{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T01:37:47Z","timestamp":1792201067386,"version":"4.4.0"},"reference-count":42,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2020,4,1]],"date-time":"2020-04-01T00:00:00Z","timestamp":1585699200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"publisher","award":["SPUM33CM30_124117\/1"],"award-info":[{"award-number":["SPUM33CM30_124117\/1"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["European Journal of Pain"],"published-print":{"date-parts":[[2020,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:label\/><jats:p>The antihyperalgesic and sedative effects of the \u03b12\u2010subunit preferring GABA<jats:sub>A<\/jats:sub> positive allosteric modulator (GAM), <jats:italic>N<\/jats:italic>\u2010desmethyl\u2010clobazam (NDMC), 20 and 60\u00a0mg, were assessed in a randomized, placebo and active\u2010controlled (clonazepam 1,5\u00a0mg), 4\u2010way crossover study, in healthy volunteers, using the ultraviolet B\u2010induced experimental pain model. Single (20, 40, 60\u00a0mg) and repeated doses (20\u00a0mg over 15\u00a0days) of NDMC pharmacokinetics were evaluated. Thirty\u2010two subjects participated in the study. Primary outcome parameter was maximal change in the area of cutaneous UVB irradiation\u2010induced secondary hyperalgesia (ASH). ASH decreased under all treatments. Mean (<jats:italic>SD<\/jats:italic>) 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\u00a0=\u00a02.3\u00a0cm<jats:sup>2<\/jats:sup> [95% CI 4.0\u20138.5], <jats:italic>p<\/jats:italic>\u00a0=\u00a0.462 and 0.4% [\u221211.9 to 12.6], <jats:italic>p<\/jats:italic>\u00a0=\u00a0.952, respectively). An overall treatment effect was found on level of sedation. Compared to placebo, sedation was higher under clonazepam (mean difference\u00a0=\u00a039\u00a0mm [30\u201349] on a visual analogue scale, <jats:italic>p<\/jats:italic>\u00a0&lt;\u00a0.001) while NDMC was free of sedative effect. NDMC pharmacokinetics after single doses showed poor absorption, but was linear. Steady\u2010state plasma concentrations of NDMC20 were attained within 14\u00a0days, with low between\u2010subjects variability. Mean steady\u2010state concentration (<jats:italic>C<\/jats:italic><jats:sub>S\u2010S<\/jats:sub>, <jats:italic>SD<\/jats:italic>) reached 209 (22) ng\/ml. NDMC absence of sedative effect and its overall well\u2010characterized 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>This article, presenting the Phase I data of the new antihyperalgesic compound, \u03b12\u2010subunit GABA<jats:sub>A<\/jats:sub> positive allosteric modulator, <jats:italic>N<\/jats:italic>\u2010desmethyl\u2010clobazam (NDMC) is exploring the modulation of a new target in the treatment of neuropathic pain. Based on these results and on its preclinical properties NDMC would qualify as a good tool compound to seek confirmation of the clinical utility of selective GABA allosteric modulators in neuropathic pain patients.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ejp.1554","type":"journal-article","created":{"date-parts":[[2020,3,14]],"date-time":"2020-03-14T17:04:45Z","timestamp":1584205485000},"page":"1094-1106","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["GABAergic modulation of secondary hyperalgesia: A randomized controlled 4\u2010way crossover trial with the \u03b12\u2010subunit preferring GABA positive allosteric modulator, <i>N<\/i>\u2010desmethyl\u2010clobazam in healthy volunteers"],"prefix":"10.1002","volume":"24","author":[{"given":"Alain","family":"Matthey","sequence":"first","affiliation":[{"name":"Division of Clinical Pharmacology and Toxicology Multidisciplinary Pain Center Geneva University Hospitals Geneva Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youssef","family":"Daali","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology and Toxicology Multidisciplinary Pain Center Geneva University Hospitals Geneva Switzerland"},{"name":"Faculty of Medicine Geneva University Geneva Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7ois","family":"Curtin","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology and Toxicology Multidisciplinary Pain Center Geneva University Hospitals Geneva Switzerland"},{"name":"Faculty of Medicine Geneva University Geneva Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antoine","family":"Poncet","sequence":"additional","affiliation":[{"name":"Division of Clinical Epidemiology Geneva University Hospitals Geneva Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jules","family":"Desmeules","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology and Toxicology Multidisciplinary Pain Center Geneva University Hospitals Geneva Switzerland"},{"name":"Faculty of Medicine Geneva University Geneva Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Besson","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology and Toxicology Multidisciplinary Pain Center Geneva University Hospitals Geneva Switzerland"},{"name":"Faculty of Medicine Geneva University Geneva Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,4]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.j.pain.0000460358.01998.15"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1468\u20101331.2010.02999.x"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1213\/ANE.0000000000002500"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-642-56833-6_2"},{"issue":"2","key":"e_1_2_8_6_1","first-page":"291","article-title":"International Union of Pharmacology. 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