title: Evaluation of anti-hyperalgesic and analgesic effects of two benzodiazepines in human experimental pain: a randomized placebo-controlled study.
abstract: OBJECTIVE
  Compounds that act on GABA-receptors produce anti-hyperalgesia in animal models, but little is known on their effects in humans. The aim of this study was to explore the potential usefulness of GABA-agonism for the control of pain in humans. Two agonists at the benzodiazepine-binding site of GABAA-receptors (clobazam and clonazepam) were studied using multiple experimental pain tests. Positive results would support further investigation of GABA agonism for the control of clinical pain.
  
  
  METHODS
  In a randomized double-blind crossover design, 16 healthy male volunteers received clobazam 20 mg, clonazepam 1 mg and tolterodine 1 mg (active placebo). The area of static hyperalgesia after intradermal capsaicin injection was the primary endpoint. Secondary endpoints were: area of dynamic hyperalgesia, response to von Frey hair stimulation, pressure pain thresholds, conditioned pain modulation, cutaneous and intramuscular electrical pain thresholds (1, 5 and 20 repeated stimulation), and pain during cuff algometry.
  
  
  RESULTS
  For the primary endpoint, an increase in the area of static hyperalgesia was observed after administration of placebo (p<0.001), but not after clobazam and clonazepam. Results suggestive for an anti-hyperalgesic effect of the benzodiazepines were obtained with all three intramuscular pain models and with cuff algometry. No effect could be detected with the other pain models employed.
  
  
  CONCLUSIONS
  Collectively, the results are suggestive for a possible anti-hyperalgesic effect of drugs acting at the GABAA-receptors in humans, particularly in models of secondary hyperalgesia and deep pain. The findings are not conclusive, but support further clinical research on pain modulation by GABAergic drugs. Because of the partial results, future research should focus on compounds acting selectively on subunits of the GABA complex, which may allow the achievement of higher receptor occupancy than unselective drugs. Our data also provide information on the most suitable experimental models for future investigation of GABAergic compounds.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01011036.
authors.affiliation: University Department of Anesthesiology and Pain Therapy, Bern University Hospital, Inselspital, Bern, Switzerland.
authors.forename: Pascal H
authors.initials: PH
authors.lastname: Vuilleumier
authors.forename: Marie
authors.initials: M
authors.lastname: Besson
authors.forename: Jules
authors.initials: J
authors.lastname: Desmeules
authors.forename: Lars
authors.initials: L
authors.lastname: Arendt-Nielsen
authors.forename: Michele
authors.initials: M
authors.lastname: Curatolo
mesh_terms: D000293:Adolescent; D000328:Adult; D000700:Analgesics / Q000008:administration & dosage*; D001569:Benzodiazepines / Q000008:administration & dosage*; D000078306:Clobazam; D002998:Clonazepam / Q000008:administration & dosage*; D003430:Cross-Sectional Studies; D004311:Double-Blind Method; D005260:Female; D018757:GABA Modulators / Q000008:administration & dosage*; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism; D059408:Pain Management / Q000379:methods; D018079:Receptors, GABA / Q000378:metabolism
chemical_list: D000700:Analgesics; D018757:GABA Modulators; D018079:Receptors, GABA; D001569:Benzodiazepines; D000078306:Clobazam; D002998:Clonazepam
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