title: A randomized, double-blind, positive-controlled, 3-way cross-over human experimental pain study of a TRPV1 antagonist (V116517) in healthy volunteers and comparison with preclinical profile.
abstract: This experimental, translational, experimental pain, single-center, randomized, double-blind, single-dose, 3-treatment, 3-period cross-over proof-of-concept volunteer trial studied the efficacy of a novel TRPV1 antagonist (V116517) on capsaicin- and UV-B-induced hyperalgesia. Heat and pressure pain thresholds, von Frey stimulus-response functions, and neurogenic inflammation were assessed together with safety. Each treatment period was 4 days. The 3 single oral treatments were 300 mg V116517, 400 mg celecoxib (a COX-2 inhibitor), and placebo. The heat pain detection and tolerance thresholds were increased significantly (P < 0.0001) by V116517. Heat pain detection and tolerance thresholds showed significantly less capsaicin hyperalgesia after V116517 (P = 0.004 and P < 0.0001, respectively). Celecoxib reduced UV-B-provoked pressure pain sensitization (P = 0.01). Laser Doppler flowmetry and erythema index after UV-B were significantly (P < 0.0001) reduced by celecoxib. Stimulus-response function in capsaicin-treated areas showed significant differences between both celecoxib and placebo and between V116517 and placebo. The body temperature showed no change, and no side effects were reported for any of the treatments. The TRPV1 antagonists and the COX-2 inhibitor showed different antihyperalgesic profiles indicating different clinical targets. In addition, the preclinical profile of V116517 in rat models of UV-B and capsaicin-induced hypersensitivity was compared with the human experimental data and overall demonstrated an alignment between 2 of the 3 end points tested. The TRPV1 antagonist showed a potent antihyperalgesic action without changing the body temperature but heat analgesia may be a potential safety issue.
authors.affiliation: SMI, Department of Health Science and Technology, Faculty of Medicine, Aalborg University, Aalborg, Denmark.|C4Pain, Aalborg, Denmark.
authors.forename: Lars
authors.initials: L
authors.lastname: Arendt-Nielsen
authors.affiliation: Purdue Pharma, Stamford, CT, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Harris
authors.affiliation: Purdue Pharma, Stamford, CT, USA.
authors.forename: Garth T
authors.initials: GT
authors.lastname: Whiteside
authors.affiliation: Purdue Pharma, Stamford, CT, USA.
authors.forename: Michele
authors.initials: M
authors.lastname: Hummel
authors.affiliation: Purdue Pharma, Stamford, CT, USA.
authors.forename: Terri
authors.initials: T
authors.lastname: Knappenberger
authors.affiliation: Purdue Pharma, Stamford, CT, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: O'Keefe
authors.affiliation: Purdue Pharma, Stamford, CT, USA.
authors.forename: Ram
authors.initials: R
authors.lastname: Kapil
authors.affiliation: Purdue Pharma, Stamford, CT, USA.
authors.forename: Don
authors.initials: D
authors.lastname: Kyle
mesh_terms: D000293:Adolescent; D000328:Adult; D000631:Aminopyridines / Q000627:therapeutic use; D000818:Animals; D002211:Capsaicin / Q000009:adverse effects; D000068579:Celecoxib / Q000627:therapeutic use; D018592:Cross-Over Studies; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use; D004195:Disease Models, Animal; D004311:Double-Blind Method; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D010146:Pain / Q000188:drug therapy* / Q000209:etiology; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D010812:Physical Stimulation / Q000009:adverse effects; D011312:Pressure / Q000009:adverse effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors*; D014466:Ultraviolet Rays / Q000009:adverse effects; D055815:Young Adult
chemical_list: C000595012:4-(3-chloro-5-(1,2-dihydroxyethyl)-2-pyridyl)-N-(5-(trifluoromethyl)-2-pyridyl)-3,6-dihydro-2H-pyridine-1-carboxamide; D000631:Aminopyridines; D052246:Cyclooxygenase 2 Inhibitors; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D000068579:Celecoxib; D002211:Capsaicin