An update and systematic review on drug therapies for the treatment of refractory chronic cough

ABSTRACT Introduction: Chronic Cough (CC) is common and often associated with significant comorbidity and decreased quality of life. In up to 50% of cases, the cough is refractory despite extensive investigation and treatment trials. It is likely that the key abnormality in refractory CC is dysfunctional, hypersensitive sensory nerves, similar to conditions such as laryngeal hypersensitivity and neuropathic pain. Areas covered: The aim of this systematic review is to assess drug therapies for refractory CC. The authors review the current management of CC and provide discussion of the similarities between neuropathic pain and refractory CC. They review repurposed and new pharmacological treatments. Several meta-analyses were performed to compare the efficacy of treatments where possible. Expert opinion: Repurposed pain medications such as gabapentin and pregabalin reduce the frequency of cough and improve quality of life. Along with speech pathology, they are important and alternate treatments for refractory CC. However, more treatments are needed and the P2X3 ion channel receptor antagonists show the most promise. With a better understanding of neuronal activation and sensitisation and their signal processing in the brain, improved animal models of cough, and the use of validated cough measurement tools, more effective treatments will develop.

[1]  J. Smith,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). , 2019, Chest.

[2]  A. McGovern,et al.  Translating Cough Mechanisms Into Better Cough Suppressants , 2017, Chest.

[3]  Surinder S Birring,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. , 2017, The Lancet. Respiratory medicine.

[4]  P. Wiffen,et al.  Tramadol for neuropathic pain in adults. , 2017, The Cochrane database of systematic reviews.

[5]  Yixin Fang,et al.  Treatment of Neurogenic Cough with Tramadol: A Pilot Study , 2017, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[6]  K. Chung,et al.  Advances in mechanisms and management of chronic cough: The Ninth London International Cough Symposium 2016. , 2017, Pulmonary pharmacology & therapeutics.

[7]  Mohammed Azmi Al-Betar,et al.  comprehensive review : Krill Herd algorithm ( KH ) and its pplications saju , 2016 .

[8]  A. Ford,et al.  S27 The effect of P2X3 antagonism (AF–219) on experimentally evoked cough in healthy volunteers and chronic cough patients , 2016, Thorax.

[9]  J. Smith,et al.  Neurophenotypes in Airway Diseases. Insights from Translational Cough Studies. , 2016, American journal of respiratory and critical care medicine.

[10]  D. Shaw,et al.  The Effects of Azithromycin in Treatment-Resistant Cough: A Randomized, Double-Blind, Placebo-Controlled Trial. , 2016, Chest.

[11]  C. Page,et al.  Ozone-Induced Hypertussive Responses in Rabbits and Guinea Pigs , 2016, The Journal of Pharmacology and Experimental Therapeutics.

[12]  S. Birring,et al.  Pregabalin and Speech Pathology Combination Therapy for Refractory Chronic Cough: A Randomized Controlled Trial. , 2016, Chest.

[13]  S. Birring,et al.  Treatment of Unexplained Chronic Cough: CHEST Guideline and Expert Panel Report. , 2016, Chest.

[14]  P. Gibson,et al.  Management of chronic refractory cough , 2015, BMJ : British Medical Journal.

[15]  S. Skerratt,et al.  Ion channel therapeutics for pain , 2015, Channels.

[16]  N. Ryan,et al.  Tramadol overdose causes seizures and respiratory depression but serotonin toxicity appears unlikely , 2015, Clinical toxicology.

[17]  Gary Layton,et al.  P2X3 receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo-controlled phase 2 study , 2015, The Lancet.

[18]  A. Morice,et al.  The global epidemiology of chronic cough in adults: a systematic review and meta-analysis , 2015, European Respiratory Journal.

[19]  Blair H. Smith,et al.  Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis , 2015, The Lancet Neurology.

[20]  N. Ryan A review on the efficacy and safety of gabapentin in the treatment of chronic cough , 2015, Expert opinion on pharmacotherapy.

[21]  K. Chung,et al.  Approach to chronic cough: the neuropathic basis for cough hypersensitivity syndrome. , 2014, Journal of thoracic disease.

[22]  Surinder S Birring,et al.  An update on measurement and monitoring of cough: what are the important study endpoints? , 2014, Journal of thoracic disease.

[23]  S. Birring,et al.  Expert opinion on the cough hypersensitivity syndrome in respiratory medicine , 2014, European Respiratory Journal.

[24]  J. Smith,et al.  Transient receptor potential vanilloid 1 (TRPV1) antagonism in patients with refractory chronic cough: a double-blind randomized controlled trial. , 2014, The Journal of allergy and clinical immunology.

[25]  S. McMahon,et al.  Chronic cough and pain: Janus faces in sensory neurobiology? , 2013, Pulmonary pharmacology & therapeutics.

[26]  S. Holgate Stratified approaches to the treatment of asthma , 2013, British journal of clinical pharmacology.

[27]  P. Gibson,et al.  Laryngeal sensory dysfunction in laryngeal hypersensitivity syndrome , 2013, Respirology.

[28]  Jackie L. Gartner-Schmidt,et al.  Development and validation of the cough severity index: A severity index for chronic cough related to the upper airway , 2013, The Laryngoscope.

[29]  K. Chung,et al.  Chronic cough as a neuropathic disorder. , 2013, The Lancet. Respiratory medicine.

[30]  I. Pavord,et al.  A longitudinal assessment of acute cough. , 2013, American journal of respiratory and critical care medicine.

[31]  C. Parada,et al.  Neuronal P2X3 receptor activation is essential to the hyperalgesia induced by prostaglandins and sympathomimetic amines released during inflammation , 2013, Neuropharmacology.

[32]  Ann M. Philbrick,et al.  Avoiding Serotonin Syndrome: The Nature of the Interaction Between Tramadol and Selective Serotonin Reuptake Inhibitors , 2012, The Annals of pharmacotherapy.

[33]  Kevin McGuinness,et al.  P159 Validation of the VitaloJAK™ 24 Hour Ambulatory Cough Monitor , 2012, Thorax.

[34]  S. Birring,et al.  Gabapentin for refractory chronic cough: a randomised, double-blind, placebo-controlled trial , 2012, The Lancet.

[35]  E. Keystone,et al.  Clinical evaluation of the efficacy of the P2X7 purinergic receptor antagonist AZD9056 on the signs and symptoms of rheumatoid arthritis in patients with active disease despite treatment with methotrexate or sulphasalazine , 2012, Annals of the rheumatic diseases.

[36]  J. Smith,et al.  Antitussive effects of memantine in guinea pigs. , 2012, Chest.

[37]  C. Mebus,et al.  Efficacy and Safety of CE-224,535, an Antagonist of P2X7 Receptor, in Treatment of Patients with Rheumatoid Arthritis Inadequately Controlled by Methotrexate , 2012, The Journal of Rheumatology.

[38]  B. Nilius,et al.  TRP channels. , 2012, Comprehensive Physiology.

[39]  Alec B. O’Connor Neuropathic Pain , 2012, PharmacoEconomics.

[40]  A. Ghosh,et al.  Comparative study of efficacy and safety of pregabalin and gabapentin in neuropathic pain , 2012 .

[41]  J. Sterne,et al.  The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials , 2011, BMJ : British Medical Journal.

[42]  P. Gibson,et al.  Chronic refractory cough as a sensory neuropathy: evidence from a reinterpretation of cough triggers. , 2011, Journal of voice : official journal of the Voice Foundation.

[43]  P. Gibson,et al.  Cough pharmacotherapy: current and future status , 2011, Expert opinion on pharmacotherapy.

[44]  K. Chung,et al.  Chronic 'cough hypersensitivity syndrome': a more precise label for chronic cough. , 2011, Pulmonary pharmacology & therapeutics.

[45]  Leonie J. Cole,et al.  Investigation of the Neural Control of Cough and Cough Suppression in Humans Using Functional Brain Imaging , 2011, The Journal of Neuroscience.

[46]  B. Canning,et al.  Encoding of the cough reflex in anesthetized guinea pigs. , 2011, American journal of physiology. Regulatory, integrative and comparative physiology.

[47]  A. Morice,et al.  Cough Hypersensitivity Syndrome: A Distinct Clinical Entity , 2011, Lung.

[48]  Matthew S. Johnson,et al.  Discovery and biological evaluation of potent, selective, orally bioavailable, pyrazine-based blockers of the Na(v)1.8 sodium channel with efficacy in a model of neuropathic pain. , 2010, Bioorganic & medicinal chemistry.

[49]  I. Pavord,et al.  Long-term low-dose erythromycin in patients with unexplained chronic cough: a double-blind placebo controlled trial , 2010, Thorax.

[50]  J. Smith,et al.  Does Central Up-regulation Of The N-Methyl-D-Aspartate Receptor Contribute To Cough Reflex Hypersensitivity? , 2010, ATS 2010.

[51]  J. Schweinfurth,et al.  Management of Recurrent Laryngeal Sensory Neuropathic Symptoms , 2010, The Annals of otology, rhinology, and laryngology.

[52]  Peter G Gibson,et al.  CICADA: Cough in Children and Adults: Diagnosis and Assessment. Australian Cough Guidelines summary statement , 2010, The Medical journal of Australia.

[53]  D. Moher,et al.  Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. , 2010, International journal of surgery.

[54]  M. Kemp Structural trends among second-generation voltage-gated sodium channel blockers. , 2010, Progress in medicinal chemistry.

[55]  Laura R. Sadofsky,et al.  TRPA1 agonists evoke coughing in guinea pig and human volunteers. , 2009, American journal of respiratory and critical care medicine.

[56]  Stacey Halum,et al.  A new treatment option for laryngeal sensory neuropathy , 2009, The Laryngoscope.

[57]  C. Woolf,et al.  Central sensitization: a generator of pain hypersensitivity by central neural plasticity. , 2009, The journal of pain : official journal of the American Pain Society.

[58]  P. Gibson,et al.  Characterization of laryngeal dysfunction in chronic persistent cough , 2009, The Laryngoscope.

[59]  I. Pavord,et al.  FACTORS AFFECTING COUGH FREQUENCY IN A MIXED POPULATION , 2009 .

[60]  A. A. Raj,et al.  Clinical cough IV:what is the minimal important difference for the Leicester Cough Questionnaire? , 2009, Handbook of experimental pharmacology.

[61]  T. Seemungal,et al.  Long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease exacerbations. , 2008, American journal of respiratory and critical care medicine.

[62]  S. Jordt,et al.  Breathtaking TRP channels: TRPA1 and TRPV1 in airway chemosensation and reflex control. , 2008, Physiology.

[63]  B. Canning,et al.  Differential effects of airway afferent nerve subtypes on cough and respiration in anesthetized guinea pigs. , 2008, American journal of physiology. Regulatory, integrative and comparative physiology.

[64]  Bernard Laurent,et al.  Prevalence of chronic pain with neuropathic characteristics in the general population , 2008, PAIN.

[65]  Z. Qiu,et al.  Clinical benefit of sequential three‐step empirical therapy in the management of chronic cough , 2008, Respirology.

[66]  I. Pavord,et al.  Prevalence, pathogenesis, and causes of chronic cough , 2008, The Lancet.

[67]  R. Scott,et al.  Clarithromycin targets neutrophilic airway inflammation in refractory asthma. , 2008, American journal of respiratory and critical care medicine.

[68]  J. Treanor,et al.  Repeated Administration of Vanilloid Receptor TRPV1 Antagonists Attenuates Hyperthermia Elicited by TRPV1 Blockade , 2007, Journal of Pharmacology and Experimental Therapeutics.

[69]  J. Smith,et al.  Ambulatory methods for recording cough. , 2007, Pulmonary pharmacology & therapeutics.

[70]  David H. Evans,et al.  An Automated System for 24-h Monitoring of Cough Frequency: The Leicester Cough Monitor , 2007, IEEE Transactions on Biomedical Engineering.

[71]  S. Birring,et al.  ERS guidelines on the assessment of cough , 2007, European Respiratory Journal.

[72]  Matthew S. Johnson,et al.  A-803467, a potent and selective Nav1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat , 2007, Proceedings of the National Academy of Sciences.

[73]  A. Morice,et al.  Opiate therapy in chronic cough. , 2007, American journal of respiratory and critical care medicine.

[74]  B. Canning The Cough Reflex in Animals: Relevance to Human Cough Research , 2007, Lung.

[75]  J. A. Peters,et al.  Transient receptor potential cation channels in disease. , 2007, Physiological reviews.

[76]  A. Jeyakumar,et al.  Effectiveness of Amitriptyline Versus Cough Suppressants in the Treatment of Chronic Cough Resulting From Postviral Vagal Neuropathy , 2006, The Laryngoscope.

[77]  I. Pavord,et al.  Recommendations for the management of cough in adults , 2006, Thorax.

[78]  B. Khakh,et al.  P2X receptors as cell-surface ATP sensors in health and disease , 2006, Nature.

[79]  B. Canning,et al.  Mechanistic studies of acid-evoked coughing in anesthetized guinea pigs. , 2006, American journal of physiology. Regulatory, integrative and comparative physiology.

[80]  D. Theodoros,et al.  Efficacy of speech pathology management for chronic cough: a randomised placebo controlled trial of treatment efficacy , 2006, Thorax.

[81]  R. Bastian,et al.  Sensory Neuropathic Cough: A Common and Treatable Cause of Chronic Cough , 2006, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[82]  A. Randall,et al.  Discovery of SB-705498: a potent, selective and orally bioavailable TRPV1 antagonist suitable for clinical development. , 2006, Bioorganic & medicinal chemistry letters.

[83]  S. Mintz,et al.  Gabapentin in the treatment of intractable idiopathic chronic cough: case reports. , 2006, The American journal of medicine.

[84]  J. Smith,et al.  Effect of codeine on objective measurement of cough in chronic obstructive pulmonary disease. , 2006, The Journal of allergy and clinical immunology.

[85]  L. Boulet,et al.  An empiric integrative approach to the management of cough: ACCP evidence-based clinical practice guidelines. , 2006, Chest.

[86]  L. Boulet,et al.  Diagnosis and management of cough executive summary: ACCP evidence-based clinical practice guidelines. , 2006, Chest.

[87]  J. Kamei,et al.  Involvement of P2X receptor subtypes in ATP-induced enhancement of the cough reflex sensitivity. , 2005, European journal of pharmacology.

[88]  W Vennart,et al.  Pharmacological modulation of pain-related brain activity during normal and central sensitization states in humans. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[89]  L. McGarvey,et al.  Idiopathic chronic cough: a real disease or a failure of diagnosis? , 2005, Cough.

[90]  D. Cockayne,et al.  P2X2 knockout mice and P2X2/P2X3 double knockout mice reveal a role for the P2X2 receptor subunit in mediating multiple sensory effects of ATP , 2005, The Journal of physiology.

[91]  O. Usmani,et al.  Chronic idiopathic cough: a discrete clinical entity? , 2005, Chest.

[92]  A. Edwards The discovery of cromolyn sodium and its effect on research and practice in allergy and immunology. , 2005, The Journal of allergy and clinical immunology.

[93]  P. Woo,et al.  Chronic Cough as a Sign of Laryngeal Sensory Neuropathy: Diagnosis and Treatment , 2005, The Annals of otology, rhinology, and laryngology.

[94]  A. Morice,et al.  Investigation and management of chronic cough using a probability-based algorithm , 2005, European Respiratory Journal.

[95]  K. Chung,et al.  Drugs to suppress cough , 2005, Expert opinion on investigational drugs.

[96]  K. Chung,et al.  Increased expression of transient receptor potential vanilloid-1 in airway nerves of chronic cough. , 2004, American journal of respiratory and critical care medicine.

[97]  Garrett Pm Tramadol overdose and serotonin syndrome manifesting as acute right heart dysfunction. , 2004 .

[98]  P. Garrett Tramadol Overdose and Serotonin Syndrome Manifesting as Acute Right Heart Dysfunction , 2004, Anaesthesia and intensive care.

[99]  S. Meeker,et al.  Identification of the tracheal and laryngeal afferent neurones mediating cough in anaesthetized guinea‐pigs , 2004, The Journal of physiology.

[100]  S. Skeans,et al.  Cough reflex in allergic dogs. , 2004, European journal of pharmacology.

[101]  K. Kaye Trouble with tramadol , 2004 .

[102]  D. J. Houlihan Serotonin Syndrome Resulting from Coadministration of Tramadol, Venlafaxine, and Mirtazapine , 2004, The Annals of pharmacotherapy.

[103]  I. Pavord,et al.  Idiopathic chronic cough and organ-specific autoimmune diseases: a case-control study. , 2004, Respiratory medicine.

[104]  D. Wyss,et al.  Effect of a novel NK1 receptor selective antagonist (NKP608) on citric acid induced cough and airway obstruction. , 2004, Pulmonary pharmacology & therapeutics.

[105]  I. Pavord,et al.  Induced sputum inflammatory mediator concentrations in chronic cough. , 2004, American journal of respiratory and critical care medicine.

[106]  Ruth A Duffy Potential therapeutic targets for neurokinin-1 receptor antagonists. , 2004, Expert opinion on emerging drugs.

[107]  D. Altman,et al.  Measuring inconsistency in meta-analyses , 2003, BMJ : British Medical Journal.

[108]  K. Chung Current and future prospects for drugs to suppress cough. , 2003, IDrugs : the investigational drugs journal.

[109]  Sally J. Singh,et al.  Development of a symptom specific health status measure for patients with chronic cough: Leicester Cough Questionnaire (LCQ) , 2003, Thorax.

[110]  K. Fletcher,et al.  Evaluation of a cough-specific quality-of-life questionnaire. , 2002, Chest.

[111]  William C. Cockerham Physicians , 2001, BMJ : British Medical Journal.

[112]  M. Mortimore,et al.  The medicinal chemistry of the P2 receptor family. , 2001, Progress in medicinal chemistry.

[113]  A. Fox,et al.  NK1 receptor antagonists--are they really without effect in the pain clinic? , 2000, Trends in pharmacological sciences.

[114]  A. Hobson,et al.  Contribution of central sensitisation to the development of noncardiac chest pain , 2000, The Lancet.

[115]  R Hill,et al.  NK1 (substance P) receptor antagonists--why are they not analgesic in humans? , 2000, Trends in pharmacological sciences.

[116]  T. Jensen,et al.  The effect of tramadol in painful polyneuropathy in relation to serum drug and metabolite levels , 1999, Clinical pharmacology and therapeutics.

[117]  K. Chung,et al.  Increased neutrophils and cytokines, TNF-α and IL-8, in induced sputum of non-asthmatic patients with chronic dry cough , 1999, Thorax.

[118]  R. Gracely,et al.  The substance P receptor antagonist CP‐99,994 reduces acute postoperative pain , 1998, Clinical pharmacology and therapeutics.

[119]  L. Boulet,et al.  Managing cough as a defense mechanism and as a symptom. A consensus panel report of the American College of Chest Physicians. , 1998, Chest.

[120]  H. Boushey,et al.  Effect of an NK1 receptor antagonist (CP-99,994) on hypertonic saline-induced bronchoconstriction and cough in male asthmatic subjects. , 1995, American journal of respiratory and critical care medicine.

[121]  R. Hargreaves,et al.  Comparison of the effects of sumatriptan and the NK1 antagonist CP-99,994 on plasma extravasation in dura mater and c-fos mRNA expression in trigeminal nucleus caudalis of rats , 1995, Neuropharmacology.

[122]  M. Moskowitz,et al.  Blockade by oral or parenteral RPR 100893 (a non‐peptide NK1 receptor antagonist) of neurogenic plasma protein extravasation within guinea‐pig dura mater and conjunctiva , 1994, British journal of pharmacology.

[123]  C. Garret,et al.  Inhibition of neurogenic inflammation in the meninges by a non-peptide NK1 receptor antagonist, RP 67580. , 1993, European journal of pharmacology.

[124]  H. Torebjörk,et al.  Central changes in processing of mechanoreceptive input in capsaicin‐induced secondary hyperalgesia in humans. , 1992, The Journal of physiology.

[125]  S. Braman,et al.  Cough. A comprehensive review. , 1977, Archives of internal medicine.