GABAergic modulation of secondary hyperalgesia- A randomized controlled 4_way crossover trial with the alpha2_subunit preferring GABA positive allosteric modulator- N_desmethyl_clobazam in healthy volunteers

A Matthey, Y Daali, F Curtin, et al

Division of Clinical Pharmacology and Toxicology, University Hospital of Geneva, Geneva, Switzerland.

European Journal of Pain

The antihyperalgesic and sedative effects of the _2_subunit preferring GABAA positive allosteric modulator (GAM), N_desmethyl_clobazam (NDMC), 20 and 60 mg, were assessed in a randomized, placebo and active_controlled (clonazepam 1,5 mg), 4_way crossover study, in healthy volunteers, using the ultraviolet B_induced experimental pain model. Single (20, 40, 60 mg) and repeated doses (20 mg over 15 days) of NDMC pharmacokinetics were evaluated. Thirty_two subjects participated in the study. Primary outcome parameter was maximal change in the area of cutaneous UVB irradiation_induced secondary hyperalgesia (ASH). ASH decreased under all treatments. Mean (SD) relative change was 79 (22)%, 83 (24)%, 77 (30)% and 92 (16)% for placebo, NDMC20, NDMC60 and clonazepam, respectively. Neither absolute change nor relative change in ASH was significantly different between NDMC60 and placebo (mean difference = 2.3 cm2 [95% CI 4.0–8.5], p = .462 and 0.4% [_11.9 to 12.6], p = .952, respectively). An overall treatment effect was found on level of sedation. Compared to placebo, sedation was higher under clonazepam (mean difference = 39 mm [30–49] on a visual analogue scale, p < .001) while NDMC was free of sedative effect. NDMC pharmacokinetics after single doses showed poor absorption, but was linear. Steady_state plasma concentrations of NDMC20 were attained within 14 days, with low between_subjects variability. Mean steady_state concentration (CS_S, SD) reached 209 (22) ng/ml. NDMC absence of sedative effect and its overall well_characterized safety coming from years of utilization as a metabolite from clobazam, raise the prospect of dose escalating trials in patients to quantify its clinical utility.

BIOSEB Instruments Used:
Electronic Von Frey 4 (BIO-EVF4),Electronic Von Frey 5 with embedded camera (BIO-EVF5)

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