ObjectiveBaclofen is a centrally acting Gamma-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.DesignWe 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 (MR) twice daily (BD) or matched placebo for 2 weeks and then crossed over to the alternative therapy after a 2-week washout. The primary endpoint was 24-hour cough frequency measured with an acoustic monitoring system. Cough responses to capsaicin were also measured and gastro-oesophageal reflux assessed by 24 h pH/impedance at screening.ResultsTwenty-two patients were randomised to receive lesogaberan/placebo or placebo/lesogaberan [female (73%), mean age 63.7 ±s.d.7.2 years, median cough duration 10.5 years (IQR 5.8–17.0), mean 45 (95%CI 29–67) reflux events in 24hrs and 2 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.ConclusionsLesogaberan improved cough hyper-sensitivity 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.
Conclusion This small pilot study suggest that opiate sensitive inhibitory mechanisms may have a role in controlling the cough reflex even in healthy subjects.
REFERENCES1 Hilton EC, Baverel PG, Woodcock A, Van Der Graaf PH, Smith JA.
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 (120mg MR), with baclofen (40mg) 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 patients 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 47.4µM (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 75.2µM (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.
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