DISCUSSION
This is the first human study to determine whether both peripherally
acting and centrally acting GABAB agonists modulate
cough responses to inhaled capsaicin compared with placebo. The data
suggests that the actions of GABAB agonists, in healthy
volunteers occur in the central rather than the peripheral nervous
system. Lesogaberan (peripherally acting GABAB agonist)
had no significant inhibitory effect on the cough reflex whereas
baclofen (centrally acting GABAB agonist) increased the
ED50. Interestingly, lesogaberan had a small but significant increase on
Emax i.e. the subjects coughed, slightly, more on this drug.
The dose response curve from our data (Figure 3) demonstrates a subtle
but significant right shift of the baclofen curve, suggesting a stronger
stimulus is required to evoke coughing when on baclofen treatment,
consistent with the existing literature. Dicpinigaitis et al, studied a
similar group pf subjects to those in this study (20 healthy volunteers,
mean age 30) who were dosed chronically with baclofen 10mg three times a
day (6) and following that study he went on to study 20mg dosing in a
similar group (7). In both of these studies the baclofen group
demonstrated a significant increase in the log C5 capsaicin
concentration. This is the concentration of capsaicin that induces 5
coughs which is broadly comparable to the ED50 in our study. There are
two small case series in the literature which have suggested baclofen
might also treat chronic cough. One was an open-label study evaluating a
4-week course of low-dose, oral baclofen against ACE inhibitor-induced
cough (8) suggesting that baclofen treatment caused a prolonged
antitussive effect. The other study reported suppression of cough and
capsaicin cough responses in two chronic cough patients after a 14-day
course of baclofen, 10mg; three times a day (5). Participants in both of
these studies did not report significant adverse effects, however, in
clinical practice patients report significant dizziness (up to 28% of
patients) and drowsiness (up to 10% of patients) which limits its use
(10).
It is worth noting that changes in experimentally evoked cough do not
necessarily equate to clinical anti-tussive effects on spontaneous
coughing. This was demonstrated by Belvisi et al., 2017 who studied the
effect of a potent TRPV1 antagonist (XEN-D0501) vs placebo on capsaicin
evoked cough and spontaneous 24-hour cough frequency (11). Despite
XEN-D0501 leading to significant reduction in the capsaicin Emax, there
was no improvement in objective cough frequency. In addition to this
some agents (such as morphine and gabapentin) that have been shown to
improve cough specific quality of life, and are currently used
off-license in a clinical setting, do not appear to modulate the C5
endpoint in cough challenge (12). However, it remains unclear which
challenge agents, methodology and endpoints are optimal at present. Thus
the main role of cough challenge seems to be in confirming target
engagement and understanding whether mechanisms translate from animal
studies to humans.
Interestingly, the data from this study suggests a difference between
the effects of lesogaberan in humans compared with a guinea pig model.
Canning et al., found that both lesogaberan and baclofen significantly
reduced citric acid evoked coughs in guinea-pigs (4). Possible
explanations for this include differences in the blood brain barrier
between species and also relatively higher levels of dosing in the
guinea pig, which may have saturated the GATs responsible for inhibiting
the CNS effects of lesogaberan.
Despite the relatively small number of subjects in this study,
statistically significant changes between the treatments were teased out
by the dose response inhalational capsaicin challenge, suggesting the
utility and power of this particular method and these endpoints when
assessing cough reflex responses. The small but statistically
significant increase in Emax with lesogaberan therapy is interesting,
paradoxical in the context of the inhibitory nature of
GABAB and difficult to explain. Our prediction was that
Emax would have reduced with lesogaberan, mirroring the changes in
animal studies. One potential explanation for the lack of reduction in
Emax with lesogaberan in healthy volunteers is that
GABAB is involved in endogenous inhibitory mechanisms
controlling cough. In the healthy state, these control mechanisms are
intact and thus additional GABAB agonism may have no
effect on cough responses, whereas in patients with chronic cough there
is increasing evidence that these descending inhibitory mechanisms may
be deficient (13-15) and in such circumstances GABABagonism could have an effect in chronic cough patients not seen in
healthy controls.
This study has some limitations. Firstly we used single doses of
lesogaberan and baclofen, as opposed to multiple dosing. However, we
were still able to replicate previous findings with baclofen after two
weeks of dosing. Another possible limitation of this study is that
capsaicin was used for the cough challenge, whereas the animal studies
used citric acid. This choice was made in light of the fact that all
previous human studies suggesting an effect of baclofen on cough
responses had all employed capsaicin challenge, furthermore this
particular challenge methodology has not been performed using citric
acid. An effect of lesogaberan on citric acid but not capsaicin evoked
cough cannot be excluded.
In conclusion, this data suggests GABAB receptor
agonists are inhibitory of the human cough reflex in health, but only
through their activity in the central nervous system. It remains to be
seen whether peripheral GABAB agonists have any effect
on the sensitized cough reflex in chronic cough patients.