New Insights Into Refractory Chronic Cough and Unexplained Chronic Cough: A 6-Year Ambispective Cohort Study.

PURPOSE: Only limited studies have depicted the unique features and management of refractory chronic cough (RCC) and unexplained chronic cough (UCC). These led to the initiation of this study, which reported the demographic characteristics, manifestations, and long-term outcomes on a large series of consecutive RCC/UCC patients, providing a guideline-led real-world clinical experience. METHODS: Retrospective baseline information was obtained from Clinical Research Database (January 2016 to May 2021). At least 6 months after the last clinic visit, included subjects were prospectively followed up. RESULTS: Three hundred and sixty-nine RCC and UCC patients (199 females, 53.9%) were analyzed. The median cough duration was 24.0 (12.0-72.0) months. Laryngeal symptoms were reported in 95.9% of the patients. The common triggers for coughing were talking (74.9%), pungent odors (47.3%), eating (45.5%), and cold air (42.8%). RCC was considered in 38.2%, and the remainder of 228 patients had UCC, with an equal sex distribution (P = 0.66). Among the 141 RCCs, 90.8% (128) had refractory reflux cough, which was more responsive to current treatments (P < 0.01). Although most features and test results between RCC and UCC were similar, UCC was more commonly inappropriately treated (P < 0.01). Nineteen (7.7-41.1) months after the final clinic visit, 31.2% still coughed persistently, while 68.8% reported cough improvement or remission. RCC reported more favorable treatment outcomes (including cough improvement, control, and spontaneous remission) than UCC (P < 0.01). Coughs with long duration before the initial cough clinic visit (P < 0.01), frequent urinary incontinence (P < 0.01), and being sensitive to "talking" (P < 0.01) or "cold air" (P < 0.01) were less likely to be solved. CONCLUSIONS: The current treatments only improve cough symptoms in two-thirds of patients. Clinical indicators for treatment failure were those coughing for long duration and being sensitive to "talking" or "cold air."

Consensus goals and standards for specialist cough clinics: the NEUROCOUGH international Delphi study.

Background: Current guidelines on the management of chronic cough do not provide recommendations for the operation of specialist cough clinics. The objective of the present study was to develop expert consensus on goals and standard procedures for specialist cough clinics. Methods: We undertook a modified Delphi process, whereby initial statements proposed by experts were categorised and presented back to panellists over two ranking rounds using an 11-point Likert scale to identify consensus. Results: An international panel of 57 experts from 19 countries participated, with consensus reached on 15 out of 16 statements, covering the aims, roles and standard procedures of specialist cough clinics. Panellists agreed that specialist cough clinics offer optimal care for patients with chronic cough. They also agreed that history taking should enquire as to cough triggers, cough severity rating scales should be routinely used, and a minimum of chest radiography, spirometry and measurements of type 2 inflammatory markers should be undertaken in newly referred patients. The importance of specialist cough clinics in promoting clinical research and cough specialty training was acknowledged. Variability in healthcare resources and clinical needs between geographical regions was noted. Conclusions: The Delphi exercise provides a platform and guidance for both established cough clinics and those in planning stages.

Ingredients of Vicks VapoRub inhibit rhinovirus-induced ATP release.

Background: Over-the-counter therapies, such as Vicks VapoRub, are frequently used in the management of upper respiratory tract infection symptoms. Of these, acute cough is the most bothersome; however, the mechanisms involved have not been fully elucidated. The temperature-sensitive transient receptor potential (TRP) channels, including TRPA1, TRPV1, TRPM8 and TRPV4, are potential candidates. TRPV4 is also thought to be involved in cough through the TRPV4-ATP-P2X3 pathway. Here, we hypothesise that Vicks VapoRub ingredients (VVRIs) modulate the TRP cough channels. Methods: Stably transfected HEK cells expressing TRP channels were challenged with VVRIs, individually or in combination, and the agonist and antagonist effects were measured using calcium signalling responses. In addition, rhinovirus serotype-16 (RV16)-infected A549 airway epithelial cells were pre-incubated with individual or combinations of VVRIs prior to hypotonic challenge and extracellular ATP release analysis. Results: Calcium signalling reconfirmed some previously defined activation of TRP channels by specific VVRIs. The combined VVRIs containing menthol, camphor and eucalyptus oil activated TRPV1, TRPV4, TRPM8 and untransfected wild-type HEK293 cells. However, pre-incubation with VVRIs did not significantly inhibit any of the channels compared with the standard agonist responses. Pre-incubation of RV16-infected A549 cells with individual or combined VVRIs, except menthol, resulted in a 0.45-0.55-fold reduction in total ATP release following hypotonic stimulation, compared with infected cells not treated with VVRIs. Conclusion: These findings suggest that some VVRIs may reduce symptoms associated with upper respiratory tract infection by modulating specific TRP receptors and by reducing RV16-induced ATP release.

Unravelling vagal hypersensitivity in chronic cough: A distinct disease.

Chronic cough (CC) is a common but poorly understood disease that has a negative impact on quality of life. For years, clinicians have been trying to find the underlying diagnosis and using existing disease models to describe the patients' illness. This presents a confusing picture of CC. Most patients with CC present with hypersensitivity of the cough reflex, which is characterised by laryngeal paraesthesia and an increased response to the tussive stimuli or an innocuous stimulus that would not trigger coughing in healthy people. Recently, it has been proposed that CC is a unique disease characterised by vagal hypersensitivity that projects to the central nervous system altering responsiveness. The evidence supports the hypothesis that CC is primarily a neurological disorder, consisting of different phenotypes.

From bench to bedside: The role of cough hypersensitivity in chronic cough.

BACKGROUND: Chronic cough is a burdensome condition characterized by persistent cough lasting longer than 8 weeks. Chronic cough can significantly affect quality of life, physical function and productivity, with many people troubled with a cough that lasts for months or even years. People with chronic cough commonly report a persistent urge to cough with frequent bouts of coughing triggered by innocuous stimuli, which has led to the concept of cough hypersensitivity. MAIN BODY: Both central and peripheral neural pathways regulate cough, and although mechanisms driving development of cough hypersensitivity are not fully known, sensitization of these neural pathways contributes to excessive cough triggering in cough hypersensitivity. Effective therapies that control chronic cough are currently lacking. Recent therapeutic development has focused on several ion channels and receptors involved in peripheral activation of cough (e.g., transient receptor potential channels, P2 × 3 receptors and voltage-gated sodium channels) or central cough processing (e.g., neurokinin-1 [NK-1] receptors and nicotinic acetylcholine receptors). CONCLUSION: These targeted therapies provide novel insights into mechanisms underlying cough hypersensitivity and may offer new treatment options for people with chronic cough. In this review, we explore preclinical and clinical studies that have improved our understanding of the mechanisms responsible for chronic cough and discuss the most promising targeted approaches to date, including trials of P2 × 3-receptor antagonists and NK-1-receptor antagonists.

Burden of chronic cough in the UK: results from the 2018 National Health and Wellness Survey.

Background: Chronic cough, defined as daily cough for at least 8 weeks, negatively affects quality of life and work productivity and increases healthcare resource utilisation. We aimed to determine the prevalence and burden of chronic cough in the UK. Methods: Study participants were general population respondents to the 2018 UK National Health and Wellness Survey (NHWS). Respondents completed survey questions relating to health, quality of life, work productivity and activity impairment, and use of healthcare resources. Prevalence estimates were projected to the UK population using post-stratification sampling weights to adjust for sampling bias. The population with chronic cough was matched 1:3 with a group without chronic cough, using propensity score matchingon age, sex and the modified Charlson Comorbidity Index. Results: Of 15 000 NHWS respondents, 715 reported chronic cough in the previous 12 months and 918 during their lifetime. Weighted to the UK adult population, the 12-month prevalence of chronic cough was 4.9% and lifetime prevalence was 6.2%. Prevalence of chronic cough was higher among older respondents and those with smoking histories. Chronic cough respondents experienced higher rates of severe anxiety and depression in the past 2 weeks than matched controls. Poor sleep quality and loss of work productivity were also observed. More chronic cough respondents visited a healthcare provider in the past 6 months than respondents without chronic cough with a mean of 5.8 and 3.7 visits per respondent, respectively. Conclusion: Adults with chronic cough report lower quality of life, reduced work productivity and greater healthcare resource utilisation than matched controls without chronic cough.

Efficacy and Safety of Eliapixant in Refractory Chronic Cough: The Randomized, Placebo-Controlled Phase 2b PAGANINI Study.

INTRODUCTION: The PAGANINI study evaluated the efficacy and safety of the selective P2X3 antagonist eliapixant in patients with refractory chronic cough (RCC). METHODS: PAGANINI was a randomized, double-blind, parallel-group, placebo-controlled, multicenter, dose-finding, phase 2b study. Adults with RCC lasting ≥ 12 months and cough severity ≥ 40 mm on a visual analog scale at screening were enrolled. Participants were randomized 1:1:1:1 to twice-daily 25 mg, 75 mg, or 150 mg oral eliapixant or placebo for 12 weeks. The primary endpoint was change from baseline in 24-h cough count after 12 weeks of intervention. RESULTS: Overall, 310 participants were randomized to twice-daily eliapixant 25 mg (n = 75), 75 mg (n = 78), 150 mg (n = 80), or placebo (n = 77). A statistically significant dose-response signal with eliapixant was detected for the primary endpoint (all dose-response models, adjusted p < 0.1; one-sided). Adverse events (AEs) were reported in 39 (51%) participants with placebo and 43-51 (57-65%) participants receiving eliapixant. The most common AE was dysgeusia, occurring in 1% (n = 1) of the placebo group and 1-16% (n = 1-13) of the eliapixant groups in a dose-related manner. One case of a moderate drug-induced liver injury occurred in a participant receiving 150 mg twice-daily eliapixant. CONCLUSION: Eliapixant demonstrated efficacy and a favorable taste tolerability profile in RCC. However, a drug-induced liver injury contributed to intensified liver monitoring in clinical trials with eliapixant and discontinuation of the entire development program in all indications by Bayer AG. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04562155; registered September 18, 2020.

Subcutaneous octreotide as a therapeutic option for refractory chronic cough: subjective response pattern and adverse effects from a retrospective single-centre case series.

Therapeutic antitussive effect of octreotide on intractable cough https://bit.ly/3mVMEc6.

Antitussive efficacy of the current treatment protocol for refractory chronic cough: our real-world experience in a retrospective cohort study.

BACKGROUND: The management of refractory chronic cough (RCC) is a great challenge. Neuromodulators have long been used for RCC with imperfect efficacy. OBJECTIVES: We summarized the outcomes of the current treatments used at our specialist cough clinic, which provides a guideline-led service and real-world experience for the future management of RCC. DESIGN: This is a single-centre retrospective observational cohort study. METHODS: Consecutive RCC patients (the first clinic visit between January 2016 and May 2021) were included into this observational cohort study. Medical records in the Chronic Cough Clinical Research Database were fully reviewed using uniform criteria. The included subjects were followed-up for at least 6 months after the final clinic visit via instant messages with the link to self-scaled cough-associated questionnaires. RESULTS: Overall, 369 RCC patients were analysed with a median age of 46.6 years and a cough duration of 24.0 months. A total of 10 different treatments were offered. However, 96.2% of patients had been prescribed at least one neuromodulator. One-third of patients had alternative treatments prescribed given the poor response to the initial therapy and 71.3% favourably responded to at least one of the treatments. Gabapentin, deanxit, and baclofen had comparable therapeutic efficacy (56.0%, 56.0%, and 62.5% respectively; p = 0.88) and overall incidences of adverse effects (28.3%, 22.0%, and 32.3% respectively; p = 0.76). However, 19.1 (7.7-41.8) months after the last clinic visit, 65.0% reported improvement (24.9%) or control of their cough (40.1%); 3.8% reported a spontaneous remission and 31.2% still had a severe cough. Both HARQ (n = 97; p < 0.001) and LCQ (n = 58; p < 0.001) demonstrated marked improvement. CONCLUSION: Trying different neuromodulators is a pragmatic strategy for RCC, which helped around two-thirds of patients. Relapse is common on withdrawal or reduction of dosage. Novel medication for RCC is an urgent clinical need. PLAIN LANGUAGE SUMMARY: This is the first report that fully represented a guideline-led treatment protocol for refractory chronic cough (RCC) based on a large series of patients, which evaluated the short- and long-term effects of the currently available treatments for RCC. We found that the therapeutic trial of different neuromodulators is a pragmatic strategy, which helped around two-thirds of patients. Gabapentin, deanxit (flupentixol/melitracen), and baclofen had similar therapeutic outcomes. This study may offer real-world experience for the future management of RCC.

The P2X3 receptor antagonist filapixant in patients with refractory chronic cough: a randomized controlled trial.

BACKGROUND: P2X3 receptor antagonists seem to have a promising potential for treating patients with refractory chronic cough. In this double-blind, randomized, placebo-controlled study, we investigated the efficacy, safety, and tolerability of the novel selective P2X3 receptor antagonist filapixant (BAY1902607) in patients with refractory chronic cough. METHODS: Following a crossover design, 23 patients with refractory chronic cough (age: 60.4 ± 9.1 years) received ascending doses of filapixant in one period (20, 80, 150, and 250 mg, twice daily, 4-days-on/3-days-off) and placebo in the other. The primary efficacy endpoint was the 24-h cough frequency on Day 4 of each dosing step. Further, subjective cough severity and health-related quality of life were assessed. RESULTS: Filapixant at doses ≥ 80 mg significantly reduced cough frequency and severity and improved cough health-related quality of life. Reductions in 24-h cough frequency over placebo ranged from 17% (80 mg dose) to 37% (250 mg dose), reductions over baseline from 23% (80 mg) to 41% (250 mg) (placebo: 6%). Reductions in cough severity ratings on a 100-mm visual analog scale ranged from 8 mm (80 mg) to 21 mm (250 mg). No serious or severe adverse events or adverse events leading to discontinuation of treatment were reported. Taste-related adverse events occurred in 4%, 13%, 43%, and 57% of patients treated with filapixant 20, 80, 150, and 250 mg, respectively, and in 12% treated with placebo. CONCLUSIONS: Filapixant proved to be efficacious, safe, and-apart from the occurrence of taste disturbances, especially at higher dosages-well tolerated during the short therapeutic intervention. Clinical trial registration EudraCT, eudract.ema.europa.eu, 2018-000129-29; ClinicalTrials.gov, NCT03535168.

Modulation of transient receptor potential (TRP) channels by plant derived substances used in over-the-counter cough and cold remedies.

BACKGROUND: Upper respiratory tract infections (URTIs) impact all age groups and have a significant economic and social burden on society, worldwide. Most URTIs are mild and self-limiting, but due to the wide range of possible causative agents, including Rhinovirus (hRV), Adenovirus, Respiratory Syncytial Virus (RSV), Coronavirus and Influenza, there is no single and effective treatment. Over-the-counter (OTC) remedies, including traditional medicines and those containing plant derived substances, help to alleviate symptoms including inflammation, pain, fever and cough. PURPOSE: This systematic review focuses on the role of the major plant derived substances in several OTC remedies used to treat cold symptoms, with a particular focus on the transient receptor potential (TRP) channels involved in pain and cough. METHODS: Literature searches were done using Pubmed and Web of Science, with no date limitations, using the principles of the PRISMA statement. The search terms used were 'TRP channel AND plant compound', 'cough AND plant compound', 'cough AND TRP channels AND plant compound', 'cough AND P2X3 AND plant compound' and 'P2X3 AND plant compound' where plant compound represents menthol or camphor or eucalyptus or turpentine or thymol. RESULTS: The literature reviewed showed that menthol activates TRPM8 and may inhibit respiratory reflexes reducing irritation and cough. Menthol has a bimodal action on TRPA1, but inhibition may have an analgesic effect. Eucalyptus also activates TRPM8 and inhibits TRPA1 whilst down regulating P2X3, aiding in the reduction of cough, pain and airway irritation. Camphor inhibits TRPA1 and the activation of TRPM8 may add to the effects of menthol. Activation of TRPV1 by camphor, may also have an analgesic effect. CONCLUSIONS: The literature suggests that these plant derived substances have multifaceted actions and can interact with the TRP 'cough' receptors. The plant derived substances used in cough and cold medicines have the potential to target multiple symptoms experienced during a cold.

Demographic, clinical, and patient-reported outcome data from 2 global, phase 3 trials of chronic cough.

BACKGROUND: The current characterization of patients with refractory or unexplained chronic cough (RCC and UCC, respectively) primarily stems from relatively small clinical studies. OBJECTIVE: To report the baseline medical history and clinical characteristics of individuals with RCC or UCC who were enrolled in COUGH-1 and COUGH-2, 2 large, global, phase 3 trials of gefapixant, a P2 × 3-receptor antagonist. METHODS: Adults with a chronic cough lasting for more than 1 year, diagnosis of RCC or UCC, and score greater than 40 mm on a 100-mm cough severity visual analog scale at both screening and baseline were eligible for enrollment. Demographics, medical history, and cough characteristics were collected at baseline. Cough-related measures included objective cough frequency, cough severity visual analog scale, Leicester Cough Questionnaire, and Hull Airway Reflux Questionnaire. The data were summarized using descriptive statistics. RESULTS: Of 2044 participants, 75% were women; mean age was 58 years, and mean cough duration was approximately 11 years. Among all participants, 73% were previously diagnosed with asthma, gastroesophageal reflux disease, or upper airway cough syndrome. The mean Leicester Cough Questionnaire total score was 10.4, with domain scores reflecting impaired cough-specific quality of life across physical, psychological, and social domains. The mean Hull Airway Reflux Questionnaire score was 39.6, with some of the most burdensome reported items being consistent with features of cough-reflex hypersensitivity. Participant characteristics and cough burden were comparable across geographic regions. CONCLUSION: Participants with RCC or UCC had characteristics consistent with published demographics associated with chronic cough. These data reflect a global population with burdensome cough of long duration and substantial impairment to quality of life. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: COUGH-1, NCT03449134 (https://www. CLINICALTRIALS: gov/ct2/show/NCT03449134); COUGH-2, NCT03449147 (https://clinicaltrials.gov/ct2/show/NCT03449147).

Investigating the diagnostic utility of high-resolution oesophageal manometry in patients with refractory respiratory symptoms.

BACKGROUND: The interaction between the respiratory and gastrointestinal systems, and the role of the latter in the development of respiratory pathology, has been examined with a focus on gastro-oesophageal reflux disease (GORD). However, little data exists examining the link between oesophageal motility and respiratory disease. AIMS AND OBJECTIVES: In this study, we examined patterns in oesophageal motility using high-resolution oesophageal manometry (HROM) in patients with refractory respiratory symptoms. METHODS: Data were collected retrospectively for all patients that were investigated using HROM at a single centre for refractory respiratory symptoms between January 1st, 2011-December 1st, 2021. Patients were selected for investigation based on airway reflux symptoms, measured by the Hull Airways Reflux Questionnaire (HARQ). RESULTS: 441 patients were investigated with HROM (64% female, mean age = 56.5 [SD = 13.9]). The commonest diagnoses of these patients were Chronic Cough (77%, n = 339), Asthma (10%, n = 44), and Interstitial Lung Disease (7%, n = 29). The prevalence of oesophageal dysmotility was 66% in our cohort. Those with oesophageal dysmotility had significantly higher HARQ scores than those with normal motility (40.6 vs 35.3, p < 0.001) and there was a significant inverse correlation between HARQ scores and distal contractile integral (DCI), a measure of oesophageal contractility. CONCLUSIONS: Two-thirds of patients with refractory respiratory symptoms were found to have oesophageal dysmotility on HROM. These findings suggest motility disorders of the oesophagus may contribute to the development and progression of respiratory disease. This study highlights the need for further prospective study of the relationship between oesophageal dysmotility and respiratory disease.

Improvements in Objective and Subjective Measures of Chronic Cough with Gefapixant: A Pooled Phase 3 Efficacy Analysis of Predefined Subgroups.

INTRODUCTION: In phase 3 trials (COUGH-1/COUGH-2), gefapixant 45 mg twice daily significantly reduced 24-h cough frequency vs placebo in refractory or unexplained chronic cough (RCC or UCC). METHODS: Here, the efficacy of gefapixant 45 mg vs placebo was evaluated across COUGH-1/COUGH-2 in predefined subgroups based on sex, region, age, cough duration, cough severity, cough frequency, and diagnosis (RCC, UCC). Awake cough frequency reductions at Week 12 and LCQ response rates (i.e., ≥ 1.3-point improvement) at Week 24 were assessed. RESULTS: Among 1360 participants analyzed, gefapixant 45 mg resulted in consistent awake cough frequency reductions overall and across predefined subgroups at Week 12. Gefapixant also resulted in improved LCQ scores across subgroups at Week 24; ≥ 70% of participants in each subgroup treated with gefapixant 45 mg had an LCQ response. CONCLUSION: These data suggest gefapixant 45 mg provides consistent objective and subjective efficacy across subgroups of individuals with RCC or UCC.

ATP, an attractive target for the treatment of refractory chronic cough.

Chronic cough is the most common complaint in respiratory clinics. Most of them have identifiable causes and some may respond to common disease-modifying therapies. However, there are many patients whose cough lacks effective aetiologically targeted treatments or remains unexplained after thorough assessments, which have been described as refractory chronic cough. Current treatments for refractory chronic cough are limited and often accompanied by intolerable side effects such as sedation. In recent years, various in-depth researches into the pathogenesis of chronic cough have led to an explosion in the development of drugs for the treatment of refractory chronic cough. There has been considerable progress in the underlying mechanisms of chronic cough targeting ATP, and ongoing or completed clinical studies have confirmed the promising antitussive efficacy of P2X3 antagonists for refractory cough. Herein, we review the foundation on which ATP target was developed as potential antitussive medications and provide an update on current clinical progresses.

Treatment of chronic cough: P2X3 receptor antagonists and beyond.

For years chronic cough (CC) has presented an enormous physical, psychological, and social burden on those who experience it, with no approved pharmacological therapies to assuage their symptoms. With our improved understanding of the pathophysiological mechanisms of CC, primarily the recognition of neuronal dysregulation in its aetiology, there appears to be a new hope for such patients. In this review we discuss the multitude of proposed pharmacological targets in CC, including the promising results produced by the antagonism of P2X3 receptors. We also assess the evidence of other peripherally acting pharmacolgical agents still in development.

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.

BACKGROUND: Gefapixant is an oral P2X3 receptor antagonist that has previously shown efficacy and safety in refractory chronic cough and unexplained chronic cough. We therefore aim to confirm the efficacy and safety of gefapixant in participants with refractory chronic cough and unexplained chronic cough. METHODS: COUGH-1 and COUGH-2 were both double-blind, randomised, parallel-group, placebo-controlled, phase 3 trials. COUGH-1 was done in 156 sites in 17 countries and COUGH-2 in 175 sites in 20 countries. We enrolled participants who were 18 years or older with a diagnosis of refractory chronic cough or unexplained chronic cough of 1 year duration or more. Participants were also required to have a cough severity visual analogue scale score of 40 mm or more at screening and baseline. Eligible participants were randomly allocated (1:1:1), using a computer-generated allocation schedule, to one of three treatment groups: placebo, gefapixant 15 mg twice per day, or gefapixant 45 mg twice per day. All study treatments were given orally. Participants were treated over a 12-week main study period in COUGH-1 and a 24-week main study period in COUGH-2; followed by extension periods for a total of up to 52 weeks of treatment in both trials. The primary outcome was placebo-adjusted mean change in 24-h cough frequency at 12 weeks in COUGH-1 and 24 weeks in COUGH-2. Both studies were registered with ClinicalTrials.gov, NCT03449134 (COUGH-1) and NCT03449147 (COUGH-2). FINDINGS: From March 14, 2018, (first participant screened) to July 26, 2019, (last participant screened) 732 patients were recruited in COUGH-1 and 1317 in COUGH-2. COUGH-1 randomly assigned and treated 730 participants (243 [33×3%] with placebo, 244 [33×4%] with gefapixant 15 mg twice per day, and 243 [33×3%] with gefapixant 45 mg twice per day); COUGH-2 randomly assigned and treated 1314 participants (435 [33×1%] with placebo, 440 [33×5%] with gefapixant 15 mg twice per day, and 439 [33×4%] with gefapixant 45 mg twice per day). Participants were mostly female (542 [74×2%] of 730 in COUGH-1 and 984 [74×9%] of 1314 in COUGH-2). The mean age was 59×0 years (SD 12×6) in COUGH-1 and 58×1 years (12×1) in COUGH-2, and the mean cough duration was 11·6 years (SD 9·5) in COUGH-1 and 11·2 years (9·8) in COUGH-2. Gefapixant 45 mg twice per day showed significant reductions in 24-h cough frequency compared with placebo at week 12 in COUGH-1 (18·5% [95% CI 32·9-0·9]; p=0·041) and at week 24 in COUGH-2 (14·6% [26·1-1·4]; p=0·031). Gefapixant 15 mg twice per day did not show a significant reduction in cough frequency versus placebo in both studies. The most common adverse events were related to taste disturbance: ageusia (36 [4·9%] of 730 in COUGH-1 and 86 [6·5%] of 1314 in COUGH-2), dysgeusia (118 [16·2%] in COUGH-1 and 277 [21·1%] in COUGH-2), hypergeusia (3 [0·4%] in COUGH-1 and 6 [0×5%] in COUGH-2), hypogeusia (19 [2·6%] in COUGH-1 and 80 [6·1%] in COUGH-2), and taste disorder (28 [3·8%] in COUGH-1 and 46 [3·5%] in COUGH-2). INTERPRETATION: Gefapixant 45 mg twice per day is the first treatment to show efficacy with an acceptable safety profile in phase 3 clinical trials for refractory chronic cough or unexplained chronic cough. FUNDING: Merck Sharp & Dohme.