title: GABAergic modulation in central sensitization in humans: a randomized placebo-controlled pharmacokinetic-pharmacodynamic study comparing clobazam with clonazepam in healthy volunteers.
abstract: Positive allosteric modulators of GABAA receptors (GAMs) acting at specific subtypes of GABAA receptors effectively restore compromised spinal pain control in rodents. Studies addressing a similar antihyperalgesic effect in humans are sparse and are hampered by sedative effects of nonselective GAMs available for use in humans. We present results from a randomized controlled double-blind crossover study in 25 healthy volunteers, which addressed potential antihyperalgesic actions of clobazam (CBZ) and clonazepam (CLN) at mildly sedating equianticonvulsive doses. Clobazam was chosen because of its relatively low sedative properties and CLN because of its use in neuropathic pain. Tolterodine (TLT) was used as an active placebo. The primary outcome parameter was a change in the area of cutaneous UVB irradiation-induced secondary hyperalgesia (ASH), which was monitored for 8 hours after drug application. Sedative effects were assessed in parallel to antihyperalgesia. Compared with TLT, recovery from hyperalgesia was significantly faster in the CBZ and CLN groups (P = 0.009). At the time point of maximum effect, the rate of recovery from hyperalgesia was accelerated by CBZ and CLN, relative to placebo by 15.7% (95% confidence interval [CI] 0.8-30.5), P = 0.040, and 28.6% (95% CI 4.5-52.6), P = 0.022, respectively. Active compounds induced stronger sedation than placebo, but these differences disappeared 8 hours after drug application. We demonstrate here that GAMs effectively reduce central sensitization in healthy volunteers. These results provide proof-of-principle evidence supporting efficacy of GAMs as antihyperalgesic agents in humans and should stimulate further research on compounds with improved subtype specificity.
authors: Division of Clinical Pharmacology and Toxicology, Multidisciplinary Pain Center, University Hospital of Geneva, Geneva, Switzerland Division of Clinical Epidemiology, University Hospital of Geneva, Geneva, Switzerland Department of Anesthesiology and Pain Medicine, Bern University Hospital, Bern, Switzerland. Department of Anesthesiology and Pain Medicine, University of Washington, WA, USA Institute of Pharmacology and Toxicology, University of Zurich, Switzerland and Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH), Zürich, Switzerland.
authors: Marie
authors: M
authors: Besson
authors: Alain
authors: A
authors: Matthey
authors: Youssef
authors: Y
authors: Daali
authors: Antoine
authors: A
authors: Poncet
authors: Pascal
authors: P
authors: Vuillemier
authors: Michele
authors: M
authors: Curatolo
authors: Hanns Ulrich
authors: HU
authors: Zeilhofer
authors: Jules
authors: J
authors: Desmeules
mesh_terms: D000293:Adolescent; D000328:Adult; D001569:Benzodiazepines / Q000097:blood* / Q000493:pharmacokinetics*; D000078306:Clobazam; D002998:Clonazepam / Q000097:blood* / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D004311:Double-Blind Method; D005260:Female; D018757:GABA Modulators / Q000097:blood* / Q000493:pharmacokinetics; D005838:Genotype; D064368:Healthy Volunteers; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy* / Q000209:etiology; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D017288:Pain Threshold / Q000187:drug effects*; D012018:Reflex / Q000187:drug effects; D012438:Saccades / Q000187:drug effects; D012867:Skin / Q000294:innervation; D013997:Time Factors; D014466:Ultraviolet Rays / Q000009:adverse effects; D055815:Young Adult
chemical_list: D018757:GABA Modulators; D001569:Benzodiazepines; D000078306:Clobazam; D002998:Clonazepam; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A