About the Author
Imran Satia M.A MB BChir (cantab) MRCP PhD
Dr. Imran Satia graduated in Medicine from the University of Cambridge in 2006. He gained his Membership of the Royal College of Physicians (London, UK) and completed his specialist training in general internal medicine and respiratory medicine. In 2017 he was awarded a PhD in the mechanisms of cough and was awarded the British Medical Association James Trust Award and the European Respiratory Society Respire 3 Marie Curie Post-Doctoral Fellowship. Imran is now on Faculty at McMaster University and the Firestone Institute for Respiratory Health working as an Assistant Professor in Respiratory Medicine. He consults on patients with asthma, refractory chronic cough, complex airways diseases and has a broad research interest in understanding the mechanisms and developing treatments for these troublesome conditions.
Current Pharmacological and Non-Pharmacological Therapies for Chronic Cough
Disclosure Statement: I.S. is currently supported by the E.J. Moran Campbell Early Career Award, McMaster University; reports grants ERS Respire 3 Marie Curie fellowship, Merck, MITACS, GSK, Bellus; personal speaker fees from Merck, GSK, AstraZeneca; consulting fees from Merck, Respiplus and Genentech outside the submitted work.
Chronic cough, defined as cough lasting 8 weeks or longer, affects approximately 10% of adults globally, but with large global variations with prevalence estimates ranging from 2-18%.1 The prevalence of chronic cough in adults over the age of 45 in the Canadian Longitudinal Study of Ageing (CLSA) was 16%, the second highest in the world.2 Interestingly, the prevalence and incidence is higher in English speaking compared with French speaking participants.3 Cough is the leading cause for ambulatory and primary care visits to physicians and one of the most common reasons for referral to specialist care.4,5 Chronic cough is associated with aging, smoking, higher body mass index, use of an ACE-inhibitor, and airways diseases. More recently, novel data has shown that symptoms of depression and psychological distress independently increase the risk of developing chronic cough by approximately 20%.6 Data from clinical trials and observational cohort studies suggest that patients with chronic cough have a median cough frequency of 20 coughs/hr.7 This may lead to distressing physical, psychological and social consequences such as urinary incontinence, exhaustion, fatigue, anxiety, frustration, embarrassment and social isolation, which all impairs quality of life.8 Chronic cough can be challenging to treat, since most over-the-counter therapies are ineffective and current treatments for chronic cough are all considered ‘off-label’.9,10 Although most cases are due to a benign cause, chronic cough can represent a serious underlying condition. A recent Canadian consensus has identified a simplified approach which can aid in the management of chronic cough and provide treatment for refractory or unexplained chronic cough.11 The guiding principles of this approach include i) investigation to rule out serious underlying conditions, ii) objective testing to prevent over and under-diagnosis, iii) treatment of identifiable diseases and traits and iv) monitoring to ensure effectiveness of treatment, including minimization of side effects and appropriate titration of treatment.
What is refractory and unexplained chronic cough?
After conducting a thorough history, examination, and appropriate investigations, an underlying disease may be detected in patients presenting with chronic cough. Treatment targeting this/these condition(s) may completely or partially resolve cough. In such cases, the chronic cough is considered ‘explained’ and a symptom of the underlying condition. In cases where an associated condition is found but does not fully resolve with appropriate treatment, the cough is considered to be “refractory chronic cough” (RCC). In cases where no underlying disease is identified, the cough is described as ‘unexplained chronic cough’(UCC).12 In patients with both RCC/UCC there are often clinical features of cough hyper-sensitivity syndrome.
What is Cough Hypersensitivity Syndrome?
Patients often describe sensations of ‘tickle’, ‘irritation’, or ‘something stuck in the throat’. Cough is often triggered by changes in temperature, perfumes, aerosols, strong smells, talking, laughing, and singing.13,14 Cough Hypersensitivity Syndrome is considered an umbrella term to describe the neuro-pathological mechanisms within the central and peripheral nervous system which may be implicated in RCC/UCC.14 This has been described as “Cough Hypersensitivity Syndrome”, as many patients cough after exposure to low levels of thermal, chemical, or mechanical stimulation.14,15
What is the underlying neurophysiology causing excessive cough?
Cough can be under both voluntary and involuntary control, but the cough reflex is the archetypal airway defensive reflex to prevent aspiration of foreign bodies or inhalation of noxious chemicals like smoke. The vagus nerve projects sensory afferents to the upper and lower respiratory tract, which, when stimulated, transmits signals to the brainstem. These signals are projected to cortical neurons in the thalamus and primary somatosensory cortex. If the stimulus is great enough, coughing will occur via the spinal motor efferent nerves to the diaphragm, intercostal muscles, and glottis. Excessive cough in patients with RCC/UCC could thus be due to i) increased activation of the airway peripheral nerve terminals by chemical irritants/mucus/alarmins (e.g., extracellular ATP), ii) hypersensitivity and/or hyper-responsiveness of the afferent vagal nerve, brainstem, and higher cortical projections and iii) impaired voluntary control and/or descending inhibitory control pathways. Recent studies suggest patients with RCC have impairment in the descending inhibitory control neurons16 and a relative lack of voluntary cough suppression17 compared to healthy controls.
What treatments are currently used for refractory or unexplained chronic cough
There are currently no approved treatments for RCC/UCC, thus the therapies described below are considered ‘off-label’ (Table 1). The American College of Chest Physicians (ACCP) and European Respiratory Society (ERS) suggest speech and language therapy and neuromodulators should be considered as appropriate therapies/interventions for the treatment of RCC/UCC.
Speech and Language Therapy
Speech and language therapy provides a safe and effective adjunct or alternate therapy in patients who do not wish to take neuromodulator medications or for those who develop intolerable side effects.18 However, access to adequately trained therapists in the management of RCC/UCC can be challenging, and patient compliance with exercises is difficult beyond the initial 4 visits that are recommended as part of the speech and language therapy care algorithm.
Treatment of Neuromodulation
Neuromodulator treatment includes low-dose morphine19, gabapentin20, and pregabalin21. All three therapies demonstrate improved symptom control and improved quality of life in randomised controlled trials; however, these trials have been small, and the doses used in the RCTs were associated with high rates of adverse events, such as dizziness, drowsiness, unsteadiness, and fatigue. One study using amitriptyline 10 mg at bedtime reported symptomatic improvement but lacked a placebo control or a validated tool to assess improvements in cough.22 In clinical practice, most patients are unable to tolerate the high doses of neuromodulators used in RCTs, hence it is recommended to start gabapentin at 100 mg TID and titrate up to a maximum of 300 mg TID, or to start pregabalin at 50-75 mg BID and increase on a weekly basis up to 150 mg twice a day.
The use of low-dose opioid therapy can be attempted after discussion with the patient on the potential benefits and harms of treatment. Low-doses, between 5-10 mg of slow- or modified-release morphine BID may be effective, and in those who achieve clinical response, the benefit is often apparent within 3-7 days.19 Another recent study showed that treatment for one week can reduce objective cough frequency by up to 72%.23 Hence, if the patient does not demonstrate clinical benefit after a 1–2-week trial, low-dose morphine can be discontinued. If there is benefit, then the dose can be titrated to minimize side effects such as constipation, drowsiness, and sedation. A clinical audit in a tertiary cough clinic has shown that approximately 36% of patients demonstrate a complete or partial response to low-dose morphine and nearly two-thirds develop no side effects.24 If cough severity improves and side effects are mild, changing the dose and timing may be useful. Alternative regimens include once daily dosing at night, alternate day dosing, or, when required, 3-4 hours before socializing, teaching or attending important public events. In patients who have been on treatment for longer periods, short periods ‘off-treatment’ can be carefully attempted to prevent tolerance.
What does the future hold for Refractory and Unexplained Chronic Cough?
In the absence of any licensed treatments, new treatments are desperately needed for RCC/UCC. Over the last 7 years, there have been successful studies demonstrating blockade of P2X3 ion channels found on peripheral airways nerves may be a successful strategy to reduce coughs.25-27 Gefapixant is an oral, non-opioid, peripherally acting P2X3 antagonist which met its primary outcome in two phase 3 studies at a dose of 45 mg BID. Subjects in these studies had been diagnosed with RCC/UCC for at least 1 year prior to study entry, showed no abnormalities on chest radiology contributing to the cough (within 5 years of the study and after the onset of chronic cough), and had cough severity visual analog scale scores of ≥ 40 mm at both the screening and baseline visits. The primary endpoint in both studies was 24-hour cough frequency and safety/tolerability. The placebo adjusted estimated relative reduction in cough frequency was approximately 18% in COUGH-1 and 15% in COUGH-2.25 These reductions were lower than expected due the significant placebo effect, the reasons for which are yet to be fully understood. The most prevalent side-effect was taste disturbance which was experienced by 60% and 69% of subjects at the highest dose of 45 mg compared with 3% and 8% of subjects in the placebo arm in COUGH-1 and COUGH-2 respectively. The putative mechanism is due to cross-selectivity against the hetero-trimer P2X2/3 which is thought to transmit taste from the tongue. Nonetheless, gefapixant has now been approved in Japan and Switzerland and is currently under-review by the U.S Food and Drug Administration (FDA), Health Canada and European Medicines Agency (EMA). Another P2X3 antagonist is currently under development by Bellus Health with its lead molecule BLU-5937 recently passing phase 2b with a placebo run-in study showing an approximate 34% reduction in 24-hour cough frequency with only a 6% taste disturbance.26 Another P2X3 antagonist, sivopixant did not meet its primary endpoint in the phase 2b dose-finding study, but the optimum dose is still unknown.27
Chronic cough is a common troubling symptom that can severely affect the physical, social, and psychological well-being of patients. Current guidelines recommend treatment of any identifiable conditions, but if the cough is refractory or unexplained, speech and language therapy along with neuromodulator treatment, such as low dose opioids, pregabalin, and gabapentin, can be trialed. Clinicians should monitor and minimize the dose and length of treatment with centrally acting neuromodulator treatment to limit side effects and tolerability in a respiratory or specialized cough clinic. Emerging therapeutic agents such as the novel oral P2X3 antagonists may provide hope to patients in the years to come.
- 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. European Respiratory Journal. 2015:ERJ-02187-2014.
- Satia I, Mayhew AJ, Sohel N, Kurmi O, Killian KJ, O’Byrne PM, et al. Prevalence, incidence, and characteristics of chronic cough among adults from the Canadian Longitudinal Study on Ageing (CLSA). ERJ Open Research. 2021.
- Satia I, Mayhew AJ, Sohel N, Kurmi O, Killian KJ, O’Connell ME, et al. Language and geographical location influence the incidence of chronic cough in the Canadian Longitudinal Study on Aging. ERJ Open Research. 2022;8(1).
- Finley CR, Chan DS, Garrison S, Korownyk C, Kolber MR, Campbell S, et al. What are the most common conditions in primary care? Systematic review. Can Fam Physician. 2018;64(11):832-40.
- Burt CW, Schappert SM. Ambulatory care visits to physician offices, hospital outpatient departments, and emergency departments; United States, 1999-2000: data from the National Health Care Survey. 2004.
- Satia I, Mayhew AJ, Sohel N, Kurmi O, Killian KJ, O’Byrne PM, et al. Impact of mental health and personality traits on the incidence of chronic cough in the Canadian Longitudinal Study on Aging. ERJ Open Res. 2022;8(2).
- Dicpinigaitis PV, Birring SS, Blaiss M, McGarvey LP, Morice AH, Pavord ID, et al. Demographic, Clinical, and Patient-Reported Outcome Data From Two Global, Phase 3 Trials of Chronic Cough. Annals of Allergy, Asthma & Immunology. 2022.
- French CL, Irwin RS, Curley FJ, Krikorian CJ. Impact of chronic cough on quality of life. Archives of internal medicine. 1998;158(15):1657-61.
- Morice A, Kastelik JA, Thompson RH. Gender differences in airway behaviour. Thorax. 2000;55(7):629.
- Schroeder K, Fahey T. Systematic review of randomised controlled trials of over the counter cough medicines for acute cough in adults. BMJ. 2002;324(7333):329.
- Satia I, Wahab M, Kum E, Kim H, Lin P, Kaplan A, et al. Chronic cough: investigations, management, current and future treatments. Canadian Journal of Respiratory, Critical Care, and Sleep Medicine. 2021;5(6):404-16.
- Gibson P, Wang G, McGarvey L, Vertigan AE, Altman KW, Birring SS, et al. Treatment of Unexplained Chronic Cough: CHEST Guideline and Expert Panel Report. Chest. 2016;149(1):27-44.
- Hilton E, Marsden P, Thurston A, Kennedy S, Decalmer S, Smith JA. Clinical features of the urge-to-cough in patients with chronic cough. Respiratory medicine. 2015;109(6):701-7.
- Morice AH, Millqvist E, Belvisi MG, Bieksiene K, Birring SS, Chung KF, et al. Expert opinion on the cough hypersensitivity syndrome in respiratory medicine. Eur Respir J. 2014;44(5):1132-48.
- Morice AH, Millqvist E, Belvisi MG, Bieksiene K, Birring SS, Chung KF, et al. Cough hypersensitivity syndrome: clinical measurement is the key to progress. Eur Respir J. 2015;45(5):1509-10.
- Hilton E, Satia I, Holt K, Woodcock AA, Belcher J, Smith JA. The Effect of Pain Conditioning on Experimentally Evoked Cough: Evidence of Impaired Endogenous Inhibitory Control Mechanisms in Refractory Chronic Cough. Eur Respir J. 2020.
- Cho PS, Fletcher HV, Turner RD, Jolley CJ, Birring SS. Impaired cough suppression in chronic refractory cough. European Respiratory Journal. 2019;53(5).
- Slinger C, Mehdi SB, Milan SJ, Dodd S, Matthews J, Vyas A, et al. Speech and language therapy for management of chronic cough. Cochrane Database of Systematic Reviews. 2019(7).
- Morice AH, Menon MS, Mulrennan SA, Everett CF, Wright C, Jackson J, et al. Opiate therapy in chronic cough. American journal of respiratory and critical care medicine. 2007;175(4):312-5.
- Ryan NM, Birring SS, Gibson PG. Gabapentin for refractory chronic cough: a randomised, double-blind, placebo-controlled trial. Lancet (London, England). 2012;380(9853):1583-9.
- Vertigan AE, Kapela SL, Ryan NM, Birring SS, McElduff P, Gibson PG. Pregabalin and Speech Pathology Combination Therapy for Refractory Chronic Cough: A Randomized Controlled Trial. Chest. 2016;149(3):639-48.
- Jeyakumar A, Brickman TM, Haben M. Effectiveness of amitriptyline versus cough suppressants in the treatment of chronic cough resulting from postviral vagal neuropathy. The Laryngoscope. 2006;116(12):2108-12.
- Al-Sheklly B, Mitchell J, Issa B, Badri H, Satia I, Collier T, et al. S35 Randomised control trial quantifying the efficacy of low dose morphine in a responder group of patients with refractory chronic cough. BMJ Publishing Group Ltd; 2017.
- Badri H, Satia I, Woodcock A, Smith J. The use of low dose morphine for the management of chronic cough in a tertiary cough clinic. C29 SENSATIONS IN THE LUNG: COUGHING AND CONSTRICTING: American Thoracic Society; 2015. p. A4117-A.
- McGarvey LP, Birring SS, Morice AH, Dicpinigaitis PV, Pavord ID, Schelfhout J, et al. Efficacy and safety of gefapixant, a P2X3 receptor antagonist, in refractory chronic cough and unexplained chronic cough (COUGH-1 and COUGH-2): results from two double-blind, randomised, parallel-group, placebo-controlled, phase 3 trials. The Lancet. 2022;399(10328):909-23.
- Inc. BH. BELLUS Health Announces Positive Topline Results from its Phase 2b SOOTHE Trial of BLU-5937 for the Treatment of Refractory Chronic Cough [Available from: https://ir.bellushealth.com/news-releases/news-release-details/bellus-health-announces-positive-topline-results-its-phase-2b.
- Niimi A, Saito J, Kamei T, Shinkai M, Ishihara H, Machida M, et al. Randomised trial of the P2X3 receptor antagonist sivopixant for refractory chronic cough. Eur Respir J. 2022;59(6).