Exploring the Role of the GABAergic Modulation in Pain Transmission in Human
Status:
Completed
Trial end date:
2018-01-31
Target enrollment:
Participant gender:
Summary
Neuropathic pain affects about 7% of the general population in European countries.
Meta-analyses indicate that only a minority of neuropathic pain patients has adequate
response to drug therapy and management of neuropathic pain is still an unmet medical need.
New insights into the contribution of defined subtypes of GABAA receptors (GABAARs) to the
different clinical effects of benzodiazepines, including analgesia, have suggested that
α1-sparing selective benzodiazepines, such as N-desmethylclobazam (NDMC), may be a new
realistic alternative for the treatment of neuropathic pain. Results from our previous study
in healthy volunteers assessing the antihyperalgesic and sedative effects of benzodiazepines
on a UVB-induced pain model of central sensitization showed that, at the time of maximum
effect, clobazam and clonazepam antihyperalgesic effect was greater than placebo by
respectively 15.7% (95% CI 0.8 - 30.5) and 28.6% (95% CI 4.5 - 52.6), p<0.05. Moreover
difference in sedation (VAS), as compared to placebo, was only significant for clonazepam
26.3mm (95%CI 15.0-37.7), p<0.001. Our preclinical data also demonstrate that, in recombinant
receptors, NDMC has a better α2- over α1GABAARs activity ratio than clobazam and diazepam.
And, unlike diazepam, NDMC caused no or modest sedation at antihyperalgesic doses in two
strains of wild-type mice. In addition NDMC α2/α1 in vitro activity profile and long term
clinical experience from its marketed parent compound (clobazam) make it an advisable
clinical candidate for further proof-of-concept assessments in human. Therefore the Geneva
University Hospitals have manufactured a new chemical entity and initiated a drug development
program for NDMC starting with this proof-of-concept phase 1b randomized double-blind
crossover (4 arms) study that will assess the analgesic and sedative effects of NDMC 20mg and
60mg compared to clonazepam 1.5 mg or placebo on a UVB-induced erythema pain model in healthy
volunteers.