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

Abstract

Aims: 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.

Methods: 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.

Results: 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.

Conclusions: TRPV-1 antagonism appears promising in the management of clinical pain, but requires further investigation.

Figure 1

Study design. 0.5 mg, 2 mg and 6 mg = dose of ABT-102; Etor = etoricoxib; PBO = placebo; Tram = tramadol

Figure 2

Procedure timing relative to study drug administration. LEP = laser evoked potential; UV_B = ultraviolet burn; VAS = visual analogue scale. *, Baseline assessment; ▾, LEP and VAS on normal and UV_B-irritated skin; •, Pharmacokinetic sampling; □, Skin reflection spectrometry measurement

Figure 3

LEP PtP-amplitude over time in normal skin (A) and UV_B-irritated skin (B) for all randomized subjects (n = 24). +P ≤ 0.05 compared with placebo; **P ≤ 0.001 compared with placebo. , ABT-102 0.5 mg; , ABT-102 2 mg; , ABT-102 6 mg; , Tramadol 100 mg; , Etoricoxib 90 mg; , Placebo

Figure 4

VAS pain scores over time in normal skin (A) and UV_B-irritated skin (B) for all randomized subjects (n = 24). +P ≤ 0.05 compared with placebo; **P ≤ 0.001 compared with placebo. (, ABT-102 0.5 mg; , ABT-102 2 mg; , ABT-102 6 mg; , Tramadol 100 mg; , Etoricoxib 90 mg; , Placebo