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

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 UVB induced hyperalgesia. Heat and pressure pain thresholds, von Frey stimulus-response functions, and neurogenic inflammation were assessed together with safety. Each treatment period was four days. The three 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 UVB provoked pressure pain sensitization (p=0.01). Laser Doppler flowmetry and erythema index after UVB 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 anti-hyperalgesic profiles indicating different clinical targets. In addition the preclinical profile of V116517 in rat models of UVB and capsaicin induced hypersensitivity was compared to the human experimental data and overall demonstrated an alignment between two of the three end points tested.The TRPV1 antagonist showed a potent anti-hyperalgesic action without changing the body temperature but heat analgesia may be a potential safety issue.