neuroblastoma cells were differentiated in culture to express three TRP channels: TRPV1, TRPA1 and TRPM8. Flow cytometry and qRT-PCR were used to measure TRP channel protein and mRNA levels following inoculation with live virus, inactivated virus, virus-induced soluble factors or pelleted virus particles. Multiplex bioassay was used to determine nerve growth factor (NGF), interleukin (IL)-1ß, IL-6 and IL-8 levels in response to infection. RESULTS: Early upregulation of TRPA1 and TRPV1 expression occurred 2-4 h post infection. This was independent of replicating virus as virus-induced soluble factors alone were sufficient to increase channel expression 50-fold and 15-fold, respectively. NGF, IL-6 and IL-8 levels, increased in infected cell supernatants, represent possible candidates. In contrast, TRPM8 expression was maximal at 48 h (9.6-fold) and required virus replication rather than soluble factors. CONCLUSIONS: We show for the first time that rhinovirus can infect neuronal cells. Furthermore, infection causes upregulation of TRP channels by channel-specific mechanisms. The increase in TRPA1 and TRPV1 levels can be mediated by soluble factors induced by infection whereas TRPM8 requires replicating virus. TRP channels may be novel therapeutic targets for controlling virus-induced cough.

Eosinophil peroxidase induces the expression and function of acid-sensing ion channel-3 in allergic rhinitis: in vitro evidence in cultured epithelial cells.

BACKGROUND: Acid-sensing ion channels (ASIC) are a family of acid-activated ligand-gated cation channels. As tissue acidosis is a feature of inflammatory conditions, such as allergic rhinitis (AR), we investigated the expression and function of these channels in AR. OBJECTIVES: The aim of the study was to assess expression and function of ASIC channels in the nasal mucosa of control and AR subjects. METHODS: Immunohistochemical localization of ASIC receptors and functional responses to lactic acid application were investigated. In vitro studies on cultured epithelial cells were performed to assess underlying mechanisms of ASIC function. RESULTS: Lactic acid at pH 7.03 induced a significant rise in nasal fluid secretion that was inhibited by pre-treatment with the ASIC inhibitor amiloride in AR subjects (n = 19). Quantitative PCR on cDNA isolated from nasal biopsies from control and AR subjects demonstrated that ASIC-1 was equally expressed in both populations, but ASIC-3 was significantly more highly expressed in AR (P < 0.02). Immunohistochemistry confirmed significantly higher ASIC-3 protein expression on nasal epithelial cells in AR patients than controls (P < 0.01). Immunoreactivity for EPO+ eosinophils in both nasal epithelium and submucosa was more prominent in AR compared with controls. A mechanism of induction of ASIC-3 expression relevant to AR was suggested by the finding that eosinophil peroxidase (EPO), acting via ERK1/2, induced the expression of ASIC-3 in epithelial cells. Furthermore, using a quantitative functional measure of epithelial cell secretory function in vitro, EPO increased the air-surface liquid depth via an ASIC-dependent chloride secretory pathway. CONCLUSIONS: This data suggests a possible mechanism for the observed association of eosinophils and rhinorrhoea in AR and is manifested through enhanced ASIC-3 expression.

Patterns of cough in the clinic.

Current guidelines for the management of cough highlight the value of a taking a careful history to establish specific features of the cough in particular its duration, typical triggers or aggravants and associated symptoms. Unfortunately the diagnostic yield from a history alone is poor and there is a need to understand the pattern of clinical cough in a more precise way. As the technology to record cough in ambulatory settings becomes more sophisticated so the possibility that precise measurement of the cough frequency, intensity and acoustic characteristics may offer diagnostically valuable information in individual patients becomes a reality. In this article the current knowledge of the clinical patterns of cough is discussed and the potential for new technology to record cough patterns in a meaningful way is considered.

Respiratory and laryngeal symptoms secondary to gastro-oesophageal reflux.

Gastro-oesophageal reflux may cause a range of laryngeal and respiratory symptoms. Mechanisms responsible include the proximal migration of gastric refluxate beyond the upper oesophageal sphincter causing direct irritation of the larynx and lower airway. Alternatively, refluxate entering the distal oesophagus alone may stimulate oesophageal sensory nerves and indirectly activate airway reflexes such as cough and bronchospasm. Recognising reflux as a cause for these extraoesophageal symptoms can be difficult as many patients do not have typical oesophageal symptoms (eg, heartburn) and clinical findings on laryngoscopy are not very specific. Acid suppression remains an effective treatment in the majority of patients but there is growing appreciation of the need to consider and treat non-acid and volume reflux. New opinions about the role of existing medical and surgical (laparoscopic techniques) treatment are emerging and a number of novel anti-reflux treatments are under development.

Clinical cough II: therapeutic treatments and management of chronic cough.

Chronic cough is a common and frequently disruptive symptom which can be difficult to treat with currently available medicines. Asthma/eosinophilic airway disease and gastro-oesophageal reflux disease are most commonly associated with chronic cough but it may also trouble patients with chronic obstructive pulmonary disease, pulmonary fibrosis and lung cancer. Over the last three decades there have been a number of key advances in the clinical approach to cough and a number of international guidelines on the management of cough have been developed. Despite the undoubted benefit of such initiatives, more effective treatments for cough are urgently needed. The precise pathophysiological mechanisms of chronic cough are unknown but central to the process is sensitization (upregulation) of the cough reflex. One well-recognized clinical consequence of this hypersensitive state is bouts of coughing triggered by apparently trivial provocation such as scents and odours and changes in air temperature. The main objective of new treatments for cough would be to identify ways to downregulate this heightened cough reflex but yet preserve its crucial role in protecting the airway. The combined efforts of clinicians, scientists and the pharmaceutical industry offer most hope for such a treatment breakthrough. The aim of this chapter is to provide some rationale for the current treatment recommendations and to offer some reflections on the management of patients with chronic cough.

Are there clinical features of a sensitized cough reflex?

Cough reflex hypersensitization is a key feature in patients with troublesome cough. The clinical consequence of this hypersensitive state is typified by bouts of coughing often triggered by low threshold stimuli encountered by the patient during normal daily activities including exposure to aerosols, scents and odours, a change in air temperature and when talking or laughing. These features are often perceived by cough patients to be the most disruptive aspect of their condition and undoubtedly contribute to impaired quality of life. Patients with troublesome cough may describe a range of additional symptoms and sensations including an 'urge to cough' or the feeling of an 'itch' at the back of the throat, or a choking sensation and occasionally chest pain or breathlessness. It is uncertain if these features arise due to the processes responsible for cough reflex sensitization or as a direct consequence of the underlying cough aetiology. In an attempt to understand the clinical features of a sensitized cough reflex, the spectrum of symptoms typically described by cough patients will be reviewed and possible underlying mechanisms considered. Since an intact cough reflex is crucial to airway protection, anti-tussive treatment that attenuates the hypersensitive cough state rather than abolishing the cough reflex completely would be preferable. Identifying such agents remains a clinical, scientific and pharmacological challenge.

Common causes and current guidelines.

Chronic cough is a common and disabling symptom. Recent guidelines have attempted to provide direction in the clinical management of cough in both primary and secondary care. They have also provided a critical review of the available literature and identified gaps in current knowledge. Despite this they have been criticized for a reliance on a low quality evidence base. In this review, we summarize the current consensus on the clinical management of chronic cough and attempt to rationalize this based on recent evidence. We have also provided an overview of the likely pathophysiological mechanisms responsible for cough and highlighted areas, where knowledge deficits exist and suggest directions for future research. Such progress will be critical in the search for new and effective treatments for cough.

Calcitonin gene-related peptide relates to cough sensitivity in children with chronic cough.

Airway neuropeptides, in particular calcitonin gene-related peptide (CGRP), are likely to be important in the pathogenesis of chronic cough. The present authors evaluated the following: 1) the relationship between cough sensitivity and bronchoalveolar lavage (BAL) neuropeptides; and 2) the effect of reflux oesophagitis (RO) on cough, cough sensitivity and BAL neuropeptides in children not selected for cough. It was hypothesised that CGRP would be increased in children with chronic cough and would relate to cough sensitivity. Capsaicin cough sensitivity was performed in children undergoing gastro-duodenal endoscopy. CGRP, substance P and neurokinin A were measured in BAL obtained nonbronchoscopically. Children were defined as "coughers" if chronic cough was present. Coughers (n = 21) had significantly reduced cough sensitivity but were just as likely as noncoughers (n = 19) to have RO. The median CGRP was significantly higher in coughers with oesophagitis than in noncoughers with oesophagitis. CGRP significantly negatively correlated to cough sensitivity in coughers but not in noncoughers. Elevated calcitonin gene-related peptide, but not substance P or neurokinin A, is only associated with chronic cough in children when oesophagitis coexists. Calcitonin gene-related peptide in bronchoalveolar lavage relates to cough sensitivity and is likely to be important in the pathophysiology of chronic cough.

Clinical cough and its mechanisms.

Cough is the commonest symptom of clinical importance and the most frequent reason for new consultations with a doctor. Although therapy directed at any underlying cause for cough can be effective there is a clinical need for new treatments specifically directed at the cough itself. A major obstacle to the development of such therapy has been an imprecise understanding of the pathophysiological mechanisms responsible for cough. In this article, we review the important clinical aspects of both acute and chronic cough, offer practical insight into the existing treatment options, highlight the current understanding of cough pathophysiology and identify important areas for future research effort.

Idiopathic chronic cough: a real disease or a failure of diagnosis?

Despite extensive diagnostic evaluation and numerous treatment trials, a number of patients remain troubled by a chronic and uncontrollable cough. Eosinophilic bronchitis, atopic cough and non-acid reflux have been recently added to the diagnostic spectrum for chronic cough. In some cases, failure to consider these conditions may explain treatment failure. However, a subset of patients with persisting symptoms may be regarded as having an idiopathic cough. These individuals are most commonly female, of postmenopausal age and frequently report viral upper respiratory tract infections as an initiating event. This paper seeks to explore the validity of idiopathic cough as a distinct clinical entity.

Patients with gastro-oesophageal reflux disease and cough have impaired laryngopharyngeal mechanosensitivity.

BACKGROUND: Laryngopharyngeal sensitivity (LPS) is important in preventing pulmonary aspiration and may be impaired by anaesthesia and stroke. It has been suggested that gastro-oesophageal reflux disease (GORD) may also impair LPS, although the underlying mechanism is unclear. The aim of this study was to compare LPS in patients with chronic cough and GORD with healthy subjects and to determine the effect of laryngopharyngeal infusions of both acid and normal saline on LPS. METHODS: Fifteen patients with chronic cough and GORD and 10 healthy subjects without GORD underwent LPS testing using the fibreoptic endoscopic evaluation of swallowing with sensory testing (FEESST) technique. LPS, as measured by the lowest air pressure required to elicit the laryngeal adductor reflex (LAR), was determined both before and after laryngopharyngeal infusions of normal saline and 0.1 N hydrochloric acid performed on separate days. RESULTS: The mean baseline LAR threshold of the patient group was significantly higher (9.5 mm Hg, range 6.0-10.0) than in normal subjects (3.68 mm Hg, range 2.5-5.0; p<0.01). Retest thresholds were not significantly different. In normal subjects LAR thresholds were significantly raised after acid but not after saline infusion (p = 0.005). There were no complications associated with the procedure. CONCLUSIONS: Patients with cough and GORD have significantly reduced LPS to air stimuli compared with healthy subjects which could potentially result in an increased risk of aspiration. Exposure to small amounts of acid significantly impaired the sensory integrity of the laryngopharynx.

Oesophageal pH monitoring is of limited value in the diagnosis of "reflux-cough".

Reflux-cough is a diagnosis based on demonstrating both gastro-oesophageal reflux and a positive response to anti-reflux therapy. The authors sought to determine early and long-term response to therapy in patients with a "positive" 24 h oesophageal pH study, and identify any features which might predict response. Patients with chronic cough were recruited from July 1998 to July 2002. Those with a positive pH study were given dietary advice and an 8-week trial of omeprazole (20 mg b.i.d.). Response was judged after 8 weeks (clinical follow-up), and at long-term follow-up (telephone questionnaire). A total of 146 patients underwent pH monitoring with 82 (56.2%) "positive" studies. Follow-up data was available in 60 patients, with 49 receiving anti-reflux therapy, of which 20 (40.8%) reported a positive treatment response. At long-term follow-up (median 30 months), there was a significantly lower response (14 out of 49, 28.5%), with no significant difference in either acid exposure times (distal/proximal) or symptom correlation between responders and nonresponders at early or long-term follow-up. In conclusion, despite "positive" pH studies, over half of the patients (55.1%) failed to respond to therapy. No features on pH monitoring accurately predicted response. Short-term response did not predict long-term response. The precise role for pH monitoring in the assessment of chronic cough remains to be defined.

Acute and chronic cough.

Individuals are generally content to self-medicate for acute cough. It is only when the cough becomes persistent that they seek medical assistance. It is not known why patients cough in association with an acute upper respiratory tract infection (URTI), although interest has focused on how viruses may influence airway sensory nerve function and contribute to heightened cough reflex sensitivity. Why some patients develop a persistent cough following a viral URTI is also unclear. Much more is known about the causes and aggravants of chronic cough although there is no broad agreement as to the best way to manage such patients. Asthma, upper gastrointestinal dysfunction and rhinitis are frequently associated with chronic cough, although the impact of cough in suppurative lung disease and interstitial lung fibrosis is rarely considered. The development of effective treatments for cough remains a challenge and will require co-operation between clinicians, scientists and the pharmaceutical industry.

Idiopathic cough, prevalence and underlying mechanisms.

A number of authors have reported a significant percentage of patients whose cause of cough remains undetermined despite a systematic evaluation as recommended in a number of International Guidelines. This subset of patients, which may be regarded as having an idiopathic cough, are often female and of peri or postmenopausal age. Sex hormones may influence the cough reflex in disease or contribute to the chronic lymphocytic airway inflammation seen in some cases and to the association with organ specific autoimmune disease reported. This paper seeks to investigate some of the possible causes of idiopathic cough.

Cough . 6: Which investigations are most useful in the diagnosis of chronic cough?

There is no consensus as to the best diagnostic strategy for chronic cough. Many protocols combine empirical trials of treatment with laboratory investigations. More precise diagnostic tools and improved therapeutic options are required. Until then, the management of chronic cough will remain a clinical challenge.