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.

Allergen challenge increases capsaicin-evoked cough responses in patients with allergic asthma.

BACKGROUND: Cough is a common and troublesome symptom in asthmatic patients, but little is known about the neuronal pathways that trigger cough. The mechanisms by which airway inflammation, airway hyperresponsiveness, and variable airflow obstruction cause cough are unclear. OBJECTIVE: We sought to investigate the effects of allergen exposure on cough reflex sensitivity. METHODS: We performed a 9-visit, randomized, single-blind, placebo-controlled, 2-way crossover study comparing cough responses to inhaled capsaicin in patients with mild atopic asthma after allergen challenge compared with diluent control. Full-dose capsaicin challenge was performed at screening to determine the capsaicin dose inducing a half-maximal response, which was subsequently administered at 30 minutes and 24 hours after inhaled allergen/diluent challenge. Spontaneous coughing was measured for 24 hours after allergen/diluent. Methacholine challenge and sputum induction were performed before and after allergen/diluent challenge. RESULTS: Twelve steroid-naive subjects completed the study (6 female subjects; mean age, 34.8 years). Allergen inhalation caused both an early (mean ± SD, 38.2% ± 13.0%) and late (mean ± SD, 23.7% ± 13.2%) decrease in FEV1 and an increase in sputum eosinophil counts 24 hours later (after diluent: median, 1.9% [interquartile range, 0.8% to 5.8%]; after allergen: median, 14.9% [interquartile range, 8.9% to 37.3%]; P = .005). There was also an increase in capsaicin-evoked coughs after allergen exposure compared with diluent at both 30 minutes (geometric mean coughs, 21.9 [95% CI, 16.5-29.20] vs 12.1 [95% CI, 8.3-17.7]; P < .001) and 24 hours (geometric mean coughs, 16.1 [95% CI, 11.3-23.0] vs 9.8 [95% CI, 6.1-15.8]; P = .001). Allergen exposure was also associated with an increase in spontaneous coughs over 24 hours. CONCLUSION: Allergen-induced bronchoconstriction and airway eosinophilia result in increased cough reflex sensitivity to capsaicin associated with an increase in 24-hour spontaneous coughing.

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.

Chronic cough is associated with increased reporting of autonomic symptoms.

BACKGROUND: Patients with some neuronal hypersensitivity syndromes experience increased autonomic symptoms. Chronic cough is thought to be a neuronal hypersensitivity disorder and, therefore, may be associated with increased autonomic symptoms. METHODS: 96 chronic cough subjects were recruited from the tertiary cough clinic based at Wythenshawe Hospital, Manchester, UK; 76 healthy controls were also recruited. Subjects were aged >18 years. Those with significant respiratory disease, significant smoking history or taking medication known to affect cough or autonomic function were excluded. Subjects completed the Composite Autonomic Symptom Score (COMPASS) 31 autonomic symptom questionnaire, the Cough Quality of Life Questionnaire (CQLQ) and a cough severity visual analogue scale (VAS). RESULTS: 96 chronic cough subjects and 76 healthy volunteers were included in the final analysis. Mann-Whitney U-tests comparing COMPASS 31 scores in both groups showed that the total COMPASS 31 score was significantly higher in the patient group (median 18.4, interquartile range (IQR) 7.5-32.0) than the control group (median 3.6, IQR 1.1-9.5; p<0.001). The chronic cough subjects had significantly higher symptom scores than the healthy volunteer groups in all domains (p≤0.001) except vasomotor symptoms (p=0.770). There was a positive association between COMPASS 31 and CQLQ in the patient group (p<0.001, r=0.432) but not COMPASS 31 and VAS (p=0.227). INTERPRETATION: Chronic cough patients do indeed report more frequent and severe autonomic symptoms than healthy volunteers, indicating that this population may suffer from dysautonomia. At present, it remains unclear whether this occurs as a result of the cough or whether both the cough and dysfunction are part of some wider vagal pathology.