Advertisement

Management of chronic refractory cough in adults

  • Dina Visca
    Affiliations
    Istituti Clinici Scientifici Maugeri IRCCS, Respiratory Rehabilitation of the Institute of Tradate, Tradate, Varese, Italy

    Department of Medicine and Surgery, Respiratory Diseases, University of Insubria, Varese-Como, Italy
    Search for articles by this author
  • Bianca Beghè
    Affiliations
    Section of Respiratory Diseases, Department of Medicine, University of Modena and Reggio Emilia, Modena, Italy
    Search for articles by this author
  • Leonardo Michele Fabbri
    Correspondence
    Corresponding author at: Section of Cardiorespiratory and Internal Medicine, Department of Medical Sciences, Azienda Ospedaliero Universitaria Sant'Anna. Via Aldo Moro 8, 44124 CONA-FERRARA, Italy.
    Affiliations
    Section of Cardiorespiratory and Internal Medicine, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
    Search for articles by this author
  • Alberto Papi
    Affiliations
    Section of Cardiorespiratory and Internal Medicine, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
    Search for articles by this author
  • Antonio Spanevello
    Affiliations
    Istituti Clinici Scientifici Maugeri IRCCS, Respiratory Rehabilitation of the Institute of Tradate, Tradate, Varese, Italy

    Department of Medicine and Surgery, Respiratory Diseases, University of Insubria, Varese-Como, Italy
    Search for articles by this author
Published:September 19, 2020DOI:https://doi.org/10.1016/j.ejim.2020.09.008

      Highlights

      • Chronic cough may be associated with known diseases or due to unknown causes.
      • Most disease-related chronic cough responds to treatment of the underlying disease.
      • If refractory to treatment of underlying disease, or of unknown cause, cough may benefit from neuromodulatory and non-pharmacologic therapy.
      • The main efficacy results of novel neuromodulatory are presented and discussed.

      Abstract

      Cough is a common respiratory symptom that is considered to be chronic when it lasts more than eight weeks. When severe, chronic cough may significantly impact an individual's quality of life, and such patients are frequently referred for specialist evaluation. Current international guidelines provide algorithms for the management of chronic cough: in most cases, treatment of the underlying disease is sufficient to improve or resolve cough symptoms. Severe chronic cough may significantly affect patients' quality of life and necessitate frequent referral for specialist evaluations. In this narrative review, we summarize non-pharmacologic and pharmacologic management of adult patients with chronic cough of known cause that persists after proper treatment (chronic refractory cough, CRC) or chronic cough of unknown cause in adult patients. If chronic cough persists even after treatment of the underlying disease, or if the chronic cough is not attributable to any cause, then a symptomatic approach with neuromodulators may be considered, with gabapentin as the first choice, and opioids or macrolides as alternatives. Speech pathology treatment and/or neuromodulators should be discussed with patients and alternative options carefully considered, taking into account risk/benefit. Novel promising drugs are under investigation (e.g. P2×3 inhibitors), but additional studies are needed in this field. Speech pathology can be combined with a neuromodulator to give an enhanced treatment response of longer duration suggesting that non-pharmacologic treatment may play a key role in the management of CRC.

      Keywords

      1. Introduction

      Cough is a physiological response to mechanical and chemical stimuli due to irritation of cough receptors located mainly in the epithelium of the upper and lower respiratory tracts, pericardium, esophagus, diaphragm, and stomach. A complex reflex arc through the vagus, phrenic, and spinal motor nerves to the expiratory musculature generates an inspiratory and forced expiratory effort to clear the airways [
      • McGarvey L.
      • Gibson P.G.
      What is chronic cough? Terminology.
      ]. Under pathological conditions of known and unknown etiologies, chronic refractory cough (CRC) may become a major medical problem because patients may need to undergo repeated examinations before reaching a diagnosis, and/or try several treatments with sometimes poor symptom control, worsening their quality of life and increasing economic burden.
      Cough is one of the most common respiratory symptoms to result in outpatient clinical referral. The initial assessment aims to classify duration and severity of the clinical presentation with guidelines from the American College of Chest Physicians (ACCP) listing three categories based upon duration: acute cough, lasting less than three weeks; subacute cough, lasting between three and eight weeks; and chronic cough, lasting more than eight weeks [
      • Irwin R.S.
      • French C.L.
      • Chang A.B.
      • Altman K.W.
      CHEST Expert Cough Panel
      Classification of cough as a symptom in adults and management algorithms: CHEST guideline and expert panel report.
      ,
      • Morice A.H.
      • Millqvist E.
      • Bieksiene K.
      • Birring S.S.
      • Dicpinigaitis P.
      • Domingo Ribas C.
      • et al.
      ERS guidelines on the diagnosis and treatment of chronic cough in adults and children.
      ,
      • Irwin R.S.
      • Baumann M.H.
      • Bolser D.C.
      • Boulet Ll-P
      • Braman S.S.
      • Brightling C.E.
      • et al.
      Diagnosis and management of cough executive summary: ACCP evidence-based clinical practice guidelines.
      ]. In the acute phase, when life-threating features are present, such as acute worsening of dyspnea, increased sputum production, hemoptysis, fever, and weight loss, management of underlying etiologies is an urgent priority. Sub-acute or chronic cough may become a bothersome symptom that significantly impairs quality of life, sometimes persisting for months or years after treatment.
      In order to optimize and select a treatment for chronic cough, and particularly CRC, current guidelines suggest applying a diagnostic algorithm to identify possible underlying diseases [
      • Irwin R.S.
      • French C.L.
      • Chang A.B.
      • Altman K.W.
      CHEST Expert Cough Panel
      Classification of cough as a symptom in adults and management algorithms: CHEST guideline and expert panel report.
      ,
      • Morice A.H.
      • Millqvist E.
      • Bieksiene K.
      • Birring S.S.
      • Dicpinigaitis P.
      • Domingo Ribas C.
      • et al.
      ERS guidelines on the diagnosis and treatment of chronic cough in adults and children.
      ,
      • Irwin R.S.
      • Baumann M.H.
      • Bolser D.C.
      • Boulet Ll-P
      • Braman S.S.
      • Brightling C.E.
      • et al.
      Diagnosis and management of cough executive summary: ACCP evidence-based clinical practice guidelines.
      ]. In the majority of cases, a number of associated conditions are identified [
      • Song W.-.J.
      • Chang Y.-.S.
      • Morice A.H
      Changing the paradigm for cough: does “cough hypersensitivity” aid our understanding?.
      ], most commonly upper airway cough syndrome (formerly named postnasal drip), asthma, gastroesophageal reflux, eosinophilic bronchitis, and intolerance to drugs such as angiotensin converting enzyme inhibitors. Other well known triggers and diseases associated with cough include cigarette smoking, occupational irritants, foreign bodies, chronic obstructive pulmonary disease (COPD), chest neoplasms, bronchiectasis, cystic fibrosis, and interstitial lung diseases. After excluding these causes, triggers and diseases, some patients may experience chronic cough of unclear etiology, which is called ‘chronic idiopathic cough’ or ‘unexplained chronic cough’. The term CRC has also been introduced, which includes cough that persists despite optimal treatment of the underlying disease(s) [
      • Irwin R.S.
      • French C.L.
      • Chang A.B.
      • Altman K.W.
      CHEST Expert Cough Panel
      Classification of cough as a symptom in adults and management algorithms: CHEST guideline and expert panel report.
      ,
      • Morice A.H.
      • Millqvist E.
      • Bieksiene K.
      • Birring S.S.
      • Dicpinigaitis P.
      • Domingo Ribas C.
      • et al.
      ERS guidelines on the diagnosis and treatment of chronic cough in adults and children.
      ,
      • Irwin R.S.
      • Baumann M.H.
      • Bolser D.C.
      • Boulet Ll-P
      • Braman S.S.
      • Brightling C.E.
      • et al.
      Diagnosis and management of cough executive summary: ACCP evidence-based clinical practice guidelines.
      ]. In this review we focus on the management of CRC of known or unknown cause in adults.
      Over the past decade, international guidelines have been developed to help physicians in clinical practice to diagnose, assess the severity of, and manage cough – particularly chronic cough [
      • Morice A.H.
      • Millqvist E.
      • Bieksiene K.
      • Birring S.S.
      • Dicpinigaitis P.
      • Domingo Ribas C.
      • et al.
      ERS guidelines on the diagnosis and treatment of chronic cough in adults and children.
      ,
      • Gibson P.
      • Wang G.
      • McGarvey L.
      • Vertigan A.E.
      • Altman K.W.
      • Birring S.S.
      • et al.
      Treatment of unexplained chronic cough: CHEST guideline and expert panel report.
      ]. These guidelines recommend identifying the potential causes of chronic cough and then suggest specific treatments for any underlying disease. Moreover, they address the treatment of cough in patients whose underlying disease remains unknown.
      The prevalence of chronic cough has been estimated as up to 13% of the general population, and may be associated with significant impairment of quality of life, together with anxiety and depression [
      • Birring S.S.
      • Prudon B.
      • Carr A.J.
      • Singh S.J.
      • Morgan M.D.L.
      • Pavord I.D
      Development of a symptom specific health status measure for patients with chronic cough: leicester Cough Questionnaire (LCQ).
      ,
      • Song W.-.J.
      • Chang Y.-.S.
      • Faruqi S.
      • Kim J.-.Y.
      • Kang M.-.G.
      • Kim S.
      • et al.
      The global epidemiology of chronic cough in adults: a systematic review and meta-analysis.
      ,
      • Chamberlain S.A.F.
      • Garrod R.
      • Douiri A.
      • Masefield S.
      • Powell P.
      • Bücher C.
      • et al.
      The impact of chronic cough: a cross-sectional European survey.
      ]. This is especially common in patients who undergo numerous consultations and/or unsuccessful therapeutic trials before getting the diagnosis unexplained chronic cough or CRC. Therefore, there is increasing interest in understanding possible mechanisms for these clinical conditions.
      In a previous perspective, we reviewed the definitions, mechanisms, and diagnosis of chronic cough in adults [
      • Spanevello A.
      • Beghé B.
      • Visca D.
      • Fabbri L.M.
      • Papi A
      Chronic cough in adults.
      ]. In this perspective we review the pharmacologic and non-pharmacologic management of chronic cough of known or unknown cause in adult patients.

      2. Cough hypersensitivity syndrome

      The European Respiratory Society (ERS) Task Force introduced the term ‘cough hypersensitivity syndrome’ in 2014, and defined it as a ‘clinical syndrome characterized by troublesome coughing triggered by low levels of thermal, mechanical or chemical exposure’ [
      • Morice A.H.
      • Millqvist E.
      • Belvisi M.G.
      • Bieksiene K.
      • Birring S.S.
      • Chung K.F.
      • et al.
      Expert opinion on the cough hypersensitivity syndrome in respiratory medicine.
      ]. In pathological conditions, inflammation of central and/or peripheral components of the cough reflex may be triggered by innocuous stimuli resulting in excessive coughing due to neuroinflammation defined as ‘cough reflex hypersensitivity’. Assuming cough hypersensitivity syndrome represents a common mechanism responsible for troublesome persistent cough of known or unknown causes, peripheral and central neural pathways for cough signal and receptors become new target for treatment and may help to understand clinical aspects of ‘difficult to treat cough’.
      The concept of cough hypersensitivity syndrome includes both chronic troublesome cough of known cause that remains troublesome even after treatment of the underlying cause (CRC), and chronic idiopathic cough with no identifiable cause.

      3. Which patients should be considered for speech pathology therapy and/or neuromodulatory therapy?

      Most chronic respiratory diseases can manifest with chronic cough as one of the symptoms, although chronic cough is rarely the dominant symptom and it usually responds to treatment of the underlying disease. Unfortunately, with the exception of asthma, in which respiratory symptoms including cough are largely reversible upon treatment, chronic cough due to other chronic respiratory diseases, such as COPD or bronchiectasis, only partially responds to specific treatment. However, unless the cough remains hacking and troublesome, this partial response is usually sufficient, and does not require additional speech pathology and/or neuro-modulatory treatment. In fact, in most cases (including chronic respiratory infections, pneumonia, bronchiectasis, interstitial lung diseases, cystic fibrosis or productive cough in COPD) cough should be reduced but not abolished as it is an important defense mechanism. In contrast, such additional treatment should be considered for patients with one or more of these diseases when chronic cough remains hacking and troublesome even after adequate treatment of the underlying disease, and in those with chronic hacking and troublesome cough of unknown origin [
      • Irwin R.S.
      • French C.L.
      • Chang A.B.
      • Altman K.W.
      CHEST Expert Cough Panel
      Classification of cough as a symptom in adults and management algorithms: CHEST guideline and expert panel report.
      ,
      • Morice A.H.
      • Millqvist E.
      • Bieksiene K.
      • Birring S.S.
      • Dicpinigaitis P.
      • Domingo Ribas C.
      • et al.
      ERS guidelines on the diagnosis and treatment of chronic cough in adults and children.
      ,
      • Irwin R.S.
      • Baumann M.H.
      • Bolser D.C.
      • Boulet Ll-P
      • Braman S.S.
      • Brightling C.E.
      • et al.
      Diagnosis and management of cough executive summary: ACCP evidence-based clinical practice guidelines.
      ]. This additional approach to treatment may be non-pharmacologic and/or pharmacologic.

      4. International guidelines for the treatment of chronic refractory cough

      The two most influential guidelines for the management of cough, and particularly CRC, are: 1) those developed [
      • Irwin R.S.
      • Baumann M.H.
      • Bolser D.C.
      • Boulet Ll-P
      • Braman S.S.
      • Brightling C.E.
      • et al.
      Diagnosis and management of cough executive summary: ACCP evidence-based clinical practice guidelines.
      ] and updated [
      • Irwin R.S.
      • French C.L.
      • Chang A.B.
      • Altman K.W.
      CHEST Expert Cough Panel
      Classification of cough as a symptom in adults and management algorithms: CHEST guideline and expert panel report.
      ] by the ACCP, and 2) those developed by the ERS [
      • Morice A.H.
      • Millqvist E.
      • Bieksiene K.
      • Birring S.S.
      • Dicpinigaitis P.
      • Domingo Ribas C.
      • et al.
      ERS guidelines on the diagnosis and treatment of chronic cough in adults and children.
      ]. The definitions, classification, diagnosis and differential diagnosis, assessment of severity, and management (non-pharmacologic and pharmacologic) are similar in these guidelines, and we refer the reader to the original documents for a detailed description. In this review we focus on the management of CRC of known and unknown origin, describing all available approaches, but highlighting whether or not they are recommended by guidelines.

      5. Non-pharmacologic treatment

      As mentioned above, coughing is the sudden expulsion of air from the lungs through the upper airways when the vocal cords are open [
      • McGarvey L.
      • Gibson P.G.
      What is chronic cough? Terminology.
      ,
      • Gibson P.
      • Wang G.
      • McGarvey L.
      • Vertigan A.E.
      • Altman K.W.
      • Birring S.S.
      • et al.
      Treatment of unexplained chronic cough: CHEST guideline and expert panel report.
      ,
      • Smith J.A.
      • Woodcock A
      Chronic cough.
      ]. The increased tension in the larynx is involved in phonation, respiratory function as part of the conducting airways, and swallowing, with laryngeal motor dysfunction at any point potentially leading to dysphonia and triggering chronic cough [
      • Smith J.A.
      • Woodcock A
      Chronic cough.
      ,
      • Chung K.F.
      • McGarvey L.
      • Mazzone S.S
      Chronic cough as a neuropathic disorder.
      ]. Voice problems and vocal cord dysmotility have been estimated in up to 40% of adults with chronic cough [
      • Vertigan A.E.
      • Theodoros D.G.
      • Gibson P.G.
      • Winkworth A.L
      Voice and upper airway symptoms in people with chronic cough and paradoxical vocal fold movement.
      ]. Singing, talking and shouting are the activities most frequently associated with increased tension of the larynx and may be identified as a trigger of chronic cough. Phonation may be associated with a decreased lower esophageal sphincter tone, which in turn can promote acid reflux from the stomach and stimulate pressure receptors in the larynx, resulting in chronic cough [
      • Perera L.
      • Kern M.
      • Hofmann C.
      • Tatro L.
      • Chai K.
      • Kuribayashi S.
      • et al.
      Manometric evidence for a phonation-induced UES contractile reflex.
      ], which, together with stimulation of pressure receptors in the larynx, may lead to chronic cough.
      The most common laryngeal motor dysfunction is vocal cord dysfunction (VCD), which consists of an involuntary vocal fold adduction during inspiration [
      • Vertigan A.E.
      • Theodoros D.G.
      • Gibson P.G.
      • Winkworth A.L
      Voice and upper airway symptoms in people with chronic cough and paradoxical vocal fold movement.
      ]. The link between voice problems and chronic cough is the rationale for the speech pathology approach in refractory cough [
      • Gibson P.G.
      • Vertigan A.E.
      Speech pathology for chronic cough: a new approach.
      ]. Indeed, speech therapy, breathing exercises, cough suppression techniques, and patient counseling have been tried in the management of chronic cough. A systematic review reporting five studies of such interventions showed improved cough severity and frequency, although few studies used validated cough measurement tools [
      • Chamberlain S.
      • Birring S.S.
      • Garrod R
      Nonpharmacological interventions for refractory chronic cough patients: systematic review.
      ]. The identification of specific components of this non-pharmacologic approach and its effectiveness on chronic cough was described by Vertigan et al. in a single-blind, randomized placebo-controlled trial [
      • Vertigan A.E.
      • Theodoros D.G.
      • Gibson P.G.
      • Winkworth A.L
      Efficacy of speech pathology management for chronic cough: a randomised placebo controlled trial of treatment efficacy.
      ]. Ninety-seven patients with refractory chronic cough were randomly assigned to the speech pathology intervention or placebo. Intervention consisted of four sessions over a two-month period by a qualified speech pathologist. The components of speech pathology treatment were education, vocal hygiene, cough suppressant strategies, and psychoeducational counseling. Chamberlain et al. conducted a multicenter randomized controlled trial in 75 patients with CRC, and observed an improvement in cough-specific quality of life (Leicester Cough Questionnaire) and cough frequency (Leicester Cough Monitor) as a consequence of implementing a combined physiotherapy and speech and language therapy intervention [
      • Chamberlain Mitchell S.A.F.
      • Garrod R.
      • Clark L.
      • Douiri A.
      • Parker S.M.
      • Ellis J.
      • et al.
      Physiotherapy, and speech and language therapy intervention for patients with refractory chronic cough: a multicentre randomised control trial.
      ].
      The educational component should determine the reasons for coughing and outline the possible negative consequences of ongoing chronic cough. Patients should understand the goals of therapy, which are to suppress cough despite the triggering sensation, and enhance patients’ ability to voluntarily control the cough. Patients are taught to substitute a competing response, such as a distraction technique, cough suppression swallow, or relaxed throat breathing in order to reduce laryngeal constriction. Psychoeducational counseling should support patients and their control over their cough, emphasizing that cough is a response to irritating stimuli rather than a phenomenon outside of their control. Vocal hygiene education aims to reduce or prevent laryngeal irritation by avoiding passive smoking, avoiding mouth breathing, and behavioral management of gastroesophageal reflux. Broaddus-Lawrence et al. documented that strategies to reduce coughing and throat clearing in individuals with voice disorders improved voice quality [
      • Broaddus-Lawrence P.L.
      • Treole K.
      • McCabe R.B.
      • Allen R.L.
      • Toppin L
      The effects of preventive vocal hygiene education on the vocal hygiene habits and perceptual vocal characteristics of training singers.
      ]. In addition, Solomon et al. found a beneficial effect on the larynx of adequate hydration, including attenuating or delaying elevation of phonatory threshold pressure [
      • Solomon N.P.
      • DiMattia M.S.
      Effects of a vocally fatiguing task and systemic hydration on phonation threshold pressure.
      ]. Further, Vertigan et al. found that speech pathology management was effective in terms of the global clinical assessment, symptom response and analysis of voice parameters [
      • Vertigan A.E.
      • Theodoros D.G.
      • Gibson P.G.
      • Winkworth A.L
      Efficacy of speech pathology management for chronic cough: a randomised placebo controlled trial of treatment efficacy.
      ].
      In a non-comparative study, Ryan et al. evaluated the presence of VCD in their participants and investigated the efficacy of speech pathology management for CRC in those with VCD. Subjects with VCD received speech pathology therapy from a speech pathologist in sessions every four weeks, which included education, vocal hygiene, cough suppression strategies, relaxed throat breathing techniques, and psychoeducational counseling [
      • Ryan N.M.
      • Vertigan A.E.
      • Gibson P.G
      Chronic cough and laryngeal dysfunction improve with specific treatment of cough and paradoxical vocal fold movement.
      ].
      The terminology of breathing exercises varies among studies, but breathing control/diaphragmatic breathing and relaxed breathing control techniques have all been described as aiming to relax the throat, neck, and shoulder muscles whilst increasing abdominal excursion and reducing upper chest movement. A non-comparative retrospective study by Murry et al. was the only one to include breathing exercises as a sole intervention rather than a composite package of care [
      • Murry T.
      • Branski R.C.
      • Yu K.
      • Cukier-Blaj S.
      • Duflo S.
      • Aviv J.E
      Laryngeal sensory deficits in patients with chronic cough and paradoxical vocal fold movement disorder.
      ]. Sixteen adults with chronic cough underwent 2–13 sessions of respiratory retraining exercises over a 4–23-week period. Patients with (VCD) and chronic cough reported an aberrant laryngeal sensation which tended to normalize following a limited course of respiratory retraining, with improvement in patients’ symptoms.
      Ryan et al. documented a reduction in cough frequency following intervention using a validated objective outcome measure, the Leicester Cough Monitor [
      • Ryan N.M.
      • Vertigan A.E.
      • Bone S.
      • Gibson P.G
      Cough reflex sensitivity improves with speech language pathology management of refractory chronic cough.
      ,
      • Birring S.S.
      • Fleming T.
      • Matos S.
      • Raj A.A.
      • Evans D.H.
      • Pavord I.D
      The Leicester Cough Monitor: preliminary validation of an automated cough detection system in chronic cough.
      ]. Seventeen adults with chronic cough were assessed before, during, and after speech language pathology intervention by a qualified speech language pathologist over a period of 14–18 weeks.. This intervention also reduced laryngeal irritation, with subsequent lower cough sensitivity and lower urge to cough, whereas the cough threshold increased.
      Patel et al. evaluated the effectiveness of outpatient-based cough physiotherapy in a pilot prospective observational study [
      • Patel A.S.
      • Watkin G.
      • Willig B.
      • Mutalithas K.
      • Bellas H.
      • Garrod R.
      • et al.
      Improvement in health status following cough-suppression physiotherapy for patients with chronic cough.
      ]. This study reported a significant reduction in cough frequency and an improvement in cough-related quality of life from the intervention, which consisted of education, counseling, cough control, breathing retraining, and vocal hygiene.
      According to current ERS guidelines, multi-component physiotherapy/speech and language therapy interventions should be considered for CRC patients who wish an alternative to drug treatment [
      • Morice A.H.
      • Millqvist E.
      • Bieksiene K.
      • Birring S.S.
      • Dicpinigaitis P.
      • Domingo Ribas C.
      • et al.
      ERS guidelines on the diagnosis and treatment of chronic cough in adults and children.
      ]. The ACCP guidelines recommend identifying patients with oral-pharyngeal dysphagia, or the presence of conditions associated with high risk of aspiration, as they are potential candidates for speech pathology treatment [
      • Irwin R.S.
      • Baumann M.H.
      • Bolser D.C.
      • Boulet Ll-P
      • Braman S.S.
      • Brightling C.E.
      • et al.
      Diagnosis and management of cough executive summary: ACCP evidence-based clinical practice guidelines.
      ].
      Despite the efficacy and advantages of speech pathology intervention, there is limited guidance in the literature as to when patients should be referred for treatment. Patients suitable for speech pathology intervention are those whose cough has persisted despite medical management. Speech pathology intervention may be particularly beneficial for patients with coexisting laryngeal disorders such as muscle tension dysphonia or inducible laryngeal obstruction [
      • Vertigan A.E.
      • Haines J.
      • Slovarp L
      An update on speech pathology management of chronic refractory cough.
      ].

      6. Pharmacologic treatment

      6.1 Neuromodulatory treatments

      Pathological mechanisms may affect central and peripheral neuromodulators or cause a hypersensitivity of the cough reflex. Most studies in CRC have focused on pharmacologic treatment or speech pathology treatment individually; few studies have evaluated the effectiveness of combined treatment. A randomized, double blind placebo-controlled trial by Vertigan et al. showed that combined treatment with pregabalin and speech pathology was more effective than speech pathology alone in terms of cough frequency, cough severity and cough-related quality of life [
      • Vertigan A.E.
      • Kapela S.L.
      • Ryan N.M.
      • Birring S.S.
      • McElduff P.
      • Gibson P.G
      Pregabalin and speech pathology combination therapy for refractory chronic cough: a randomized controlled trial.
      ]. In addition, the effect of the combined approach was still beneficial for the four weeks after cessation of pharmacological treatment (Fig. 1) [
      • Vertigan A.E.
      • Kapela S.L.
      • Ryan N.M.
      • Birring S.S.
      • McElduff P.
      • Gibson P.G
      Pregabalin and speech pathology combination therapy for refractory chronic cough: a randomized controlled trial.
      ].
      Fig. 1
      Fig. 1Mean (95% CI) cough severity visual analog scale by visit and treatment group. Reproduced and modified with permission from Vertigan et al., Chest 2016
      [
      • Vertigan A.E.
      • Kapela S.L.
      • Ryan N.M.
      • Birring S.S.
      • McElduff P.
      • Gibson P.G
      Pregabalin and speech pathology combination therapy for refractory chronic cough: a randomized controlled trial.
      ]
      .
      A number of agents, both opioid and non-opioid, are thought to suppress cough via activity on the central cough center [
      • Irwin R.S.
      • French C.L.
      • Chang A.B.
      • Altman K.W.
      CHEST Expert Cough Panel
      Classification of cough as a symptom in adults and management algorithms: CHEST guideline and expert panel report.
      ,
      • Morice A.H.
      • Millqvist E.
      • Bieksiene K.
      • Birring S.S.
      • Dicpinigaitis P.
      • Domingo Ribas C.
      • et al.
      ERS guidelines on the diagnosis and treatment of chronic cough in adults and children.
      ,
      • Morice A.H.
      • Millqvist E.
      • Belvisi M.G.
      • Bieksiene K.
      • Birring S.S.
      • Chung K.F.
      • et al.
      Expert opinion on the cough hypersensitivity syndrome in respiratory medicine.
      ,
      • Smith J.A.
      • Woodcock A
      Chronic cough.
      ]. They modulate the enhanced neural sensitization, which is the key component of CRC. Codeine is the opiate traditionally used for cough, but despite widespread use data are limited (and conflicting) regarding efficacy in chronic cough, and a range of side effects have been reported. In a double-blind, placebo-controlled crossover study by Smith et al., 21 patients with COPD were randomly assigned to codeine 60 mg twice a day or placebo for one day [
      • Smith J.
      • Owen E.
      • Earis J.
      • Woodcock A.
      Effect of codeine on objective measurement of cough in chronic obstructive pulmonary disease.
      ]. No significant difference was noted between the groups in cough counts or subjective cough scores, although the study size was small and the dose of codeine low [
      • Smith J.
      • Owen E.
      • Earis J.
      • Woodcock A.
      Effect of codeine on objective measurement of cough in chronic obstructive pulmonary disease.
      ]. While codeine is not effective in chronic refractory cough, and not recommended by ERS guidelines (Table 1) [
      • Morice A.H.
      • Millqvist E.
      • Bieksiene K.
      • Birring S.S.
      • Dicpinigaitis P.
      • Domingo Ribas C.
      • et al.
      ERS guidelines on the diagnosis and treatment of chronic cough in adults and children.
      ], it may be useful in prolonged cough persisting after acute respiratory infections, including COVID-19 [
      • Torjesen I.
      Covid-19: NICE advises against using NSAIDs for fever in patients with suspected cases.
      ].
      Table 1Summary of guideline recommended options for the pharmacologic treatment of chronic refractory cough
      • Irwin R.S.
      • French C.L.
      • Chang A.B.
      • Altman K.W.
      CHEST Expert Cough Panel
      Classification of cough as a symptom in adults and management algorithms: CHEST guideline and expert panel report.
      ,
      • Irwin R.S.
      • French C.L.
      • Chang A.B.
      • Altman K.W.
      CHEST Expert Cough Panel
      Classification of cough as a symptom in adults and management algorithms: CHEST guideline and expert panel report.
      ,
      • Smith J.A.
      • Woodcock A
      Chronic cough.
      .
      DrugsSmith and Woodcock 2016CHEST Guidelines 2018ERS guidelines 2020
      MorphineRecommendedDiscouragedRecommended
      GabapentinRecommendedRecommendedRecommended
      PregabalinRecommendedRecommendedRecommended
      TramadolNeither recommended nor discouragedNeither recommended nor discouragedNeither recommended nor discouraged
      CodeineNeither recommended nor discouragedNeither recommended nor discouragedNot recommended
      DextromethorphanNeither recommended nor discouragedNeither recommended nor discouragedNeither recommended nor discouraged
      AmitriptylineTo be consideredNeither recommended nor discouragedNeither recommended nor discouraged
      Morphine is effective in some but not all patients, and limited data are available from prospective studies. In a double-blind crossover trial by Morice et al., 27 patients who had a persistent cough of greater than three months duration and who had failed specific treatment were randomly assigned to receive slow-release morphine (5 mg twice daily) or placebo for four weeks. Morphine improved daily cough severity scores, although the cough reflex was unaltered [
      • Morice A.H.
      • Menon M.S.
      • Mulrennan S.A.
      • Everett C.F.
      • Wright C.
      • Jackson J.
      • et al.
      Opiate therapy in chronic cough.
      ]. Somnolence and constipation are common side effects, yet despite this morphine is recommended by guidelines (Table 1) [
      • Morice A.H.
      • Millqvist E.
      • Bieksiene K.
      • Birring S.S.
      • Dicpinigaitis P.
      • Domingo Ribas C.
      • et al.
      ERS guidelines on the diagnosis and treatment of chronic cough in adults and children.
      ,
      • Smith J.A.
      • Woodcock A
      Chronic cough.
      ].
      Tramadol is an opioid similar to codeine and morphine. A pilot prospective study by Dion et al. on 16 patients with neurogenic cough highlighted the antitussive properties of tramadol [
      • Dion G.R.
      • Teng S.E.
      • Achlatis E.
      • Fang Y.
      • Amin M.R
      Treatment of neurogenic cough with tramadol: a pilot study.
      ]. However, tramadol is neither recommended nor discouraged by guidelines (Table 1) [
      • Irwin R.S.
      • French C.L.
      • Chang A.B.
      • Altman K.W.
      CHEST Expert Cough Panel
      Classification of cough as a symptom in adults and management algorithms: CHEST guideline and expert panel report.
      ,
      • Morice A.H.
      • Millqvist E.
      • Bieksiene K.
      • Birring S.S.
      • Dicpinigaitis P.
      • Domingo Ribas C.
      • et al.
      ERS guidelines on the diagnosis and treatment of chronic cough in adults and children.
      ,
      • Smith J.A.
      • Woodcock A
      Chronic cough.
      ].
      Gabapentin and pregabalin are gamma aminobutyric acid (GABA) analogs that bind to the voltage-gated calcium channels and inhibit centrally neurotransmitter release. They are neuromodulators commonly used to control pain and epilepsy. Lee et al. reported data from 28 patients with chronic cough on the effectiveness of gabapentin: 68% had a clinically positive response, especially when laryngeal neuropathy was present; however, 17.8% complained of dizziness or somnolence [
      • Lee B.
      • Woo P.
      Chronic cough as a sign of laryngeal sensory neuropathy: diagnosis and treatment.
      ]. In addition, Mintz et al. described six cases in which gabapentin was administered for intractable cough; complete resolution or a significant improvement in cough was observed in five of these cases [
      • Mintz S.
      • Lee J.K.
      Gabapentin in the treatment of intractable idiopathic chronic cough: case reports.
      ]. Fatigue and drowsiness were reported as side effects [
      • Mintz S.
      • Lee J.K.
      Gabapentin in the treatment of intractable idiopathic chronic cough: case reports.
      ]. Further, in a randomized trial by Ryan et al. in 62 patients who had experienced CRC for more than eight weeks, treatment with gabapentin for 10 weeks significantly improved cough-specific quality of life (Leicester Cough Questionnaire score), cough severity (visual analogue scale) and cough reflex sensitivity (defined by quantity of capsaicin needed to induce five coughs) with limited side effects, most commonly nausea, confusion, dizziness, dry mouth and fatigue (Fig. 2) [
      • Ryan N.M.
      • Birring S.S.
      • Gibson P.G
      Gabapentin for refractory chronic cough: a randomised, double-blind, placebo-controlled trial.
      ]. After withdrawal of gabapentin, there was reduced effectiveness, in terms of Leicester Cough Questionnaire and mean cough severity, further supporting its antitussive effect.
      Fig. 2
      Fig. 2Mean efficacy variable score for gabapentin versus placebo, during and after treatment in terms of cough severity. The dose was escalated from Days 1–6, and reduced from Days 78–83. Treatment was stopped completely by Visit 4 (Week 12; dotted line). Reproduced and modified with permission from Ryan et al. Lancet 2012
      [
      • Ryan N.M.
      • Birring S.S.
      • Gibson P.G
      Gabapentin for refractory chronic cough: a randomised, double-blind, placebo-controlled trial.
      ]
      .
      In a recent randomized clinical trial by Dong et al. gabapentin was compared to baclofen in the treatment of suspected refractory gastro-esophageal reflux-induced chronic cough [
      • Dong R.
      • Xu X.
      • Yu L.
      • Ding H.
      • Pan J.
      • Yu Y.
      • et al.
      Randomised clinical trial: gabapentin vs baclofen in the treatment of suspected refractory gastro-oesophageal reflux-induced chronic cough.
      ]. Two hundred and thirty-four patients who failed an eight-week course of omeprazole and domperidone were recruited and randomly assigned to receive either gabapentin or baclofen for eight weeks. The authors concluded that the two drugs had similar therapeutic efficacy, but that gabapentin was preferable because of fewer side effects. These findings suggest that gabapentin does not act by reducing peripheral sensitization, but additional placebo-controlled randomized controlled trials are needed to explore how long a patient with CRC should remain on gabapentin to achieve resolution of symptoms. Gabapentin is recommended by current guidelines as a potential pharmacologic treatment for CRC (Table 1) [
      • Irwin R.S.
      • French C.L.
      • Chang A.B.
      • Altman K.W.
      CHEST Expert Cough Panel
      Classification of cough as a symptom in adults and management algorithms: CHEST guideline and expert panel report.
      ,
      • Morice A.H.
      • Millqvist E.
      • Bieksiene K.
      • Birring S.S.
      • Dicpinigaitis P.
      • Domingo Ribas C.
      • et al.
      ERS guidelines on the diagnosis and treatment of chronic cough in adults and children.
      ,
      • Smith J.A.
      • Woodcock A
      Chronic cough.
      ].
      Administration of pregabalin decreases levels of neurotransmitters such as glutamate, noradrenaline, and substance P [
      • Halum S.L.
      • Sycamore D.L.
      • McRae B.R
      A new treatment option for laryngeal sensory neuropathy.
      ]. In a case report by Li et al., pregabalin prescribed to alleviate postherpetic neuralgia also relieved the patient's chronic cough, with no serious adverse events reported after two years of follow-up [
      • Li J.
      • Ye L.
      Effect of pregabalin for the treatment of chronic refractory cough: a case report.
      ]. Halum et al. documented its effectiveness on laryngeal sensory neuropathy through a retrospective study in 12 consecutive patients [
      • Halum S.L.
      • Sycamore D.L.
      • McRae B.R
      A new treatment option for laryngeal sensory neuropathy.
      ]. The risk/benefit of pregabalin versus gabapentin for the treatment of CRC needs to be carefully considered. The magnitude of change in the Leicester Cough Questionnaire and cough severity in this pregabalin study was greater than the gabapentin study [
      • Ryan N.M.
      • Birring S.S.
      • Gibson P.G
      Gabapentin for refractory chronic cough: a randomised, double-blind, placebo-controlled trial.
      ,
      • Ryan N.M.
      A review on the efficacy and safety of gabapentin in the treatment of chronic cough.
      ], however, adverse effects were more common with pregabalin than with gabapentin. Some aspects of the study design may have amplified the differences between gabapentin and placebo. First, the known CNS effects of gabapentin might have impacted treatment masking, thus favoring gabapentin. Second, baseline cough frequency was higher in the gabapentin group, although not significantly, providing more ‘space’ for a positive effect. Third, the population examined was highly selected, possibly identifying the optimal target population, but limiting the use of gabapentin to very few patients in real life. In addition, pregabalin has a greater abuse potential than gabapentin, most likely due to its more rapid absorption and faster onset of action. Pregabalin is a treatment option recommended by current guidelines (Table 1) [
      • Irwin R.S.
      • French C.L.
      • Chang A.B.
      • Altman K.W.
      CHEST Expert Cough Panel
      Classification of cough as a symptom in adults and management algorithms: CHEST guideline and expert panel report.
      ,
      • Morice A.H.
      • Millqvist E.
      • Bieksiene K.
      • Birring S.S.
      • Dicpinigaitis P.
      • Domingo Ribas C.
      • et al.
      ERS guidelines on the diagnosis and treatment of chronic cough in adults and children.
      ,
      • Smith J.A.
      • Woodcock A
      Chronic cough.
      ].
      Dextromethorphan is probably the most commonly used non-opioid agent for cough; it is considered to have opiate properties [
      • Abdul Manap R.
      • Wright C.E.
      • Gregory A.
      • Rostami-Hodjegan A.
      • Meller S.T.
      • Kelm G.R.
      • et al.
      The antitussive effect of dextromethorphan in relation to CYP2D6 activity.
      ]. However, few studies have evaluated the efficacy of dextromethorphan in chronic cough, and those available were conducted in adults and used small sample sizes (16–99 patients in each study), with conflicting results [
      • Yancy W.S.
      • McCrory D.C.
      • Coeytaux R.R.
      • Schmit K.M.
      • Kemper A.R.
      • Goode A.
      • et al.
      Efficacy and tolerability of treatments for chronic cough: a systematic review and meta-analysis.
      ,
      • Matthys H.
      • Bleicher B.
      • Bleicher U.
      Dextromethorphan and codeine: objective assessment of antitussive activity in patients with chronic cough.
      ]. Due to the absence of appropriately designed and powered randomized clinical trials, dextromethorphan is neither recommended nor discouraged by guidelines [
      • Irwin R.S.
      • French C.L.
      • Chang A.B.
      • Altman K.W.
      CHEST Expert Cough Panel
      Classification of cough as a symptom in adults and management algorithms: CHEST guideline and expert panel report.
      ,
      • Morice A.H.
      • Millqvist E.
      • Bieksiene K.
      • Birring S.S.
      • Dicpinigaitis P.
      • Domingo Ribas C.
      • et al.
      ERS guidelines on the diagnosis and treatment of chronic cough in adults and children.
      ,
      • Smith J.A.
      • Woodcock A
      Chronic cough.
      ].
      Amitriptyline is a tricyclic antidepressant and inhibitor of serotonin reuptake that has been investigated by Jeyakumar et al. for the treatment of CRC due to post-viral vagal neuropathy [
      • Jeyakumar A.
      • Brickman T.M.
      • Haben M.
      Effectiveness of amitriptyline versus cough suppressants in the treatment of chronic cough resulting from postviral vagal neuropathy.
      ]. In this prospective, randomized, controlled study in 28 patients, the majority of patients receiving amitriptyline achieved a complete response, whereas none of those receiving the combination of codeine and guaifenesin responded [
      • Jeyakumar A.
      • Brickman T.M.
      • Haben M.
      Effectiveness of amitriptyline versus cough suppressants in the treatment of chronic cough resulting from postviral vagal neuropathy.
      ]. The authors do not report whether any patients experienced side effects during the study. Secondly, Bastian et al. conducted a prospective uncontrolled cohort study in 12 consecutive patients [
      • Bastian R.W.
      • Vaidya A.M.
      • Delsupehe K.G
      Sensory neuropathic cough: a common and treatable cause of chronic cough.
      ]. All patients were treated with a single dose of open label 10 mg of amitriptyline for 21 days. At least a 40% reduction in self-reported symptoms was recorded, suggesting that a trial of amitriptyline 10 mg (or of other anti-neuralgia type medications) may be helpful in chronic cough [
      • Bastian R.W.
      • Vaidya A.M.
      • Delsupehe K.G
      Sensory neuropathic cough: a common and treatable cause of chronic cough.
      ]. Finally, a retrospective case series by Norris et al. in 12 patients with recurrent laryngeal nerve sensory neuropathic symptoms documented improvement in neuropathic symptoms when treatment with amitriptyline over two months [
      • Norris B.K.
      • Schweinfurth J.M.
      Management of recurrent laryngeal sensory neuropathic symptoms.
      ]. Four patients with no response or intolerable side effects were prescribed gabapentin [
      • Norris B.K.
      • Schweinfurth J.M.
      Management of recurrent laryngeal sensory neuropathic symptoms.
      ]. Amitriptyline is neither recommended nor discouraged by guidelines (Table 1) [
      • Irwin R.S.
      • French C.L.
      • Chang A.B.
      • Altman K.W.
      CHEST Expert Cough Panel
      Classification of cough as a symptom in adults and management algorithms: CHEST guideline and expert panel report.
      ,
      • Morice A.H.
      • Millqvist E.
      • Bieksiene K.
      • Birring S.S.
      • Dicpinigaitis P.
      • Domingo Ribas C.
      • et al.
      ERS guidelines on the diagnosis and treatment of chronic cough in adults and children.
      ,
      • Smith J.A.
      • Woodcock A
      Chronic cough.
      ].
      Taking into account all the studies mentioned so far, several neuromodulators with at least one positive randomized controlled trial were evaluated. These therapies seem promising for the treatment of chronic cough. The CHEST Expert Cough Panel recommends only gabapentin (Table 1) [
      • Irwin R.S.
      • French C.L.
      • Chang A.B.
      • Altman K.W.
      CHEST Expert Cough Panel
      Classification of cough as a symptom in adults and management algorithms: CHEST guideline and expert panel report.
      ], the risk-benefit profile to be reassessed after six months before continuing the drug. ERS guidelines recommend a trial of low dose slow-release morphine (5–10 mg twice daily) in adults with CRC. They also suggest a trial of gabapentin or pregabalin in adults with CRC [
      • Morice A.H.
      • Millqvist E.
      • Bieksiene K.
      • Birring S.S.
      • Dicpinigaitis P.
      • Domingo Ribas C.
      • et al.
      ERS guidelines on the diagnosis and treatment of chronic cough in adults and children.
      ].
      In conclusion, there are few effective treatments for cough with an acceptable therapeutic ratio; more selective agents with a more favorable side effect profile are needed.
      A possible role of inhaled drugs in the management of CRC has been also investigated. Local anesthetics (e.g., lidocaine or bupivacaine) are currently used in the palliative management of cough associated with malignancies. In addition, an older study with ipratropium bromide reported a significant reduction in cough severity and a good safety profile in patients with chronic persistent cough, although the sample size was small (N = 14) and results have not been subsequently replicated [
      • Holmes P.W.
      • Barter C.E.
      • Pierce R.J.
      Chronic persistent cough: use of ipratropium bromide in undiagnosed cases following upper respiratory tract infection.
      ]. Subsequent preclinical research suggests that tiotropium can directly modulate airway sensory nerve activity and thereby the cough reflex, through a mechanism unrelated to its anticholinergic activity [
      • Birrell M.A.
      • Bonvini S.J.
      • Dubuis E.
      • Maher S.A.
      • Wortley M.A.
      • Grace M.S.
      • et al.
      Tiotropium modulates transient receptor potential V1 (TRPV1) in airway sensory nerves: a beneficial off-target effect?.
      ].

      6.2 Experimental pharmacologic neuromodulatory treatments

      The recognition that chronic cough is characterized by hypersensitivity of the peripheral and central neural pathways involved in cough has expanded the range of potential therapeutic targets currently under evaluation. A novel approach is to focus on molecular pathways rather than neural mechanisms [
      • Roe N.A.
      • Lundy F.T.
      • Litherland G.J.
      • McGarvey L.P.A
      Therapeutic targets for the treatment of chronic cough.
      ].
      The primary vagal fibers mediating cough are A-fibers and C-fibers, which are responsive to mechanical and chemical stimuli, respectively [
      • Mazzone S.B.
      • Undem B.J.
      Vagal afferent innervation of the airways in health and disease.
      ]. P2×3 receptors are expressed by airway vagal afferent nerves and contribute to the hypersensitization of sensory neurons [
      • Ford A.P.
      In pursuit of P2×3 antagonists: novel therapeutics for chronic pain and afferent sensitization.
      ]. Based on laboratory studies, increased sensitivity of P2×3 receptors on the airway sensory nerve fibers (e.g., vagal afferent C fibers) could mediate sensitization of the cough reflex and could therefore be a potential cause of refractory cough [
      • Abdulqawi R.
      • Dockry R.
      • Holt K.
      • Layton G.
      • McCarthy B.G.
      • Ford A.P.
      • et al.
      P2×3 receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo-controlled phase 2 study.
      ]. Adenosine triphosphate (ATP) plays a significant role in the activation of sensory C fibers, and this activation is inhibited by blockade of P2×3 and P2×2/3 receptors. In a randomized, cross-over trial of 24 patients with refractory cough, an investigational P2×3 antagonist, gefapixant, previously known as AF-219, decreased cough counts during the two-week study blocks by 75% compared with placebo [
      • Abdulqawi R.
      • Dockry R.
      • Holt K.
      • Layton G.
      • McCarthy B.G.
      • Ford A.P.
      • et al.
      P2×3 receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo-controlled phase 2 study.
      ]. However, taste disturbance was noted in all patients taking gefapixant and caused six patients to withdraw from the study; nausea was also common (38%). In a Phase 2, double-blind, two-period study by Morice et al. there was a reduction in the cough reflex in patients treated with gefapixant 100 mg [
      • Morice A.H.
      • Kitt M.M.
      • Ford A.P.
      • Tershakovec A.M.
      • Wu W.-.C.
      • Brindle K.
      • et al.
      The effect of gefapixant, a P2×3 antagonist, on cough reflex sensitivity: a randomised placebo-controlled study.
      ]. Two randomized, double-blind, placebo-controlled, two period crossover, dose-escalation studies by Smith et al. of gefapixant at lower doses has reported efficacy with fewer side effects [
      • Smith J.A.
      • Kitt M.M.
      • Butera P.
      • Smith S.A.
      • Li Y.
      • Xu Z.J.
      • et al.
      Gefapixant in two randomised dose-escalation studies in chronic cough.
      ]. Finally, in a multicenter randomized placebo-controlled parallel trial Smith et al. investigated the effect of gefapixant on chronic cough [
      • Smith J.A.
      • Kitt M.M.
      • Morice A.H.
      • Birring S.S.
      • McGarvey L.P.
      • Sher M.R.
      • et al.
      MK-7264, a P2×3 receptor antagonist, reduces cough frequency in patients with refractory chronic cough: results from a randomized, controlled, Phase 2b clinical trial.
      ]. Data are available only as an abstract, in which the authors describe a significant improvement in the cough frequency when compared to placebo [
      • Smith J.A.
      • Kitt M.M.
      • Morice A.H.
      • Birring S.S.
      • McGarvey L.P.
      • Sher M.R.
      • et al.
      MK-7264, a P2×3 receptor antagonist, reduces cough frequency in patients with refractory chronic cough: results from a randomized, controlled, Phase 2b clinical trial.
      ]. These results support a promising therapeutic target in development for P2×3 receptor hypersensitivity in refractory cough, but further study is needed to determine safety and efficacy in a larger number of patients.
      Transient receptor potential (TRP) channels are present in abundance in the airways and are expressed in many cell types of the airway including primary sensory afferent nerves, epithelial cells and smooth muscle cells [
      • Roe N.A.
      • Lundy F.T.
      • Litherland G.J.
      • McGarvey L.P.A
      Therapeutic targets for the treatment of chronic cough.
      ]. Several agents for pain are in development that target these receptors. However, since TRP channels are directly activated by changes in temperature, chemicals, mechanical stimulation, pH and osmolality, and may evoke cough, they been proposed also as treatments for chronic cough. Of particular interest in relation to cough are members of the vanilloid (TRPV1, TRPV4), anykrin (TRPA1) and melastatin (TRPM8) families. To date, pharmacologic modulation of TRP channels for the treatment of cough has been disappointing and remains to be investigated as a potential target for chronic cough. TRPV1 was the first channel to be considered as a key regulator of cough, but two Phase 2, double-blind crossover studies by Belvisi et al. and Khalid et al. on TRPV1 failed to show improvements in spontaneous cough frequency [
      • Belvisi M.G.
      • Birrell M.A.
      • Wortley M.A.
      • Maher S.A.
      • Satia I.
      • Badri H.
      • et al.
      XEN-D0501, a novel transient receptor potential vanilloid 1 antagonist, does not reduce cough in patients with refractory cough.
      ,
      • Khalid S.
      • Murdoch R.
      • Newlands A.
      • Smart K.
      • Kelsall A.
      • Holt K.
      • et al.
      Transient receptor potential vanilloid 1 (TRPV1) antagonism in patients with refractory chronic cough: a double-blind randomized controlled trial.
      ]. The TRPA1 channel is activated by a range of physical and chemical factors including cold temperatures, mechanical stimulation, inflammatory mediators and acrolein (a component of cigarette smoke). Although animal studies demonstrated effectiveness of TRPA1 antagonists in reducing cough in response to tussive challenges, in a double-blind placebo-controlled study in patients there was no reduction in cough frequency over 24 h, or no reduction in citric acid-induced cough [
      • Roe N.A.
      • Lundy F.T.
      • Litherland G.J.
      • McGarvey L.P.A
      Therapeutic targets for the treatment of chronic cough.
      ]. TRPV4 is recognized as an osmosensor and responds to diverse stimuli including non-noxious temperatures, shear stress and mechanical stimulation. A clinical trial with the TRPV4 antagonist, GSK2798745, was terminated early, presumably due to lack of efficacy [
      • Roe N.A.
      • Lundy F.T.
      • Litherland G.J.
      • McGarvey L.P.A
      Therapeutic targets for the treatment of chronic cough.
      ]. Finally, TRPM8 is activated by cooling compounds such as menthol, icilin and eucalyptol [
      • Roe N.A.
      • Lundy F.T.
      • Litherland G.J.
      • McGarvey L.P.A
      Therapeutic targets for the treatment of chronic cough.
      ].
      Voltage-gated sodium channels (NaV) mediate the initiation and propagation of action potentials in afferent sensory nerves and represent a potential therapeutic target for cough. Lidocaine, a non-selective NaV channel blocker, has been used clinically to alleviate cough and has been reported to be safe [
      • Lim K.G.
      • Rank M.A.
      • Hahn P.Y.
      • Keogh K.A.
      • Morgenthaler T.I.
      • Olson E.J.
      Long-term safety of nebulized lidocaine for adults with difficult-to-control chronic cough: a case series.
      ]. However, a Phase 2 double-blind crossover study using a novel blocker targeting a subtype selective inhibition of the NaV1.7 (GSK2339345) failed to illustrate an antitussive response [
      • Smith J.A.
      • McGarvey L.P.A.
      • Badri H.
      • Satia I.
      • Warren F.
      • Siederer S.
      • et al.
      Effects of a novel sodium channel blocker, GSK2339345, in patients with refractory chronic cough.
      ].
      The tachykinins, substance P, neurokinin A and neurokinin B are released both from the peripheral endings of afferent nerves (predominately C-fibers) and from central neural structures. The tachykinin receptor, neurokinin 1 receptor, has gained attention as a target for chronic cough treatment. In a Phase 2, double-blind study (VOLCANO-1) by Smith et al. on 244 patients, significant improvements in objective cough frequency and sustained reductions in daytime cough frequency were documented [
      • Smith J.
      • Allman D.
      • Badri H.
      • Miller R.
      • Morris J.
      • Satia I.
      • et al.
      The neurokinin-1 receptor antagonist orvepitant is a novel antitussive therapy for chronic refractory cough: results from a Phase 2 pilot study (VOLCANO-1).
      ].
      Nicotinic acetylcholine receptors, or nAChRs, respond to the neurotransmitter acetylcholine and to nicotine and are found in the central and peripheral nervous system. Dicpinigaitis et al. studied the alpha7 (α7) subtype of the nAChRs, which is responsible for the antitussive effect of nicotine through the activation of GABAergic interneurons in the brainstem [
      • Dicpinigaitis P.
      • Canning B.
      • DeVita R.
      • Perelman M.
      • Liu Q.
      • Hay D.
      • et al.
      The antitussive effects of alpha7 (α7) nicotinic receptor agonists.
      ].
      Azithromycin belongs to the class of macrolide antibiotics. It is commonly used in the treatment of a variety of infections, including community-acquired respiratory tract infections and mycobacterial infections, and macrolide antibiotics also have anti-inflammatory actions. Hodgson et al. investigated the potential effects of azithromycin on chronic cough in a randomized, double-blind, placebo-controlled study [
      • Hodgson D.
      • Anderson J.
      • Reynolds C.
      • Oborne J.
      • Meakin G.
      • Bailey H.
      • et al.
      The effects of azithromycin in treatment-resistant cough: a randomized, double-blind, placebo-controlled trial.
      ]. Treatment with azithromycin for eight weeks failed to improve health status in patients with chronic cough when compared with placebo.
      Erythromycin was studied by Yousaf et al. in a randomized, double-blind, placebo-controlled parallel trial; the authors documented no difference in the change in cough frequency between the erythromycin and placebo group, although there was a significant difference in the change in sputum neutrophils over a 12 week period (a reduction with erythromycin and an increase with placebo) [
      • Yousaf N.
      • Monteiro W.
      • Parker D.
      • Matos S.
      • Birring S.
      • Pavord I.D
      Long-term low-dose erythromycin in patients with unexplained chronic cough: a double-blind placebo controlled trial.
      ].
      PA-101 is a novel formulation of cromolyn sodium and thought to act as a mast cell stabilizer. In a randomized placebo-controlled trial by Birring et al. PA-101 was delivered via a high efficiency eFlow nebulizer to 52 patients with idiopathic pulmonary fibrosis and chronic cough [
      • Birring S.S.
      • Wijsenbeek M.S.
      • Agrawal S.
      • van den Berg J.W.K.
      • Stone H.
      • Maher T.M.
      • et al.
      A novel formulation of inhaled sodium cromoglicate (PA101) in idiopathic pulmonary fibrosis and chronic cough: a randomised, double-blind, proof-of-concept, phase 2 trial.
      ]. No treatment benefit was observed for PA101 [
      • Birring S.S.
      • Wijsenbeek M.S.
      • Agrawal S.
      • van den Berg J.W.K.
      • Stone H.
      • Maher T.M.
      • et al.
      A novel formulation of inhaled sodium cromoglicate (PA101) in idiopathic pulmonary fibrosis and chronic cough: a randomised, double-blind, proof-of-concept, phase 2 trial.
      ].
      In conclusion, there have been important developments in elucidating pathophysiological mechanisms underlying chronic cough. Additional information regarding neurobiology has introduced a number of novel pharmacological treatment options, including drugs targeting the P2×3 receptor, which seems to be the most promising.

      7. Conclusions

      Cough is one of the most common respiratory symptoms, and is defined as chronic when it lasts for more than eight weeks. In the majority of cases, it represents the most troublesome symptom of common respiratory and non-respiratory diseases. If chronic cough persists even after treatment of the underlying disease, or if the chronic cough is not attributable to any cause, then a symptomatic approach with neuromodulators may be considered, with gabapentin as the first choice [
      • Irwin R.S.
      • French C.L.
      • Chang A.B.
      • Altman K.W.
      CHEST Expert Cough Panel
      Classification of cough as a symptom in adults and management algorithms: CHEST guideline and expert panel report.
      ,
      • Morice A.H.
      • Millqvist E.
      • Bieksiene K.
      • Birring S.S.
      • Dicpinigaitis P.
      • Domingo Ribas C.
      • et al.
      ERS guidelines on the diagnosis and treatment of chronic cough in adults and children.
      ,
      • Smith J.A.
      • Woodcock A
      Chronic cough.
      ], and opioids or macrolides as alternatives. Speech pathology treatment and/or neuromodulators should be discussed with patients and alternative options carefully considered, taking into account risk/benefit.
      Novel promising drugs are under investigation (e.g. P2×3 inhibitors), but additional studies are needed in this field. Speech pathology can be combined with a neuromodulator to give an enhanced treatment response of longer duration suggesting that non-pharmacologic treatment may play a key role in the management of CRC. International guidelines, based on consensus opinion and observational data, provide detailed investigation and treatment algorithms [
      • Irwin R.S.
      • French C.L.
      • Chang A.B.
      • Altman K.W.
      CHEST Expert Cough Panel
      Classification of cough as a symptom in adults and management algorithms: CHEST guideline and expert panel report.
      ,
      • Morice A.H.
      • Millqvist E.
      • Bieksiene K.
      • Birring S.S.
      • Dicpinigaitis P.
      • Domingo Ribas C.
      • et al.
      ERS guidelines on the diagnosis and treatment of chronic cough in adults and children.
      ,
      • Smith J.A.
      • Woodcock A
      Chronic cough.
      ]. However, there are broad national and international differences in the delivery of health care resulting in differences in available diagnostic tests and management strategies, both in primary and specialist care. Quality of life is frequently impaired in patients with chronic cough, who often also have increased economic burden. Smith et al. provides a simplified approach through four steps: identification and treatment of obvious causes; focused testing for, and treatment, of asthma, gastroesophageal reflux and rhinosinusitis; investigations to rule out rarer causes of cough; and management of idiopathic or refractory chronic cough [
      • Smith J.A.
      • Woodcock A
      Chronic cough.
      ]. The lack of knowledge or limited economical resources in several areas may be handled by identification of referral centers for multidisciplinary management (respiratory physician, ear, nose and throat specialist, gastroenterologist, psychologist, lung function and molecular biology lab, respiratory physiotherapist and speech therapist) of chronic refractory cough and the feasibility of clinical trials to implement this field.

      Declaration of Competing Interest

      None.

      Acknowledgements

      Editorial support (in the form of critically reviewing the content written by the authors, and editing for grammar and journal style) was provided by David Young of Young Medical Communications and Consulting Ltd.

      References

        • McGarvey L.
        • Gibson P.G.
        What is chronic cough? Terminology.
        J Allergy Clin Immunol Pract. 2019; 7: 1711-1714https://doi.org/10.1016/j.jaip.2019.04.012
        • Irwin R.S.
        • French C.L.
        • Chang A.B.
        • Altman K.W.
        • CHEST Expert Cough Panel
        Classification of cough as a symptom in adults and management algorithms: CHEST guideline and expert panel report.
        Chest. 2018; 153: 196-209https://doi.org/10.1016/j.chest.2017.10.016
        • Morice A.H.
        • Millqvist E.
        • Bieksiene K.
        • Birring S.S.
        • Dicpinigaitis P.
        • Domingo Ribas C.
        • et al.
        ERS guidelines on the diagnosis and treatment of chronic cough in adults and children.
        Eur Respir J. 2020; 551901136https://doi.org/10.1183/13993003.01136-2019
        • Irwin R.S.
        • Baumann M.H.
        • Bolser D.C.
        • Boulet Ll-P
        • Braman S.S.
        • Brightling C.E.
        • et al.
        Diagnosis and management of cough executive summary: ACCP evidence-based clinical practice guidelines.
        Chest. 2006; 129 (1S–23S)https://doi.org/10.1378/chest.129.1_suppl.1S
        • Song W.-.J.
        • Chang Y.-.S.
        • Morice A.H
        Changing the paradigm for cough: does “cough hypersensitivity” aid our understanding?.
        Asia Pac Allergy. 2014; 4: 3https://doi.org/10.5415/apallergy.2014.4.1.3
        • Gibson P.
        • Wang G.
        • McGarvey L.
        • Vertigan A.E.
        • Altman K.W.
        • Birring S.S.
        • et al.
        Treatment of unexplained chronic cough: CHEST guideline and expert panel report.
        Chest. 2016; 149: 27-44https://doi.org/10.1378/chest.15-1496
        • Birring S.S.
        • Prudon B.
        • Carr A.J.
        • Singh S.J.
        • Morgan M.D.L.
        • Pavord I.D
        Development of a symptom specific health status measure for patients with chronic cough: leicester Cough Questionnaire (LCQ).
        Thorax. 2003; 58: 339-343https://doi.org/10.1136/thorax.58.4.339
        • Song W.-.J.
        • Chang Y.-.S.
        • Faruqi S.
        • Kim J.-.Y.
        • Kang M.-.G.
        • Kim S.
        • et al.
        The global epidemiology of chronic cough in adults: a systematic review and meta-analysis.
        Eur Respir J. 2015; 45: 1479-1481https://doi.org/10.1183/09031936.00218714
        • Chamberlain S.A.F.
        • Garrod R.
        • Douiri A.
        • Masefield S.
        • Powell P.
        • Bücher C.
        • et al.
        The impact of chronic cough: a cross-sectional European survey.
        Lung. 2015; 193: 401-408https://doi.org/10.1007/s00408-015-9701-2
        • Spanevello A.
        • Beghé B.
        • Visca D.
        • Fabbri L.M.
        • Papi A
        Chronic cough in adults.
        Eur J Intern Med. 2020; (online)https://doi.org/10.1016/j.ejim.2020.03.018
        • Morice A.H.
        • Millqvist E.
        • Belvisi M.G.
        • Bieksiene K.
        • Birring S.S.
        • Chung K.F.
        • et al.
        Expert opinion on the cough hypersensitivity syndrome in respiratory medicine.
        Eur Respir J. 2014; 44: 1132-1148https://doi.org/10.1183/09031936.00218613
        • Smith J.A.
        • Woodcock A
        Chronic cough.
        N Engl J Med. 2016; 375: 1544-1551https://doi.org/10.1056/NEJMcp1414215
        • Chung K.F.
        • McGarvey L.
        • Mazzone S.S
        Chronic cough as a neuropathic disorder.
        Lancet Respir Med. 2013; 1: 414-422https://doi.org/10.1016/S2213-2600(13)70043-2
        • Vertigan A.E.
        • Theodoros D.G.
        • Gibson P.G.
        • Winkworth A.L
        Voice and upper airway symptoms in people with chronic cough and paradoxical vocal fold movement.
        J Voice. 2007; 21: 361-383https://doi.org/10.1016/j.jvoice.2005.12.008
        • Perera L.
        • Kern M.
        • Hofmann C.
        • Tatro L.
        • Chai K.
        • Kuribayashi S.
        • et al.
        Manometric evidence for a phonation-induced UES contractile reflex.
        Am J Physiol - Gastrointest Liver Physiol. 2008; 294: G885-G891https://doi.org/10.1152/ajpgi.00470.2007
        • Gibson P.G.
        • Vertigan A.E.
        Speech pathology for chronic cough: a new approach.
        Pulm Pharmacol Ther. 2009; 22: 159-162https://doi.org/10.1016/j.pupt.2008.11.005
        • Chamberlain S.
        • Birring S.S.
        • Garrod R
        Nonpharmacological interventions for refractory chronic cough patients: systematic review.
        Lung. 2014; 192: 75-85https://doi.org/10.1007/s00408-013-9508-y
        • Vertigan A.E.
        • Theodoros D.G.
        • Gibson P.G.
        • Winkworth A.L
        Efficacy of speech pathology management for chronic cough: a randomised placebo controlled trial of treatment efficacy.
        Thorax. 2006; 61: 1065-1069https://doi.org/10.1136/thx.2006.064337
        • Chamberlain Mitchell S.A.F.
        • Garrod R.
        • Clark L.
        • Douiri A.
        • Parker S.M.
        • Ellis J.
        • et al.
        Physiotherapy, and speech and language therapy intervention for patients with refractory chronic cough: a multicentre randomised control trial.
        Thorax. 2017; 72: 129-136https://doi.org/10.1136/thoraxjnl-2016-208843
        • Broaddus-Lawrence P.L.
        • Treole K.
        • McCabe R.B.
        • Allen R.L.
        • Toppin L
        The effects of preventive vocal hygiene education on the vocal hygiene habits and perceptual vocal characteristics of training singers.
        J Voice. 2000; 14: 58-71https://doi.org/10.1016/s0892-1997(00)80095-8
        • Solomon N.P.
        • DiMattia M.S.
        Effects of a vocally fatiguing task and systemic hydration on phonation threshold pressure.
        J Voice. 2000; 14: 341-362https://doi.org/10.1016/s0892-1997(00)80080-6
        • Ryan N.M.
        • Vertigan A.E.
        • Gibson P.G
        Chronic cough and laryngeal dysfunction improve with specific treatment of cough and paradoxical vocal fold movement.
        Cough. 2009; 5: 4https://doi.org/10.1186/1745-9974-5-4
        • Murry T.
        • Branski R.C.
        • Yu K.
        • Cukier-Blaj S.
        • Duflo S.
        • Aviv J.E
        Laryngeal sensory deficits in patients with chronic cough and paradoxical vocal fold movement disorder.
        Laryngoscope. 2010; 120: 1576-1581https://doi.org/10.1002/lary.20985
        • Ryan N.M.
        • Vertigan A.E.
        • Bone S.
        • Gibson P.G
        Cough reflex sensitivity improves with speech language pathology management of refractory chronic cough.
        Cough. 2010; 6: 5https://doi.org/10.1186/1745-9974-6-5
        • Birring S.S.
        • Fleming T.
        • Matos S.
        • Raj A.A.
        • Evans D.H.
        • Pavord I.D
        The Leicester Cough Monitor: preliminary validation of an automated cough detection system in chronic cough.
        Eur Respir J. 2008; 31: 1013-1018https://doi.org/10.1183/09031936.00057407
        • Patel A.S.
        • Watkin G.
        • Willig B.
        • Mutalithas K.
        • Bellas H.
        • Garrod R.
        • et al.
        Improvement in health status following cough-suppression physiotherapy for patients with chronic cough.
        Chron Respir Dis. 2011; 8: 253-258https://doi.org/10.1177/1479972311422547
        • Vertigan A.E.
        • Haines J.
        • Slovarp L
        An update on speech pathology management of chronic refractory cough.
        J Allergy Clin Immunol Pract. 2019; 7: 1756-1761https://doi.org/10.1016/j.jaip.2019.03.030
        • Vertigan A.E.
        • Kapela S.L.
        • Ryan N.M.
        • Birring S.S.
        • McElduff P.
        • Gibson P.G
        Pregabalin and speech pathology combination therapy for refractory chronic cough: a randomized controlled trial.
        Chest. 2016; 149: 639-648https://doi.org/10.1378/chest.15-1271
        • Smith J.
        • Owen E.
        • Earis J.
        • Woodcock A.
        Effect of codeine on objective measurement of cough in chronic obstructive pulmonary disease.
        J Allergy Clin Immunol. 2006; 117: 831-835https://doi.org/10.1016/j.jaci.2005.09.055
        • Torjesen I.
        Covid-19: NICE advises against using NSAIDs for fever in patients with suspected cases.
        BMJ. 2020; 369: m1409https://doi.org/10.1136/bmj.m1409
        • Morice A.H.
        • Menon M.S.
        • Mulrennan S.A.
        • Everett C.F.
        • Wright C.
        • Jackson J.
        • et al.
        Opiate therapy in chronic cough.
        Am J Respir Crit Care Med. 2007; 175: 312-315https://doi.org/10.1164/rccm.200607-892OC
        • Dion G.R.
        • Teng S.E.
        • Achlatis E.
        • Fang Y.
        • Amin M.R
        Treatment of neurogenic cough with tramadol: a pilot study.
        Otolaryngol Head Neck Surg. 2017; 157: 77-79https://doi.org/10.1177/0194599817703949
        • Lee B.
        • Woo P.
        Chronic cough as a sign of laryngeal sensory neuropathy: diagnosis and treatment.
        Ann Otol Rhinol Laryngol. 2005; 114: 253-257https://doi.org/10.1177/000348940511400401
        • Mintz S.
        • Lee J.K.
        Gabapentin in the treatment of intractable idiopathic chronic cough: case reports.
        Am J Med. 2006; 119: e13-e15https://doi.org/10.1016/j.amjmed.2005.10.046
        • Ryan N.M.
        • Birring S.S.
        • Gibson P.G
        Gabapentin for refractory chronic cough: a randomised, double-blind, placebo-controlled trial.
        Lancet. 2012; 380: 1583-1589https://doi.org/10.1016/S0140-6736(12)60776-4
        • Dong R.
        • Xu X.
        • Yu L.
        • Ding H.
        • Pan J.
        • Yu Y.
        • et al.
        Randomised clinical trial: gabapentin vs baclofen in the treatment of suspected refractory gastro-oesophageal reflux-induced chronic cough.
        Aliment Pharmacol Ther. 2019; 49: 714-722https://doi.org/10.1111/apt.15169
        • Halum S.L.
        • Sycamore D.L.
        • McRae B.R
        A new treatment option for laryngeal sensory neuropathy.
        Laryngoscope. 2009; 119: 1844-1847https://doi.org/10.1002/lary.20553
        • Li J.
        • Ye L.
        Effect of pregabalin for the treatment of chronic refractory cough: a case report.
        Med (United States). 2019; 98: e15916https://doi.org/10.1097/MD.0000000000015916
        • Ryan N.M.
        A review on the efficacy and safety of gabapentin in the treatment of chronic cough.
        Expert Opin Pharmacother. 2015; 16: 135-145https://doi.org/10.1517/14656566.2015.981524
        • Abdul Manap R.
        • Wright C.E.
        • Gregory A.
        • Rostami-Hodjegan A.
        • Meller S.T.
        • Kelm G.R.
        • et al.
        The antitussive effect of dextromethorphan in relation to CYP2D6 activity.
        Br J Clin Pharmacol. 1999; 48: 382-387https://doi.org/10.1046/j.1365-2125.1999.00029.x
        • Yancy W.S.
        • McCrory D.C.
        • Coeytaux R.R.
        • Schmit K.M.
        • Kemper A.R.
        • Goode A.
        • et al.
        Efficacy and tolerability of treatments for chronic cough: a systematic review and meta-analysis.
        Chest. 2013; 144: 1827-1838https://doi.org/10.1378/chest.13-0490
        • Matthys H.
        • Bleicher B.
        • Bleicher U.
        Dextromethorphan and codeine: objective assessment of antitussive activity in patients with chronic cough.
        J Int Med Res. 1983; 11: 92-100https://doi.org/10.1177/030006058301100206
        • Jeyakumar A.
        • Brickman T.M.
        • Haben M.
        Effectiveness of amitriptyline versus cough suppressants in the treatment of chronic cough resulting from postviral vagal neuropathy.
        Laryngoscope. 2006; 116: 2108-2112https://doi.org/10.1097/01.mlg.0000244377.60334.e3
        • Bastian R.W.
        • Vaidya A.M.
        • Delsupehe K.G
        Sensory neuropathic cough: a common and treatable cause of chronic cough.
        Otolaryngol Head Neck Surg. 2006; 135: 17-21https://doi.org/10.1016/j.otohns.2006.02.003
        • Norris B.K.
        • Schweinfurth J.M.
        Management of recurrent laryngeal sensory neuropathic symptoms.
        Ann Otol Rhinol Laryngol. 2010; 119: 188-191https://doi.org/10.1177/000348941011900307
        • Holmes P.W.
        • Barter C.E.
        • Pierce R.J.
        Chronic persistent cough: use of ipratropium bromide in undiagnosed cases following upper respiratory tract infection.
        Respir Med. 1992; 86: 425-429https://doi.org/10.1016/S0954-6111(06)80010-7
        • Birrell M.A.
        • Bonvini S.J.
        • Dubuis E.
        • Maher S.A.
        • Wortley M.A.
        • Grace M.S.
        • et al.
        Tiotropium modulates transient receptor potential V1 (TRPV1) in airway sensory nerves: a beneficial off-target effect?.
        J Allergy Clin Immunol. 2014; 133: 679-687https://doi.org/10.1016/j.jaci.2013.12.003
        • Roe N.A.
        • Lundy F.T.
        • Litherland G.J.
        • McGarvey L.P.A
        Therapeutic targets for the treatment of chronic cough.
        Curr Otorhinolaryngol Rep. 2019; 7: 116-128https://doi.org/10.1007/s40136-019-00239-9
        • Mazzone S.B.
        • Undem B.J.
        Vagal afferent innervation of the airways in health and disease.
        Physiol Rev. 2016; 96: 975-1024https://doi.org/10.1152/physrev.00039.2015
        • Ford A.P.
        In pursuit of P2×3 antagonists: novel therapeutics for chronic pain and afferent sensitization.
        Purinergic Signal. 2012; 8: 3-26https://doi.org/10.1007/s11302-011-9271-6
        • Abdulqawi R.
        • Dockry R.
        • Holt K.
        • Layton G.
        • McCarthy B.G.
        • Ford A.P.
        • et al.
        P2×3 receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo-controlled phase 2 study.
        Lancet. 2015; 385: 1198-1205https://doi.org/10.1016/S0140-6736(14)61255-1
        • Morice A.H.
        • Kitt M.M.
        • Ford A.P.
        • Tershakovec A.M.
        • Wu W.-.C.
        • Brindle K.
        • et al.
        The effect of gefapixant, a P2×3 antagonist, on cough reflex sensitivity: a randomised placebo-controlled study.
        Eur Respir J. 2019; 541900439https://doi.org/10.1183/13993003.00439-2019
        • Smith J.A.
        • Kitt M.M.
        • Butera P.
        • Smith S.A.
        • Li Y.
        • Xu Z.J.
        • et al.
        Gefapixant in two randomised dose-escalation studies in chronic cough.
        Eur Respir J. 2020; 1901615https://doi.org/10.1183/13993003.01615-2019
        • Smith J.A.
        • Kitt M.M.
        • Morice A.H.
        • Birring S.S.
        • McGarvey L.P.
        • Sher M.R.
        • et al.
        MK-7264, a P2×3 receptor antagonist, reduces cough frequency in patients with refractory chronic cough: results from a randomized, controlled, Phase 2b clinical trial.
        Am J Respir Crit Care Med. 2017; 195: A7608https://doi.org/10.1164/ajrccm-conference.2017.195.1_MeetingAbstracts.A7608
        • Belvisi M.G.
        • Birrell M.A.
        • Wortley M.A.
        • Maher S.A.
        • Satia I.
        • Badri H.
        • et al.
        XEN-D0501, a novel transient receptor potential vanilloid 1 antagonist, does not reduce cough in patients with refractory cough.
        Am J Respir Crit Care Med. 2017; 196: 1255-1263https://doi.org/10.1164/rccm.201704-0769OC
        • Khalid S.
        • Murdoch R.
        • Newlands A.
        • Smart K.
        • Kelsall A.
        • Holt K.
        • et al.
        Transient receptor potential vanilloid 1 (TRPV1) antagonism in patients with refractory chronic cough: a double-blind randomized controlled trial.
        J Allergy Clin Immunol. 2014; 134: 56-62https://doi.org/10.1016/j.jaci.2014.01.038
        • Lim K.G.
        • Rank M.A.
        • Hahn P.Y.
        • Keogh K.A.
        • Morgenthaler T.I.
        • Olson E.J.
        Long-term safety of nebulized lidocaine for adults with difficult-to-control chronic cough: a case series.
        Chest. 2013; 143: 1060-1065https://doi.org/10.1378/chest.12-1533
        • Smith J.A.
        • McGarvey L.P.A.
        • Badri H.
        • Satia I.
        • Warren F.
        • Siederer S.
        • et al.
        Effects of a novel sodium channel blocker, GSK2339345, in patients with refractory chronic cough.
        Int J Clin Pharmacol Ther. 2017; 55: 712-719https://doi.org/10.5414/CP202804
        • Smith J.
        • Allman D.
        • Badri H.
        • Miller R.
        • Morris J.
        • Satia I.
        • et al.
        The neurokinin-1 receptor antagonist orvepitant is a novel antitussive therapy for chronic refractory cough: results from a Phase 2 pilot study (VOLCANO-1).
        Chest. 2020; 157: 111-118https://doi.org/10.1016/j.chest.2019.08.001
        • Dicpinigaitis P.
        • Canning B.
        • DeVita R.
        • Perelman M.
        • Liu Q.
        • Hay D.
        • et al.
        The antitussive effects of alpha7 (α7) nicotinic receptor agonists.
        Eur Respir J. 2017; 50: OA4409https://doi.org/10.1183/1393003.congress-2017.OA4409
        • Hodgson D.
        • Anderson J.
        • Reynolds C.
        • Oborne J.
        • Meakin G.
        • Bailey H.
        • et al.
        The effects of azithromycin in treatment-resistant cough: a randomized, double-blind, placebo-controlled trial.
        Chest. 2016; 149: 1052-1060https://doi.org/10.1016/j.chest.2015.12.036
        • Yousaf N.
        • Monteiro W.
        • Parker D.
        • Matos S.
        • Birring S.
        • Pavord I.D
        Long-term low-dose erythromycin in patients with unexplained chronic cough: a double-blind placebo controlled trial.
        Thorax. 2010; 65: 1107-1110https://doi.org/10.1136/thx.2010.142711
        • Birring S.S.
        • Wijsenbeek M.S.
        • Agrawal S.
        • van den Berg J.W.K.
        • Stone H.
        • Maher T.M.
        • et al.
        A novel formulation of inhaled sodium cromoglicate (PA101) in idiopathic pulmonary fibrosis and chronic cough: a randomised, double-blind, proof-of-concept, phase 2 trial.
        Lancet Respir Med. 2017; 5: 806-815https://doi.org/10.1016/S2213-2600(17)30310-7