An oral TRPV1 antagonist attenuates laser radiant-heat-evoked potentials and pain ratings from UV(B)-inflamed and normal skin

• Published in: British journal of clinical pharmacology Vol. 75; no. 2; p. 404
• Main Authors: Schaffler, Klaus, Reeh, Peter, Duan, W Rachel, Best, Andrea E, Othman, Ahmed A, Faltynek, Connie R, Locke, Charles, Nothaft, Wolfram
• Format: Journal Article
• Language: English
• Published: England 01.02.2013
• Subjects: Administration, Oral; Adult; Analgesics, Opioid - pharmacology; Cross-Over Studies; Cyclooxygenase 2 Inhibitors - pharmacology; Double-Blind Method; Etoricoxib; Evoked Potentials - drug effects; Hot Temperature - adverse effects; Humans; Indazoles - pharmacology; Lasers, Gas - adverse effects; Male; Pain; Pain Measurement - drug effects; Pyridines - pharmacology; Severity of Illness Index; Skin - radiation effects; Sulfones - pharmacology; Tramadol - pharmacology; TRPV Cation Channels - antagonists & inhibitors; Ultraviolet Rays - adverse effects; Urea - analogs & derivatives; Urea - pharmacology
• ISSN: 1365-2125
• DOI: 10.1111/j.1365-2125.2012.04377.x

Laser (radiant-heat) evoked potentials (LEPs) from vertex-EEG peak-to-peak (PtP) amplitude were used to determine acute antinociceptive/antihyperalgesic efficacy of ABT-102, a novel TRPV1 antagonist efficacious in preclinical pain models, compared with active controls and placebo in normal and UV(B)-inflamed skin. This was a randomized, placebo- and active-controlled, double-blind, intra-individual, crossover trial. Twenty-four healthy subjects received six sequences of single doses of ABT-102 (0.5, 2, 6 mg), etoricoxib 90 mg, tramadol 100 mg and placebo. Painful stimuli were induced by CO(2) -laser on normal and UV(B) -inflamed skin. LEPs and visual analogue scale (VAS-pain) ratings were taken at baseline and hourly up to 8 h post-dose from both skin types. Compared with placebo, significant mean decreases in the primary variable of LEP PtP-amplitude from UV(B)-inflamed skin were observed with ABT-102 6 mg (P < 0.001), ABT-102 2 mg (P = 0.002), tramadol 100 mg (P < 0.001), and etoricoxib 90 mg (P = 0.001) over the 8 h period; ABT-102 0.5 mg was similar to placebo. ABT-102 6 mg was superior to active controls over the 8 h period (P < 0.05) whereas ABT-102 2 mg was comparable. Improvements in VAS scores compared with placebo were observed with ABT-102 6 mg (P < 0.001) and ABT-102 2 mg (P = 0.002). ABT-102 average plasma concentrations were 1.3, 4.4 and 9.4 ng ml(-1) for the 0.5, 2 and 6 mg doses, respectively. There were no clinically significant safety findings. TRPV-1 antagonism appears promising in the management of clinical pain, but requires further investigation.