An oral TRPV1 antagonist attenuates laser radiant‐heat‐evoked potentials and pain ratings from UV_B‐inflamed and normal skin

Abstract

AIMSLaser (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 UVB-inflamed skin. METHODSThis 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 CO2-laser on normal and UVB-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. RESULTSCompared with placebo, significant mean decreases in the primary variable of LEP PtP-amplitude from UVB-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. CONCLUSIONSTRPV-1 antagonism appears promising in the management of clinical pain, but requires further investigation. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• ABT-102, a novel TRPV1 antagonist, has demonstrated efficacy in several preclinical models of pain. Laser (radiant-heat) evoked potential amplitudes and pain visual analogue scales, approved in numerous past algesimetric studies, were used to evaluate the antinociceptive and antihyperalgesic effects of ABT-102 compared with placebo and two active controls in normal and UVB-inflamed skin. WHAT THIS STUDY ADDS• The results obtained using this model indicated that ABT-102 was well tolerated and dose-dependently efficacious in reducing both thermal hyperalgesia and non-hyperalgesic pain. The algesimetric model showed reproducibility and confirmed its suitability in a small number of normal healthy subjects.

Effects of the TRPV1 antagonist ABT‐102 on body temperature in healthy volunteers: pharmacokinetic/ pharmacodynamic analysis of three phase 1 trials

“…In a recent experimental pain study in healthy human volunteers, 6 mg single dose of ABT-102 (Cmax, 15 ng ml -1 , Caverage during experiment, 9 ng ml -1 ) demonstrated superior antinociceptive efficacy to etoricoxib and tramadol [31]. Taken together, the model estimated transient body temperature increase is estimated to be 0.6 to 0.8°C at ABT-102 analgesic exposures in humans.…”

Ultraviolet Radiation on the Skin: A Painful Experience?

“…Chizh and colleagues reported that TRPV1 antagonists can modestly reduce both hypersensitivity and flare area resulting from UVB inflammation [87]. Further to these observations, a more recent study confirmed the therapeutic effects of TRPV1 antagonists, demonstrating the antinociceptive and antihyperalgesic effects of a new selective drug to these vanilloid channels [88]. Adding to the role of TRPV receptor family in UVB- hypersensitivity, another study claimed that UVB induces expression of TRPV4 channels at the epidermis, eliciting a proalgesic effect [89].…”

Clinical efficacy of low‐level laser therapy on localized canine atopic dermatitis severity score and localized pruritic visual analog score in pedal pruritus due to canine atopic dermatitis

“…Assuming the effects of LLLT would be localized to the treated area, an intra‐individual design was used to maximize results from the study patients. This design has successfully been used in previous studies investigating various forms of laser therapy …”

“…This design has successfully been used in previous studies investigating various forms of laser therapy. 12,[27][28][29][30]…”