Effective antitussives for the cough patient: An unmet need

Effective antitussives for the cough patient: An unmet need

ARTICLE IN PRESS Pulmonary Pharmacology & Therapeutics 20 (2007) 438–445 www.elsevier.com/locate/ypupt Effective antitussives for the cough patient:...

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ARTICLE IN PRESS

Pulmonary Pharmacology & Therapeutics 20 (2007) 438–445 www.elsevier.com/locate/ypupt

Effective antitussives for the cough patient: An unmet need K.F. Chung National Heart & Lung Institute, Imperial College London & Royal Brompton & Harefield NHS Trust, London SW3, UK Received 3 October 2006; accepted 26 October 2006

Abstract Chronic cough is a prevalent symptom in the community but it is likely that only a small fraction of chronic coughers seek medical attention. Chronic cough can be controlled by addressing the ‘cause’ of the cough, but not all cough is controlled using this approach; an ‘idiopathic’ cough or cough of unknown aetiology is becoming more well-recognized. In these patients and in those whose cough has not responded to treatment of the cause(s), there is a lack of efficacious antitussive therapies (‘non-specific’ antitussives). Even in those whose cough is controlled by treatment of the cause, an efficacious antitussive for symptomatic relief would be useful for breakthrough symptoms. It is necessary to address the mechanisms underlying chronic cough, particularly the process of sensitization, both peripherally and centrally, that is the basis of chronic cough; such a process may persist even in the absence of the initiating event that first induced the cough. Currently-available antitussives in both acute and chronic cough are not very effective. Novel targets that may result in effective antitussives have been identified and with the development of clinical tools to measure cough accurately and reliably (e.g. cough counts and cough-specific quality-of-life questionnaires) and the evoked cough response (e.g. citric acid or capsaicin challenges), clinical trials should be performed. The chronic cough population is clinically heterogeneous but is characterized by an enhanced cough reflex; this should be the target population for study. Patients with chronic cough are in desperate need of effective antitussives that can be used either on demand or on a long-term basis. r 2006 Elsevier Ltd. All rights reserved. Keywords: Antitussives; Chronic cough; Idiopathic cough; Cough challenge

1. Introduction This review focuses on an unmet need in cough therapy, that of an effective antitussive pharmacological agent that will suppress cough directly. Setting up clinical trials of potential antitussive agents in cough patients should resolve this unmet need. 2. Cough in the community Data collected 20–30 years ago indicate that chronic cough is prevalent in 18% of the US population, in up to 16% of an English population living in the South-East of the country, and in 11% of the Swedish population [1–3]. In a trans-European survey of the European Community Respiratory Health Survey (ECRHS) consisting of 18,277 Tel.: +44 0207 351 8995; fax: +44 0207 351 8126.

E-mail address: [email protected] 1094-5539/$ - see front matter r 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.pupt.2006.10.015

subjects aged between 20 and 48, about one-third reported that they had been woken up by an attack of cough in the last 12 months, and about 20% reported a non-productive or productive cough during the winter months [4]. A recent survey conducted through general practitioner practices of 4003 responders to a mailed questionnaire in Northern England has revealed a prevalence of chronic cough of 12% with the cough described as severe in 7%. Regurgitation, irritable bowel syndrome, smoking and declining social class were strong predictors of cough [5], but this association was not confirmed. Further close characterisation of these chronic coughers in the community is needed in order to determine the severity of cough, whether these patients have sought medical attention and the cause of these chronic symptoms. More recent epidemiological surveys have provided data linking exposure to cigarette smoking or environmental pollutants to cough. In a cross-sectional study of adults in Switzerland, the prevalence of chronic cough by smoking

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status was found to be nearly 3-fold increased at 9.2% in 3232 current smokers when compared with 4229 neversmokers (3.3%) and with 2175 ex-smokers (3.0%) [6]. Significant associations have been reported between environmental tobacco smoke exposure and respiratory symptoms including cough. For example, an odds ratio for developing cough in school-aged children when both parents are smokers was 1.67 [7]. Environmental pollutants particularly PM10 particulates have been associated in adults and school children with productive cough or chronic nocturnal dry cough [8–10]. More recent evidence for a cause and effect comes from epidemiological studies relating a fall in cough in populations where PM10 levels have fallen [11]. Conversely, increases in levels of PM10 are related to reductions in peak expiratory flows and with increasing reporting of cough, sputum production and sore throat in children with or without asthma [12]. Increases in environmental pollution over the last decades have been associated with an increased prevalence of cough in the cities in the Italian Po valley [13]. Other components of air traffic pollution have also been associated with chronic cough. An increase of 10 mg/m3 in NO2 levels has been associated with an increase in chronic cough prevalence [6,9]. 3. Unmet needs in the clinic Perhaps the increase in the number of patients seen in cough clinics may relate to an actual increase in the number of patients with chronic cough within the community. One of the commonest complaints that doctors in general practice or respiratory specialists are confronted with is that of a cough. Guidelines are now available to provide management plans when the clinician is confronted with a patient with cough [14–16]. After exclusion of serious illnesses such as cancer, diagnoses such as asthma, chronic obstructive pulmonary disease (COPD) or bronchiectasis may be made and the patient managed accordingly. Associated conditions such as gastro-oesophageal reflux disease (GORD) or rhino-sinusitis may be treated since these are recognized to cause cough. Alternatively, there may be no obvious associated causes (‘idiopathic cough’) or treatment of associated causes may not improve the cough, and these patients may comprise up to 30% of the cough patients presenting at certain cough clinics [17–19]. Little is known about the long-term effects of treatment in the patients with chronic cough in whom medical intervention has led to successful suppression of cough, and issues such as whether the cough recurred or not, and exactly what level of control of cough was achieved need to be documented. There is a current need for more effective anti-tussive drugs, since cough by itself, although not lifethreatening, can cause general debility, weakness and social embarrassment, which contribute to a deterioration in quality of life [20]. This also applies to patients who also experience severe bouts of uncontrollable cough that can lead to loss of consciousness, cardiac arrythmias or urinary

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incontinence. For such treatments, the requirement would be not only an effective antitussive, but an agent that has a rapid onset of action. Such agents may be used on demand to abort or control an onset of coughing bouts. 4. Current cough treatments The first task of the physician is to reach a diagnosis as to the cause of the cough, and apply appropriate treatment to the cause first. Treatment of the cause may be successful in suppressing the cough. In conditions such as asthma, cough-variant asthma or eosinophilic bronchitis, inhaled corticosteroid therapy is often used with success. In a case report of a patient with the hypereosinophilic syndrome due to FIP1L1-PDGFR fusion gene encoding a tyrosine kinase presenting predominantly with chronic persistent cough, there was evidence of eosinophil infiltration in the airways, and the cough was controlled partly with high dose prednisolone, and later completely by the tyrosine kinase inhibitor imatinib [21]. This case report provides support for a direct role for the eosinophil in causing cough, and the success of inhaled corticosteroids in controlling chronic cough associated with airway eosinophilia is likely to be secondary to suppression of the eosinophilia. GORD is commonly associated with chronic cough, and proton pump inhibitors (PPI) or histamine H2-receptor antagonists are recommended. Early case reports have hailed up to 100% success of these treatments in controlling cough, but a recent Cochrane meta-analysis of therapy with PPI concludes that there is ‘insufficient evidence to definitely conclude that GORD treatment with these agents is beneficial for cough associated with GORD in adults’ [22]. In a small study, we found a small but significant effect of PPI therapy on cough associated with GORD diagnosed by 24-h oesophageal pH monitoring [23]. The possibility of non-acid volume reflux or of abnormal upper oesophageal motility problems as a cause of chronic cough has been evoked, but these associations have yet to be established. Extremely good success of surgical correction of GORD in patients whose cough did not respond to PPI therapy has been reported [24], and in this group there may have been patients with non-acid volume reflux, but more experience is needed. Increasingly, there is a recognition that reflux of gastric contents can also cause laryngeal pathology that in turn could be the cause of cough, a condition labelled as laryngopharyngeal reflux [25]. Clearly, the treatment of cough associated with GORD remains unsatisfactory, and such patients may benefit from effective antitussive therapies in addition to specific treatments related to GORD. Post-nasal drip syndrome (PNDS) or nasal catarrh is another well-recognized cause chronic cough. Topical corticosteroids sometimes with a nasal decongestant or antibiotics or antihistamines are used for treating rhinosinusitis, and first generation antihistamines may be more effective than the newer antihistamines in controlling

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cough. However, otorhinolaryngologists do not agree that cough is a predominant symptom of patients with the PNDS [26], and it may be that the PNDS is caused by laryngopharyngeal reflux [27] that could primarily cause cough. In an open study in 25 patients complaining of PNDS with radiological evidence of rhinosinusitis associated with cough, we found that after 6 weeks of treatment with topical corticosteroids, topical antihistamines, and a topical anticholinergic, only ten patients reported an improvement in cough with no effect in the other patients (unpublished data). There is some controversy as to whether cough in conditions usually associated with the production of mucus such as COPD or bronchiectasis should be suppressed as this could lead to mucus accumulation with increased risk of lung infections. In both COPD and bronchiectasis, an enhanced cough reflex has been demonstrated [28,29], and therefore part of the excessive cough which has been demonstrated in COPD patients with the use of cough counters [30] may be related to an enhanced cough reflex. In the use of antitussives in these conditions, a fine balance may be needed to inhibit excessive coughing while leaving the protective response intact. Nevertheless, there is great interest in developing antitussives for COPD. 5. The enhanced cough reflex The sensory receptors and pathways regulating cough continue to be the subject of investigation, and are likely to be abnormally regulated in chronic cough [31]. One of the important observations to derive from studies of patients with persistent cough is the presence of an increased tussive response to inhaled irritants such as capsaicin or citric acid. This process of ‘sensitization’ may invoke both ‘peripheral’ and/or ‘central’ mechanisms. Central sensitization may occur by integration of signals from various sensory nerve subtypes in the central nervous system to initiate exaggerated reflexes and sensation [32]. Substance P may represent an important central mechanism for sensitization of the cough reflex, and its persistence. In a model of allergic inflammation, neuroplastic changes in the response of vagal primary afferent neurones are present, such that Ad mechanosensors release substance P, when under normal conditions they do not [33]. Substance P in the nucleus tractus solitarius can increase bronchopulmonary C fibre reflex activity [34]. Peripheral mechanisms of heightened cough reflex may occur also through the increased expression of substance P in ganglionic neurones or through the modulation of ion channel expression (e.g. TRPV1 receptors) in vagal afferents or through the release of inflammatory mediators such as prostaglandins or bradykinin that could enhance the response of the cough receptor [35,36]. This concept of cough sensitization may underlie the persistence of cough (Fig. 1). There may be two mechanisms that may be separate. For example, the acute phase of the cough may be caused by a respiratory virus or by an

episode of GORD through direct stimulation of cough receptors. The inducing agent may also be involved in the process of sensitization that may now contribute to a more persistent cough. The initiating event may now have disappeared, leaving a persistent cough with or without apparent cause. This could form the basis for idiopathic cough, or for a cough that does not respond to specific therapies of associated cause(s). The initial episode of cough itself may contribute to sensitization. According to this hypothesis, a non-specific approach to cough suppression is always necessary. Studies of the mechanisms of sensitization have led to the identification of several targets that could lead to the development of potential antitussives. 6. Non-specific antitussives in clinical trials Codeine is probably the most commonly prescribed opioid-derived antitussive. Although previous studies have recorded antitussive activities against induced cough in normal volunteers [37], more recent studies have shown that it is ineffective against the acute cough of the common cold [38], or against the cough of COPD patients [39]. These more recent studies provide conflicting results from earlier studies in which codeine was reported to be effective [40,41]. The non-narcotic antitussive, dextromethorphan, has been demonstrated to have some effect on cough associated with upper respiratory tract infections; but in this study where cough counts were measured, a reduction of 17% in cough counts compared with placebo was reported [42]. Whether this degree of reduction is noticeable by the patient is not reported. The main issue with the opioids such as morphine, diamorphine, and codeine is that any potentially effective dose is usually associated with physical dependence, respiratory depression and gastrointestinal colic. The use of morphine and diamorphine has been restricted to the severe distressing cough (usually with pain and distress) that often occurs in advanced lung cancer, at doses that cause sedation, respiratory depression and constipation. Recent use of slow-release morphine tablets in chronic intractable cough has shown a small effect on cough as measured by visual analogue scale or by quality of life measures, without effect on capsaicin C2 values [43]. This raises the issue that the small positive effects could have resulted from the well-known sedating and euphoric effects of opiates. The potential addictive effects of morphine should not be underestimated. 7. Potential new classes of antitussives Potentially new antitussive therapies have been reviewed [44]. 7.1. Nociceptin Nociceptin/orphanin is the endogenous peptide ligand for the orphan ‘‘opioid like’’ NOP1, which is a

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Acute cough

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Resolution

Cause Viruses Acid reflux Dust etc.

Sensitisation Damage

Chronic cough

Fig. 1. Persistence of cough results from sensitization or damage of afferent pathways, while the inciting cause induces acute (transient) cough by direct stimulation of afferent cough pathways. The physical act of coughing may itself perpetuate cough.

G-protein-coupled seven transmembrane receptor and does not act through any of the known opioid receptors. It attenuates capsaicin-induced bronchoconstriction, an action possibly due to inhibition of tachykinin release from sensory C-fibres. Nociceptin administered intravenously or via the intracerebroventricular route suppresses capsaicinand mechanically induced cough [45,46]. A clinical trial of nociceptin is underway in acute cough. 7.2. Tachykinin receptor antagonists Tachykinins are present in capsaicin-sensitive primary afferent nerves and their effects are mediated via tachykinin receptor subtypes, NK1R, NK2R, NK3R. Tachykinins have also been implicated in the central ‘sensitization’ of cough and, in the guinea-pig, an NK2 and NK3 receptor antagonist, SR48968, inhibited citric-acid induced cough, while an NK1 receptor antagonist was ineffective [47,48]. However, studies in man have been negative so far. A study in asthmatic subjects found no effect of CP-99,994 against bronchoconstriction and cough induced by hypertonic saline [49]. In a recent study of a dual NK1-NK2 antagonist, DNK333, no effect was found on chronic dry cough of COPD patients (unpublished data). Perhaps, more studies need to be performed, particularly with the potential of central sensitization as a mechanism for chronic cough. 7.3. TRPV1 antagonists Transient receptor potential vallinoid receptor (TRPV)-1 is an ionotropic receptor that serves as a non-selective cation channel resulting in membrane depolorization present on subpopulations of primary afferent neurones. The TRPV-1 receptor is localized to small-diameter afferent neurones in dorsal root and vagal sensory ganglia and is stimulated by protons, the endogenous receptor agonist of TRPV-1, an endogenous eicosanoid, anandamide, and inflammatory mediators such as 12-HPETE and LTB4. TRPV-1 channel activity is strongly modulated by the action of inflammatory mediators such as prostaglandins and bradykinin, through a protein kinase A or Cmediated receptor phosphorylation [50,51]. There is an increase in expression of TRPV-1 on airway epithelial nerves of patients with chronic cough [52]. Capsazepine is

one of the first receptor antagonists of TRPV1 available, and it blocks capsaicin- and citric acid-induced cough [53]. Better TRPV-1 antagonists have been developed, and although being tried mostly as an analgesic, they are being developed as antitussives [54]. 7.4. Potassium channel openers Several potassium channels are located on vagal sensory neurones. A benzimidazalone compound, NS1619, is an opener of a large conductance Ca2+-activated channel (BKCa). It inhibits citric acid-induced cough and the generation of action potentials in the guinea pig tracheal Ad- and C-fibres stimulated by hyperosmolality [55]. These effects are prevented by iberiotoxin, a BKCa channel selective blocker. An ATP-sensitive K+ channel opener, pinacidil, also inhibits cough induced by capsaicin in the guinea-pig, an effect reversed by the ATP-sensitive K+ channel blocker, glibenclamide [55]. Moguistine may work as an ATP-sensitive K+ channel opener [56]. Phase II studies have shown a reduction in cough frequency in chronic bronchitis, but there has been no further development. Hypotension may be a problem. 7.5. Chloride channels and diuretics Isotonic solutions of low chloride concentrations can stimulate action potential discharge of a subpopulation of Ad- and C-fibres in guinea pigs, and activates afferent fibres in the dog. In guinea pigs, frusemide and Clinhibitors inhibit citric acid-induced cough [57] while in man, the diuretic frusemide, an inhibitor of the Na+/K+/ Cl co-transporter, inhibits cough induced by low chloride content solutions but not by capsaicin [58]. Frusemide inhibits to some extent airway afferent action potential discharge, and sensitizes slowly adapting pulmonary stretch receptors and desensitizes rapidly adapting receptors in rat airways [59]. The mechanism by which frusemide works is unknown [60], and a clinical trial with frusemide in cough is needed. 7.6. Methylxanthines Theobromine has been recently shown to inhibit citric acid-induced cough in guinea-pigs and capsaicin-induced

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cough in normal volunteers [61]. However, it has not been tried yet in patients with chronic cough. This comment applies to all potential antitussives in that effectiveness of the agent in normal volunteers does not guarantee effectiveness in patients with chronic cough, since the cough reflex pathway is altered in chronic cough. A recent Cochrane meta-analysis found that no proper controlled studies have been conducted on the effect of methylxanthines on cough in children, and recommended that such studies be carried out [62]. There have been no studies of phoshodiesterase (PDE) inhibitors although a study in guinea pigs showed that a PDE4 inhibitor was more effective than aminophylline in inhibiting cough associated with allergic inflammation [63]. 8. Potential antitussives from clinical observations Several potential antitussives for chronic cough have been reported in the medical literature as case reports or open uncontrolled studies, that are worth reviewing. Baclofen used as an anti-spasticity agent and also an agonist of the GABAB receptor has been reported to cause a small beneficial effect in two patients with chronic cough [64]; the potential use of this compound is further supported by its ability to inhibit capsaicin-induced cough in normal subjects [65]. Interestingly, a range of centrallyacting drugs has been reported to control cough in groups of patients in whom other measures have been unsuccessful. In five patients with cancer complaining of intractable cough not responding to codeine or morphine and of pruritius, paroxetine, a serotonin reuptake inhibitor used for treatment of depression, was particularly effective [66]. There are positive reports of the effects of the tricyclic antidepressant, amitryptiline, in 12 patients and of gabapentin and carbamazepine, anti-epileptic drugs, in two and one patient, respectively [67–69]. The need for further studies on the antitussive effects of these agents is supported by their use in the treatment of neuropathic pain, and there are similar processing peripheral and central mechanisms for chronic cough and chronic pain that could be controlled by these drugs [70]. In addition, it is also possible that similar processing mechanisms pertain to the sensation of dyspnoea, such that if cough and dysponea were associated together as in COPD or in advanced lung cancer, a potential non-specific antitussive might also improve dyspnoea (and also pain). Lignocaine aerosol could be investigated for control of intractable bouts of cough, since this was shown to be quickly effective in 62 patients with COPD [71]; nebulized terbutaline was equally effective. One particular treatment reported in five patients illustrates the fact that cough is a symptom that results not only from a central sensitization process but from direct irritation of the epithelial mucosa. Five patients who experienced cough while in the supine position were shown to demonstrate large airway collapse while supine, and their cough was suppressed by the use of nasal continuous positive airway pressure [72].

9. Why have there been no new antitussives introduced? The recently- updated guidelines of the American College of Chest Physicians on the investigation and management of cough in adults and children note that over half of the recommendations particularly pertaining to treatments are based more on opinion than on evidence, using evidence based on non-randomized, case-control or observational studies [73]. This indicates (at least in the published literature so far) that good randomized placebocontrolled, double-blind studies of antitussives are lacking. One should analyse the potential reasons for this, which could include a perceived lack of unmet needs in chronic cough, a lack of potential agents as antitussives, a feeling that no good end-points can be reliably measured, and a lack of interest from clinicians and pharmacologists to developing antitussives. As discussed above, there is no lack of potential agents that could be tried, and certainly no lack of interest from clinicians and pharmacologists to developing more effective indirect antitussives since there is a clinical unmet need there. There are significant populations of patients with chronic cough whose cough are not controlled using available management guidelines. However, there are issues as to what type of patients should be included for studies of non-specific antitussives. It is clear that if the agent was aimed at treating specifically GORD as a specific antitussive, patients with GORD and chronic cough would be recruited. However, such a specific category of patients with cough should probably not be used for a trial of a non-specific antitussive. So what about the type of cough patient for clinical trials of non-specific antitussives? I think the population that needs to be studied should include patients with a persistent cough despite adequate treatment of any associated causes or without an associated cause; those with a diagnosis of asthma should be excluded. They all should demonstrate a certain level of hypertussive response (e.g. using capsaicin challenge) and of documented cough counts (e.g. using a portable cough counter). One may wish to study patients with a certain level of severity of chronic cough on the basis of a certain number of cough counts or of the degree of hypertussive cough reflex. The common denominator here is the presence of a cough sensitization process. Given the size of the cohort that may be needed for such studies, it is likely that such studies will be multicentric, involving several cough clinics. Other categories of patient could be specifically COPD patients with a level of chronic cough that is causing a deterioration of quality of life. Studies using the post-viral acute cough probably reflect a different ‘type’ of cough from COPD: firstly, it is usually transient, which also poses issues of recruitment of volunteers at the right window of opportunity, and secondly the mechanisms of acute cough are likely to be different from those of chronic cough. Perhaps, the most important hurdle until recently has been the uncertainty of the outcome measures for such a

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study. Assessment of cough has often been on the basis of unvalidated measures of patient’s perceptive response or on the basis of a tussive challenge. Over the last 5–10 years, several tools needed for the assessment of cough have been developed and validated including cough-specific quality of life questionnaires, objective cough counts, and cough challenges that can be used in clinical trial environments [74]. The ability to make cough counts using ambulatory systems that can automatically record and analyse cough events has been an advance, and represents a objective assessment of the severity of cough. In terms of clinical trials of antitussives, what is not clear is how much of a reduction in the frequency of cough would be deemed to be clinically significant for the patient. For this reason, cough count is not the only aspect of cough that is important because the perceived severity by the patient is needed, and validated quality of life questionnaires are now available to assess this. Finally, useful complementary information can be obtained by measuring cough responses to tussive agents such as citric acid or capsaicin: in many instances, one would expect anti-tussive agents to reduce the hypertussive response of chronic cough [17]. 10. Conclusion There is a desperate need for new effective antitussive drugs since many patients do not respond to treatment of the associated cause of their cough and also often the cough is idiopathic. In addition, current antitussives such as the opioid-based antitussives are only efficacious at doses that cause side-effects. Potential antitussives of several classes are available, but they need to be tested in cough patients who have an enhanced cough reflex. The time has come to proceed to well-designed placebocontrolled double-blind trials of these potential agents, in a similar way that trials of therapies for asthma and COPD have been carried out over the last 2–3 decades. These latter studies have made a great impact on the way we now manage these conditions.

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