Prescribing the right therapy for the treatment of chronic cough: a critical focus on current and investigational options

KEYWORDS:

• Chronic cough
• P2X3 receptor antagonists
• pharmacotherapy

1. Introduction

Chronic cough is a debilitating condition resulting in patients coughing hundreds to thousands of times per day [1]. Although chronic cough has been defined in the 2000s as cough lasting for more than 8 weeks in adults and 4 weeks in children [2,3], according to the current European Respiratory Society (ERS) guidelines, defining a chronic cough on the basis of longevity is an evident arbitrary paradigm [4]. However, despite these definitions, there is no consensus on the real prevalence of chronic cough in the community, although it is estimated that around 12% of the general population may be affected and certainly cough remains one of the most common symptoms for which patients seek medical attention [5].

Chronic cough is an important symptom associated with several respiratory disorders, such as asthma, eosinophilic bronchitis, chronic obstructive pulmonary disease (COPD), postnasal drip syndrome, upper airway cough syndrome secondary to rhinosinus diseases, and interstitial lung diseases (ILDs), along with non-respiratory disorders such as gastroesophageal reflux disease (GORD), that should be ruled out or treated according to specific algorithms to assess whether chronic cough is a separate entity or it is related to other comorbidities [5,6]. For example, in certain patient populations, the use of drugs such as the angiotensin-converting enzyme (ACE) inhibitor for the treatment of hypertension may result in chronic cough as a frequent adverse event [6]. Moreover, but of no less importance, smoking habits can be a major remediable cause of chronic cough, most frequently in patients with COPD [4].

Unfortunately, the current investigations and treatment algorithms of chronic cough are mainly based on expert opinions or consensus, with few data originating from well-designed randomized clinical trials (RCTs) [4,5]. Being a symptom and not a diagnosis, chronic cough should be considered itself a treatable trait of other disorders that often have not been yet diagnosed [7]. Thus, in the majority of patients from a pharmacological and clinical point of view, the first step to treat chronic cough is to diagnose and treat the underlying disease appropriately.

2. Expert opinion

Since the diagnosis of asthma is based on clinical evaluation, no consensus exists on sensitive and specific biomarkers linking chronic cough with asthma. However, eosinophilic inflammation assessed via either sputum eosinophilia, blood eosinophilia, or exhaled nitric oxide could represent a suitable biomarker to help in directing the treatment of patients with asthma [4]. In patients with asthma with proven eosinophilic inflammation, anti-inflammatory or bronchodilator agents could be used to treat chronic cough. However, the quality of evidence for the usefulness of these drugs has been ranked as low, based on a small number of short-term trials with inhaled corticosteroids (ICS) and bronchodilators in both children and adults with chronic cough. Short-term trials with leukotriene receptor antagonists have also been suggested, but to date only in adults with chronic cough, and with modest success [4]. On the other hand, there is moderate quality of evidence from short-term trials with ICS plus long-acting bronchodilator combinations in patients with COPD [4,8].

The role of GORD remains controversial as a cause of chronic cough. It has been demonstrated that acid reflux secondary to GORD was weakly related with chronic cough [9]. Interestingly, however, nonacid reflux has also been suggested to have a potential role in chronic cough [10]. Furthermore to date, it is not possible to exclude that chronic cough could be related to oesophago-pharyngeal reflux rather than GORD [4]. As expected, therefore, the use of anti-acid drugs, such as proton-pump inhibitors and H₂-receptor antagonists, should not be used to treat chronic cough, although the quality of evidence for this recommendation is low [4]. Unfortunately, no evidence is currently available concerning the efficacy of drugs with promotility activity, such as baclofen, metoclopramide, and domperidone, to treat chronic cough in patients with nonacid reflux [4].

Upper airways cough syndrome (UACS) refers to different signs and symptoms associated with postnasal drip syndrome, rhinitis, and rhinosinusitis [11]. UACS may act as a trigger for hypersensitivity to chronic cough, reflecting a condition of airway inflammation resulting from asthma and/or airway reflux [4]. The common usage of H₁-receptor antagonists to treat chronic cough is based on decades of clinical experience. Nevertheless, no strong scientific evidence is available on the efficacy of H₁-receptor antagonists as a treatment for chronic cough in patients suffering by UACS, although it is thought that the first-generation H1-receptor antagonists may have antitussive properties since they, but not second-generation H₁-receptor antagonists, penetrate the central nervous system where they may exert some anticholinergic activity [12].

ILDs are poorly responsive to general antitussive treatments, although some benefits have been noted following treatment with pirfenidone in an open-label study and for a novel formulation of sodium cromoglicate in a proof-of-concept study in patients with idiopathic pulmonary fibrosis accompanied by chronic cough [13,14].

Concerning patients with iatrogenic cough, since ACE inhibitors increase the sensitivity of the cough reflex in some subjects, these medications should be administered with caution to patients with history of chronic cough or withdrawn if chronic cough occurs after their administration.

Chronic cough has also been shown to decrease after smoking cessation, although it is important to consider that cough sensitivity may be enhanced within the initial 2 weeks after smoking cessation [15,16]. Nonetheless, despite the appropriate treatment of any underlying comorbidity, a certain percentage of patients are affected by refractory or unexplained chronic cough, a condition in which cough persists despite the treatment of the underlying disease according to the current international guidelines and recommendations [4,5,17]. In this difficult to treat population, several drug classes that have not been approved for the treatment of cough have been investigated as possible treatments, including both opioids and non-opioids agents [18].

Across opioids, although codeine is usually used to treat cough, the current data concerning efficacy are limited and conflicting in patients with refractory or unexplained chronic cough, and the occurrence of adverse events has been reported [18]. Conversely, morphine is effective on most, but not all, the patients affected by refractory or unexplained chronic cough [18] and therefore morphine has been strongly recommended based on a moderate level of evidence [4]. However, the use of morphine should be carefully assessed as a long-term treatment with this drug, even with low-dose slow-release formulations, which may be associated with common adverse events, such as somnolence, constipation, and an increased risk of drug addiction. Furthermore, the regular use of morphine is under strict regulatory controls worldwide, as a controlled drug [18,19].

Gabapentin and pregabalin are gamma aminobutyric acid (GABA) analogues that can bind to the voltage-gated calcium channels, leading to the inhibition of central neurotransmitter release [18]. These neuromodulator drugs are usually administered to manage pain and epilepsy. However, several studies have demonstrated a certain level of effectiveness of these agents in the treatment of patients with refractory or unexplained chronic cough, and a trial with gabapentin or pregabalin has been suggested in such patients, although the quality of evidence remains low [4].

The effect of the novel P2X3 receptor antagonist gefapixant administered at 15 mg and 45 mg BID has been investigated in two large RCTs enrolling more than 2000 patients suffering from refractory or unexplained chronic cough (COUGH-1 and COUGH-2) [20]. Gefapixant at the higher dose significantly reduced the 24 h cough frequency vs. placebo in both the RCTs, showing a favorable safety profile reporting a similar frequency of serious adverse events in treatment and placebo groups, although a greater frequency of taste-related adverse events was recorded with gefapixant 45 mg compared to placebo [20].

Detailed information concerning the strength of recommendation and quality of evidence of neuromodulator drugs for the treatment of refractory or unexplained chronic cough is shown in Table 1.

Table 1. Strength of recommendation and quality of evidence of neuromodulator drugs for the treatment of refractory or unexplained chronic cough as reported by international guidelines and recommendations [4,5,17]

	Recommendation			Updated quality of current evidence according with GRADE
	Smith and Woodcock, 2016 (NEJM) [5]	Gibson et al., 2016 (CHEST) [17]	Morice et al., 2020 (ERS) [4]
Drugs included in the current guidelines and recommendations
Low-doses slow-release morphine	Recommended	Not recommended	Strong recommendation	+++
Codeine	Not reported	Not reported	Not recommended	/
Gabapentin	Recommended	Recommended	Conditional recommendation	++
Pregabalin	Recommended	Not reported	Conditional recommendation	++
Investigational drug
Gefapixant 45 mg	NA	NA	NA	++++

ERS: European Respiratory Society; GRADE: Grading of Recommendations Assessment, Development, and Evaluation; NA: not applicable, waiting for approval; NEJM: New England Journal of Medicine; /: not calculable; ++: low quality; +++: moderate quality; ++++: high quality.

The pooled analysis of COUGH-1 and COUGH-2 studies [21] reported a percentage estimated relative reduction of 18.6 (95%CI 9.2–27.1) for gefapixant vs. placebo in the 24 h cough frequency. Considering that the degree of cough reduction required to be considered a minimal clinically important difference (MCID) has been identified between 20% and 30% [22], the question whether the beneficial effect elicited by gefapixant, although statistically significant, may lead to real clinical impact remains open. Effectively, the U.S. Food and Drug Administration has issued a complete response letter regarding the new drug application for gefapixant for the treatment of refractory or unexplained chronic cough, requesting additional information related to measurement of efficacy [23].

The COUGH-1 and COUGH-2 studies [20] reported also a very large and unexpected placebo response. Although such a placebo effect could be related with the neurobiological mechanisms and psychological effects of immersion in a clinical environment, we cannot exclude that the beneficial placebo effect was due to better-than-usual clinical monitoring and patient care by the study investigators during the trial period [24,25]. This suggests that a significant and possibly clinically appreciable reduction in cough frequency may be achieved simply by increasing the intensity and quality of medical care provided by physicians, regardless of any pharmacological treatment, and that the patients enrolled in the COUGH-1 and COUGH-2 studies [20] probably suffered from a less severe form of refractory or unexplained chronic cough than that detected at baseline.

Indeed, the current findings of the COUGH-1 and COUGH-2 studies [20,21] should be interpreted with caution since they result from Abstracts at ERS and American Thoracic Society Congresses and ClinicalTrials.gov records (NCT03449134, NCT03449147), with no peer-reviewed publication currently available. In any case, the Japan Ministry of Health, Labor and Welfare has recently approved gefapixant 45 mg for adults with refractory or unexplained chronic cough [23]. Certainly, the further development of this drug and other P2X3 receptor antagonists is eagerly awaited, since there remains a clear unmet need in treating chronic refractory cough in patients who have had other potential causes of their cough excluded.

To date, refractory of unexplained chronic cough may be treated only with the unapproved use of neuromodulators, such as the GABA analogues, gabapentin, and pregabalin, as well as the opioid morphine. However, the position of the current guidelines and recommendations [4,5,17] on the use of neuromodulators are sometimes conflicting, mainly because of the limited data from RCTs supporting a real clinical benefit of gabapentin, pregabalin, and low doses of morphine [5]. Sequential therapeutic trials of each drug has been suggested [4], and the treatment should be stopped if no response is detected. However, such an approach should be strictly agreed with the patient since, when effective as often, these drugs can take weeks or even months to show a beneficial effect. The availability of novel effective drugs for the treatment of refractory or unexplained chronic cough is eagerly awaited.

Declaration of Interest

P Rogliani, C Page and L Calzetta have all acted as consultants for Merck Sharp and Dohme. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

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Funding

This manuscript has not been funded.