Abstract
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.