How often do healthy people cough?

Objective cough frequency has been reported in several respiratory conditions but the amount that healthy individuals cough daily is unclear. Seventy-nine healthy volunteers (38 males, median [IQR] age 41y [IQR 30-53]) completed 24-hour ambulatory cough monitoring (VitaloJAK™). The audio recording was filtered using a custom written algorithm to remove non-cough sounds and then all individual explosive cough sounds in the filtered file were tagged electronically by trained cough counters. Most coughing occurred during the day and cough numbers over 24 h were generally low (geometric mean of 4.6 coughs) but there was large variability; ranging from 0 to 136 coughs overall. Cough frequency was independent of participant characteristics apart from sex with males coughing significantly, 4-5 fold, more than females during the day and over 24 h (median [IQR] 16.1 [3.8-33.4] vs. 4.1 [1.0-15.0] total coughs; p = 0.015). This is the first report to describe cough frequency in a balanced group of healthy adults using an accurate cough monitoring system. The data reveal a further example of sexual dimorphism in cough, which warrants additional investigation.

Novel capsaicin cough endpoints effectively discriminate between healthy controls and patients with refractory chronic cough.

RATIONALE: Chronic cough is a common problem, substantially affecting quality of life. Effective treatments and diagnostic clinical tools for refractory chronic cough are lacking which remains a diagnosis of exclusion. OBJECTIVES: To investigate capsaicin evoked cough responses in healthy volunteers and refractory chronic cough patients and assess the discriminatory ability of novel endpoints. METHODS: Dose-response capsaicin cough challenges were performed, and receiver operating characteristic curves constructed to evaluate the discriminatory value of novel endpoints; Emax (maximum number of coughs evoked by any capsaicin concentration) and ED50 (capsaicin concentration evoking at least half of Emax). MEASUREMENTS AND MAIN RESULTS: Ninety-three healthy volunteers (median age 39yrs(IQR; 29-52), 47 females) and 51 refractory chronic cough patients (59yrs(53-67), 31 females) were studied. Emax was significantly higher in the patient group compared to healthy volunteers (p < 0.001) and ED50 was significantly lower (p = 0.001). Both parameters were influenced by gender; females had a higher Emax (p = 0.009) and more sensitive ED50 (p < 0.001) but there were no correlations with other patient demographics. There was a significant relationship between Emax and cough frequency in the patient group (p < 0.001). Emax effectively discriminated between the groups (AUC = 0.83, 95% CI; 0.75-0.90, p < 0.001) independently of ED50 which was less favourable (AUC = 0.66, 95% CI; 0.57-0.76, p = 0.002). Emax and ED50 were shown to be repeatable, and the dose-response method well tolerated. CONCLUSION: Novel capsaicin dose-response endpoints effectively discriminate between healthy controls and refractory chronic cough patients, which may better represent pathophysiological mechanisms and show promise for development as a tool to identify patients with cough hyper-excitability. CLINICAL TRIAL REGISTRATION: www.isrctn.com; ISRCTN23684347.

A double-blind randomised placebo-controlled trial investigating the effects of lesogaberan on the objective cough frequency and capsaicin-evoked coughs in patients with refractory chronic cough.

Objective: Baclofen is a centrally acting γ-aminobutyric acid type B (GABAB) receptor agonist which reduces gastro-oesophageal reflux and suppresses the cough reflex; however, central nervous system side-effects limit its use. Lesogaberan is a novel peripherally acting GABAB agonist, but its effects on refractory chronic cough are unknown. Design: We performed a single-centre, placebo-controlled, double-blind randomised crossover study in patients with chronic cough, refractory to the treatment of underlying conditions. Patients were randomised to treatment with lesogaberan 120 mg modified release twice daily or matched placebo for 2 weeks and then crossed over to the alternative therapy after a 2-week washout. The primary end-point was 24-h cough frequency measured with an acoustic monitoring system. In addition, cough responses to capsaicin were measured, and gastro-oesophageal reflux assessed by 24-h pH/impedance at screening. Results: 22 patients were randomised to receive lesogaberan/placebo or placebo/lesogaberan (female (73%); mean±sd age 63.7±7.2 years; median (interquartile range) cough duration 10.5 (5.8-17.0) years; mean (95% CI) 45 (29-67) reflux events in 24 h; two patients had abnormal oesophageal acid exposure times). Although lesogaberan reduced cough counts by 26% over placebo, this did not reach statistical significance (p=0.12). However, lesogaberan did significantly improve cough responses to capsaicin (p=0.04) and the number of cough bouts (p=0.04) compared with placebo. Lesogaberan was well tolerated in this study. Conclusions: Lesogaberan improved cough hypersensitivity and the number of bouts of coughing, but not coughs per hour. This implies a possible role for peripheral GABAB receptors in refractory chronic cough.

Effect of centrally and peripherally acting GABAB agonism on the healthy human cough reflex.

BACKGROUND: Currently there are no effective licensed anti-tussive therapies. Understanding how the neuronal mechanisms mediating the cough reflex in animal models translate to humans is important for the development of effective therapies. Pre-clinical studies suggest that the activation of GABAB receptors in both the peripheral and central nervous systems inhibit cough. OBJECTIVE: To compare the effect of central and peripherally acting GABAB agonists (lesogaberan and baclofen) on the cough reflex in healthy volunteers. METHODS: We performed a single center, double-blind, double-dummy, three-way crossover trial in healthy controls comparing single doses of lesogaberan (120 mg MR), with baclofen (40 mg) and placebos. Cough responses to inhaled capsaicin were assessed at screening and 2h post-dose on each study day. The primary endpoint was the maximum number of coughs evoked at any concentration of capsaicin (Emax) and the secondary endpoint was the concentration evoking 50% of the maximal response (ED50). RESULTS: Fifteen participants enrolled onto the study (median age 29 (IQR 25-44) years; 7 females, mean BMI 24.6(±3.0). Lesogaberan treatment produced a small, statistically significant increase in Emax compared with placebo [mean 13.4coughs (95%CI 10.1-17.9) vs. 11.8coughs (8.8-15.9), p = 0.04], but had no effect on ED50 [geometric mean 47.4 µM (95%CI 24.4-91.7) vs 37.6 µM (95%CI 19.2-73.5), p = 0.37]. In contrast, baclofen had no significant effect on Emax (11.1, 95%CI 8.1-15.4) (p = 0.23), but significantly increased ED50 compared with placebo (geometric mean 75.2 µM (95%CI 37.2-151.8), p = 0.002). CONCLUSION: This data suggests the anti-tussive actions of GABAB agonists, in healthy volunteers, occur in the central rather than the peripheral nervous system.

An open-label study of the tolerability and potential efficacy of memantine for treating refractory chronic cough.

Blocking NMDA receptors with memantine in refractory chronic cough patients is poorly tolerated and demonstrates no improvement in cough https://bit.ly/3kgx2g1.

A Randomized Controlled Trial to Assess the Effect of Lidocaine Administered via Throat Spray and Nebulization in Patients with Refractory Chronic Cough.

BACKGROUND: Refractory chronic cough (RCC) is a debilitating condition for which there are no licensed treatments. Lidocaine is a nonselective inhibitor of voltage-gated sodium channels with potential antitussive effects, but randomized placebo-controlled studies evaluating its efficacy in RCC are lacking. OBJECTIVE: To investigate the efficacy of nebulized lidocaine and lidocaine throat spray versus matched placebos in RCC. METHODS: This was a randomized, double-blind, double-dummy, placebo-controlled, 3-way crossover study, comparing the effect of single doses of nebulized lidocaine with lidocaine delivered by a throat spray and matched placebo. The primary end point was cough frequency over the 10 hours following treatment. Secondary end points were visual analog scale scores for urge-to-cough and cough severity; an exploratory analysis evaluated hourly cough rates up to 5 hours after treatment. RESULTS: Twenty-six subjects with RCC were recruited (22 females; mean age, 53.5 ± 12.1 years; FEV1 %predicted, 105.2 ± 16.8 L; forced vital capacity %predicted, 112.4 ± 18 L). Lidocaine throat spray, but not nebulized lidocaine, significantly reduced 10-hour cough frequency as compared with placebo (throat spray, 22.6 coughs/h; nebulization, 26.9 coughs/h; and placebos, 27.6 coughs/h; P = .04,). Lidocaine throat spray showed the greatest effect on cough compared with placebo in the first hour after administration (31.7 coughs/h vs 74.2 coughs/h; P = .004). Both nebulizer and spray treatments significantly alleviated urge-to-cough and cough severity visual analog scale scores compared with placebo (P < .05). There were no serious adverse events associated with lidocaine therapy. CONCLUSIONS: Lidocaine throat spray was effective in reducing cough frequency in patients with RCC. Voltage-gated sodium channel inhibitors applied to pharynx have potential as therapies for RCC.

Aprepitant for Cough in Lung Cancer. A Randomized Placebo-controlled Trial and Mechanistic Insights.

Rationale: Effective cough treatments are a significant unmet need in patients with lung cancer. Aprepitant is a licensed treatment for nausea and vomiting, which blocks substance P activation of NK-1 (neurokinin 1) receptors, a mechanism also implicated in cough.Objectives: To assess aprepitant in patients with lung cancer with cough and evaluate mechanisms in vagal nerve tissue.Methods: Randomized double-blind crossover trial of patients with lung cancer and bothersome cough. They received 3 days of aprepitant or matched placebo; after a 3-day washout, patients crossed to the alternative treatment. The primary endpoint was awake cough frequency measured at screening and Day 3 of each treatment; secondary endpoints included patient-reported outcomes. In vitro, the depolarization of isolated guinea pig and human vagus nerve sections in grease-gap recording chambers, indicative of sensory nerve activation, was measured to evaluate the mechanism.Measurements and Main Results: Twenty patients with lung cancer enrolled, with a mean age 66 years (±7.7); 60% were female and 80% had non-small cell cancer, 50% had advanced stage, and 55% had World Health Organization performance status 1. Cough frequency improved with aprepitant, reducing by 22.2% (95% confidence interval [CI], 2.8-37.7%) over placebo while awake (P = 0.03), 30.3% (95% CI, 12.7-44.3) over 24 hours (P = 0.002), and 59.8% (95% CI, 15.1-86.0) during sleep (P = 0.081). Patient-reported outcomes all significantly improved. Substance P depolarized both guinea pig and human vagus nerve. Aprepitant significantly inhibited substance P-induced depolarization by 78% in guinea pig (P = 0.0145) and 94% in human vagus (P = 0.0145).Conclusions: Substance P activation of NK-1 receptors appears to be an important mechanism driving cough in lung cancer, and NK-1 antagonists show promise as antitussive therapies.

The Effect of Pain Conditioning on Experimentally Evoked Cough: Evidence of Impaired Endogenous Inhibitory Control Mechanisms in Refractory Chronic Cough.

The pathophysiology of refractory chronic cough (RCC) is unclear. We hypothesised that endogenous inhibitory control mechanisms, such as those activated by noxiousstimuli inducing pain (conditioned pain modulation (CPM)), may be capable of inhibiting coughing and urge to cough evoked by inhaled capsaicin. Furthermore, these mechanisms may be impaired in patients with RCC.The objective was to investigate the effects of pain on cough and urge to cough (UTC) in healthy volunteers (HV) and RCC. HV and RCC patients underwent a randomised, controlled, 4-way cross-over study comparing the effect of 4 interventions on capsaicin evoked coughing and UTC. The interventions comprised immersing a hand in i) noxious cold-water, ii) warm water, iii) warm water but instructed to voluntarily supress coughing and iv) no intervention. The co-primary outcomes were numbers of evoked coughs and UTC scores.Twenty HV (mean age 50.1(±SD14.2), M:F 10:10) and 20 RCC (age 60.1(±7.9), M:F 9:11) participated. Overall, noxious cold water reduced capsaicin evoked UTC scores and cough numbers compared with warm water (1.6 (95% C.I. 1.3-2.0) versus 2.2 (1.8-2.6) p<0.001; 4.8 coughs (3.7-6.2) versus 7.9 coughs (6.7-9.5) p<0.001, respectively). HV and RCC demonstrated similar reductions in the UTC during noxious cold-water immersion, but noxious cold water and voluntary suppression interventions were less effective in RCC than HV in reducing capsaicin evoked cough (p=0.041).Endogenous inhibitory control mechanisms, specifically those activated by pain, can reduce both coughing and the UTC. Impairment of endogenous inhibitory control mechanisms may contribute to excessive coughing in RCC.

Gefapixant in two randomised dose-escalation studies in chronic cough.

BACKGROUND AND OBJECTIVES: Gefapixant has previously demonstrated efficacy in the treatment of refractory chronic cough at a high daily dose. The current investigations explore efficacy and tolerability of gefapixant, a P2X3 receptor antagonist, for the treatment of chronic cough using a dose-escalation approach. MATERIALS AND METHODS: Two randomised, double-blind, placebo-controlled, crossover, dose-escalation studies recruited participants with refractory chronic cough. Patients were assigned to receive ascending doses of gefapixant (study 1: 50-200 mg, study 2: 7.5-50 mg) or placebo for 16 days, then crossed-over after washout. The primary end-point was awake cough frequency assessed using a 24-h ambulatory cough monitor at baseline and on day 4 of each dose. Patient-reported outcomes included a cough severity visual analogue scale and the cough severity diary. RESULTS: In clinical studies, gefapixant doses ≥30 mg produced maximal improvements in cough frequency compared with placebo (p<0.05); reported cough severity measures improved at similar doses. Taste disturbance exhibited a different relationship with dose, apparently maximal at doses ≥150 mg. CONCLUSIONS: P2X3 antagonism with gefapixant demonstrates anti-tussive efficacy and improved tolerability at lower doses than previously investigated. Studies of longer duration are warranted.

Cough in Patients With Lung Cancer: A Longitudinal Observational Study of Characterization and Clinical Associations.

BACKGROUND: Cough is common in patients with lung cancer, and current antitussive treatments are suboptimal. There are little published data describing cough in patients with lung cancer or work assessing clinical associations. The aim of this study is to fill that gap. METHODS: This was a longitudinal prospective observational single-cohort study over 60 days. Patients were assessed through self-reported validated scales and, in a subsample, ambulatory cough monitoring at study entry (day 0), day 30, and day 60. RESULTS: At study entry, 177 patients were included and 153 provided data at day 60. The median duration of cough was 52 weeks (interquartile range, 8.5-260). Cough was described as severe enough to warrant treatment in 62% of the patients. Depending on the scale used, performance status was associated with both cough severity and cough impact (P < .001) at study entry, whereas higher cough severity at study entry was associated with female sex (P = .02), asthma (P = .035), and reflux disease (P < .001). Cough impact at study entry was additionally associated with experiencing nausea (P = .018). Cancer characteristics (ie, cancer stage, histology) were not associated with cough severity nor cough impact; neither was smoking or COPD. CONCLUSIONS: This is the first study to describe characteristics of cough in patients with lung cancer and to identify clinical associations that may be relevant for its treatment. Our data suggest that cough is a frequent and distressing symptom and an unmet clinical need. Its association with gastrointestinal symptoms in this study may improve our understanding of pathophysiology and therapeutic options for cough occurring in patients with lung cancer.

Use of zonal distribution of lung crackles during inspiration and expiration to assess disease severity in idiopathic pulmonary fibrosis.

PURPOSE OF THE STUDY: To measure the number and distribution of crackles in patients with idiopathic pulmonary fibrosis (IPF) and assess how this relates to measures of disease severity. STUDY DESIGN: Fourteen patients with IPF had both the number of crackles per litre of lung volume and lung function measured every 3 months for 1 year. Crackle counts were expressed according to position (upper and lower zones) and whether they occurred during inspiration and expiration. RESULTS: At baseline, crackle count per unit volume was higher at the bases than the apices and higher during inspiration than during expiration. There was a significant relationship between lung function and number of crackles per unit volume. Upper zone crackles during inspiration (crackle count vs forced vital capacity (FVC): r=0.69, p=0.007) and lower zone crackles during expiration (crackle count vs FVC: r=0.55, p=0.04) demonstrated the strongest relationship with lung function. CONCLUSIONS: Number and distribution of crackles in IPF relate to physiological measures of disease severity. Inspiratory lower zone crackles were universal and extensive but the presence, hence, development of inspiratory upper zone crackles and expiratory lower zone crackles correlated with measures of poorer lung function. The presence or appearance of these assessed using chest auscultation provides a clinician with simple measure of disease severity, and possibly progression, prompting further physiological assessment and review of treatment.

XEN-D0501, a Novel Transient Receptor Potential Vanilloid 1 Antagonist, Does Not Reduce Cough in Patients with Refractory Cough.

RATIONALE: Heightened cough responses to inhaled capsaicin, a transient receptor potential vanilloid 1 (TRPV1) agonist, are characteristic of patients with chronic cough. However, previously, a TRPV1 antagonist (SB-705498) failed to improve spontaneous cough frequency in these patients, despite small reductions in capsaicin-evoked cough. OBJECTIVES: XEN-D0501 (a potent TRPV1 antagonist) was compared with SB-705498 in preclinical studies to establish whether an improved efficacy profile would support a further clinical trial of XEN-D0501 in refractory chronic cough. METHODS: XEN-D0501 and SB-705498 were profiled against capsaicin in a sensory nerve activation assay and in vivo potency established against capsaicin-induced cough in the guinea pig. Twenty patients with refractory chronic cough participated in a double-blind, randomized, placebo-controlled crossover study evaluating the effect of 14 days of XEN-D0501 (oral, 4 mg twice daily) versus placebo on awake cough frequency (primary outcome), capsaicin-evoked cough, and patient-reported outcomes. MEASUREMENTS AND MAIN RESULTS: XEN-D0501 was more efficacious and 1,000-fold more potent than SB-705498 at inhibiting capsaicin-induced depolarization of guinea pig and human isolated vagus nerve. In vivo XEN-D0501 completely inhibited capsaicin-induced cough, whereas 100 times more SB-705498 was required to achieve the same effect. In patients, XEN-D0501 substantially reduced maximal cough responses to capsaicin (mean change from baseline, XEN-D0501, -19.3 ± 16.4) coughs; placebo, -1.8 ± 5.8 coughs; P < 0.0001), but not spontaneous awake cough frequency (mean change from baseline, XEN-D0501, 6.7 ± 16.9 coughs/h; placebo, 0.4 ± 13.7 coughs/h; P = 0.41). CONCLUSIONS: XEN-D0501 demonstrated superior efficacy and potency in preclinical and clinical capsaicin challenge studies; despite this improved pharmacodynamic profile, spontaneous cough frequency did not improve, ruling out TRPV1 as an effective therapeutic target for refractory cough. Clinical trial registered with www.clinicaltrialsregister.eu (2014-000306-36).

Capsaicin-evoked cough responses in asthmatic patients: Evidence for airway neuronal dysfunction.

BACKGROUND: Cough in asthmatic patients is a common and troublesome symptom. It is generally assumed coughing occurs as a consequence of bronchial hyperresponsiveness and inflammation, but the possibility that airway nerves are dysfunctional has not been fully explored. OBJECTIVES: We sought to investigate capsaicin-evoked cough responses in a group of patients with well-characterized mild-to-moderate asthma compared with healthy volunteers and assess the influences of sex, atopy, lung physiology, inflammation, and asthma control on these responses. METHODS: Capsaicin inhalational challenge was performed, and cough responses were analyzed by using nonlinear mixed-effects modeling to estimate the maximum cough response evoked by any concentration of capsaicin (Emax) and the capsaicin dose inducing half-maximal response (ED50). RESULTS: Ninety-seven patients with stable asthma (median age, 23 years [interquartile range, 21-27 years]; 60% female) and 47 healthy volunteers (median age, 38 years [interquartile range, 29-47 years]; 64% female) were recruited. Asthmatic patients had higher Emax and lower ED50 values than healthy volunteers. Emax values were 27% higher in female subjects (P = .006) and 46% higher in patients with nonatopic asthma (P = .003) compared with healthy volunteers. Also, patients with atopic asthma had a 21% lower Emax value than nonatopic asthmatic patients (P = .04). The ED50 value was 65% lower in female patients (P = .0001) and 71% lower in all asthmatic patients (P = .0008). ED50 values were also influenced by asthma control and serum IgE levels, whereas Emax values were related to 24-hour cough frequency. Age, body mass index, FEV1, PC20, fraction of exhaled nitric oxide, blood eosinophil counts, and inhaled steroid treatment did not influence cough parameters. CONCLUSION: Patients with stable asthma exhibited exaggerated capsaicin-evoked cough responses consistent with neuronal dysfunction. Nonatopic asthmatic patients had the highest cough responses, suggesting this mechanism might be most important in type 2-low asthma phenotypes.

Neurophenotypes in Airway Diseases. Insights from Translational Cough Studies.

RATIONALE: Most airway diseases, including chronic obstructive pulmonary disease (COPD), are associated with excessive coughing. The extent to which this may be a consequence of increased activation of vagal afferents by pathology in the airways (e.g., inflammatory mediators, excessive mucus) or an altered neuronal phenotype is unknown. Understanding whether respiratory diseases are associated with dysfunction of airway sensory nerves has the potential to identify novel therapeutic targets. OBJECTIVES: To assess the changes in cough responses to a range of inhaled irritants in COPD and model these in animals to investigate the underlying mechanisms. METHODS: Cough responses to inhaled stimuli in patients with COPD, healthy smokers, refractory chronic cough, asthma, and healthy volunteers were assessed and compared with vagus/airway nerve and cough responses in a cigarette smoke (CS) exposure guinea pig model. MEASUREMENTS AND MAIN RESULTS: Patients with COPD had heightened cough responses to capsaicin but reduced responses to prostaglandin E2 compared with healthy volunteers. Furthermore, the different patient groups all exhibited different patterns of modulation of cough responses. Consistent with these findings, capsaicin caused a greater number of coughs in CS-exposed guinea pigs than in control animals; similar increased responses were observed in ex vivo vagus nerve and neuron cell bodies in the vagal ganglia. However, responses to prostaglandin E2 were decreased by CS exposure. CONCLUSIONS: CS exposure is capable of inducing responses consistent with phenotypic switching in airway sensory nerves comparable with the cough responses observed in patients with COPD. Moreover, the differing profiles of cough responses support the concept of disease-specific neurophenotypes in airway disease. Clinical trial registered with www.clinicaltrials.gov (NCT 01297790).

P2X3 receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo-controlled phase 2 study.

BACKGROUND: Preclinical studies suggest that P2X3 receptors are expressed by airway vagal afferent nerves and contribute to the hypersensitisation of sensory neurons. P2X3 receptors could mediate sensitisation of the cough reflex, leading to chronic cough. We aimed to investigate the efficacy of a first-in-class oral P2X3 antagonist, AF-219, to reduce cough frequency in patients with refractory chronic cough. METHODS: We did a double-blind, placebo-controlled, two-period, crossover study at one UK centre. With a computer-generated sequence, we randomly assigned patients with refractory chronic cough to AF-219, 600 mg twice a day, or to placebo (1:1), and then, after a 2 week washout, assigned patients to receive the other treatment. Patients, health-care providers, and investigators were masked to sequence assignment. We assessed daytime cough frequency (primary endpoint) at baseline and after 2 weeks of treatment using 24 h ambulatory cough recordings. The primary analysis used a mixed effects model with the intention-to-treat population. This study was registered at ClinicalTrials.gov, number NCT01432730. FINDINGS: Of 34 individuals assessed between Sept 22, 2011, and Nov 29, 2012, we randomly assigned 24 patients (mean age 54·5 years; SD 11·1). In the observed case analysis, cough frequency was reduced by 75% when patients were allocated to AF-219 compared when allocated to placebo (p=0·0003). Daytime cough frequency fell from a mean 37 coughs per h (SD 32) to 11 (8) coughs per h after AF-219 treatment versus 65 (163) coughs per h to 44 (51) coughs per h after placebo. Six patients withdrew before the end of the study because of taste disturbances, which were reported by all patients taking AF-219. INTERPRETATION: P2X3 receptors seem to have a key role in mediation of cough neuronal hypersensitivity. Antagonists of P2X3 receptors such as AF-219 are a promising new group of antitussives. FUNDING: Afferent Pharmaceuticals.

Transient receptor potential vanilloid 1 (TRPV1) antagonism in patients with refractory chronic cough: a double-blind randomized controlled trial.

BACKGROUND: Inhalation of capsaicin, the extract of hot chili peppers, induces coughing in both animals and human subjects through activation of transient receptor potential vanilloid 1 (TRPV1) on airway sensory nerves. Therefore the TRPV1 receptor is an attractive target for the development of antitussive agents. OBJECTIVE: We sought to assess the antitussive effect of TRPV1 antagonism in patients with refractory chronic cough. METHODS: Twenty-one subjects with refractory chronic cough (>8 weeks) attending a specialist clinic were recruited to a randomized, double-blind, placebo-controlled crossover trial assessing a TRPV1 antagonist (SB-705498). Cough reflex sensitivity to capsaicin (concentration of capsaicin inducing at least 5 coughs) and 24-hour cough frequency were coprimary end points assessed after a single dose of SB-705498 (600 mg) and matched placebo. Cough severity and urge to cough were reported on visual analog scales, and cough-specific quality of life data were also collected. RESULTS: Treatment with SB-705498 produced a significant improvement in cough reflex sensitivity to capsaicin at 2 hours and a borderline significant improvement at 24 hours compared with placebo (adjusted mean difference of +1.3 doubling doses at 2 hours [95% CI, +0.3 to +2.2; P = .0049] and +0.7 doubling doses at 24 hours [95% CI, +0.0 to +1.5; P = .0259]). However, 24-hour objective cough frequency was not improved compared with placebo. Patient-reported cough severity, urge to cough, and cough-specific quality of life similarly suggested no effect of SB-705498. CONCLUSION: This study raises important questions about both the role of TRVP1-mediated mechanisms in patients with refractory chronic cough and also the predictive value of capsaicin challenge testing in the assessment of novel antitussive agents.