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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.

This study demonstrated the efficacy of Neodolpasse in a human pain model. The observed effect was mainly caused by central mechanisms and was found to be superior for the fixed-dose combination of orphenadrine and diclofenac compared with the individual ingredients. Both components contributed to the effect of the combination in an additive fashion, which can be explained by the different molecular mechanisms of action of each drug.

LEP algesimetry is sensitive to analgesics with different modes of action and may enable the effects of novel analgesics to be assessed during early clinical development.

Objective experimental algesimetry was used to assess quantitative differences in analgesic properties between acetylsalicylic acid (ASA, 750 mg) and a special combination of ASA, trilithium citrate and quinine-2 HCl (750 mg, 126 mg, 4.5 mg) in a placebo-controlled double-blind crossover study on nine healthy subjects. Radiant heat stimulation was applied with a CO2 laser and somatosensory evoked vertex potentials (LSEP) were recorded while the subjects were simultaneously engaged in an adaptive pursuit tracking task in order to stabilize their vigilance. The N1 amplitude of the LSEP decreased under both verum medications; however, the drug combination was significantly more effective. The time course of this effect was attended by a marked intradiurnal variation of the LSEP amplitudes. The role of lithium in the combination with ASA and quinine-2 HCl (Togal) and an amplification of the analgesic potency of ASA are discussed.