GABAergic modulation of Secondary hyperalgesia: A randomized controlled 4 ‐way crossover trial with the α2‐subunit preferring GABA positive allosteric modulator, N‐Desmethyl‐Clobazam in healthy volunteers

AbstractThe antihyperalgesic and sedative effects of the α2‐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 UVB‐induced experimental pain model. Single (20, 40, 60 mg) and repeated doses (20mg over 15 days) NDMC pharma cokinetic were evaluated.Thirty ‐two subjects participated to 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 to 8.5], p=0.462 and 0.4% [ ‐11.9 to 12.6], p=0.952, respectively). An overall treatment effect was found on level of sedation. Compared to placebo, sedation was higher under clonazepam (mean difference= 39 mm [30 to 49] on a visual analog scale, p<0.001) while NDMC was free of sedative effect. NDMC pharmacokinetic 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...
Source: European Journal of Pain - Category: Anesthesiology Authors: Tags: ORIGINAL ARTICLE Source Type: research