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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.

The aim of the study was to evaluate the analgesic/antihyperalgesic efficacy and to establish the dose-response relationship of morphine immediate release (IR) and oxycodone IR in a human experimental algesimetric model. Calculated effect ratios for peak-to-peak (PtP) amplitudes of laser-evoked potentials (LEPs) and visual analog scales (VAS) postlaser pain on UVB-irradiated skin (main target variables) were 1.68 and 1.18 respectively for oxycodone 10mg/morphine 20mg, 3.00 and 1.63 respectively for oxycodone 15 mg/morphine 30 mg, and 1.12 and 1.25 respectively for oxycodone 20mg/morphine 40 mg. The effect on the laser-PtP amplitude of morphine at the highest dose (40 mg) and of oxycodone at all doses (10, 15, 20mg) was considered to be clinically relevant based on a difference from placebo of ≥ 2.5 μV. For both compounds, a statistically significant linear trend was observed between dose groups in at least 1 of the 2 main target variables (adjusted P value for both end points <.001 at all doses). Hyperalgesia developed over time vs baseline due to acute exposure to UVB irradiation and to topical/occlusive 1% capsaicin solution. For both compounds, the principal onset of analgesic/antihyperalgesic drug effects was around 0.5 hours with an average peak at about 1 to 2 hours and the effect lasting for more than 3 hours (morphine 20 and 30 mg) or 6 hours (morphine 40 mg and oxycodone all doses). In conclusion, the study demonstrated a solid outcome of a mixed objective/subjective human experimental algesimetric model to approach dose-response relationships and analgesic/antihyperalgesic effects of 2 opioids.

It is known that sedation by H1 antihistaminic drugs can be reduced or avoided if slow release formulations are used for their administration, probably because of a slower increase of the drug concentration in plasma and brain. The aim of this study was to compare two different formulations of dimenhydrinate (CAS 523-87-5), a single fast release tablet with three chewing gums (divided dose principle), with regard to their efficacy in a motion sickness model and their detrimental effect on vigilance and central nervous system (CNS) performance. Caloric stimulation of the eardrum (air at 44 degrees C) was used to induce the symptoms of motion sickness in 24 symptomatic volunteers in a three-way cross-over design comparing three chewing gums (Superpep forte, chewed for 30 min each) containing 20 mg dimenthydrinate each with a 50 mg dimenhydrinate tablet and placebo. During caloric stimulation the following parameters were measured in order to compare efficacy: Quantitative analysis of sodium excretion by sweat (main target parameter), subjective well being (vertigo) by visual analogue scales (VAS) and frequency of binocular nystagmus by computer nystagmography. Unwanted effects on vigilance and CNS performance were measured by means of the N1-P2 peak to peak amplitudes of auditory evoked potentials (AEPs) as an objective, quantitative parameter of vigilance and the latency to correct responses and the number of correct responses (complex choice reaction task) in the oculodynamic test (ODT) as parameters of complex choice reaction ability. As a main efficacy result sodium excretion by sweat was markedly reduced by the chewing gums and by the tablet. The differences to placebo were highly significant (chewing gums vs. placebo p < 0.0001, tablet vs. placebo p < 0.0001). There was no relevant and no significant difference between both medications (p = 0.308). The secondary efficacy parameters, frequency of binocular nystagm and the VAS vertigo were markedly reduced by both medications in comparison to placebo, i.e. both medications were markedly effective. In both cases, however, this result failed statistical significance. The unwanted depressing effects on vigilance and CNS performance of the chewing gums were less pronounced than that of tablets. The N1/P2 peak-to-peak amplitudes of the AEPs were significantly reduced by both the chewing gums and the tablets. The effect of the tablets was, however, larger than that of the chewing gums. This highly significant (tablet vs. chewing gums, p = 0.0003) difference shows that the tablet had a larger depressing effect on vigilance (greater sedation). In line with this result, the number of correct responses in the ODT was markedly and significantly reduced by the tablet (p = 0.0027) but not significantly by the chewing gums (p = 0.8140). The difference between the tablet and the chewing gums was highly significant (p = 0.0052). The complex choice reaction time was markedly and nearly significantly (p = 0.0558) prolonged by the tablet whereas the chewing gums produced only a v...

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