TRPV1 is a cation channel activated by a range of noxious stimuli and highly expressed in nociceptive fibres. TRPV1 receptors are involved in pain and sensitisation associated with tissue injury and inflammation; hence, TRPV1 antagonists are potentially useful for the treatment of such pain states. SB-705498 is a potent, selective and orally bioavailable TRPV1 antagonist with demonstrated efficacy in a number of preclinical pain models. In this first-time-into-human study, we have investigated the pharmacodynamic and antihyperalgesic activity of SB-705498. The compound was safe and well tolerated at single oral doses up to 400mg. In a cohort of 19 healthy volunteers, we used a randomised placebo-controlled single-blind cross-over design to assess the effects of SB-705498 (400mg) on heat-evoked pain and skin sensitisation induced by capsaicin or UVB irradiation. Compared with placebo, SB-705498 reduced the area of capsaicin-evoked flare (P=0.0047). The heat pain threshold on non-sensitised skin was elevated following SB-705498 (estimated difference from placebo [95% confidence intervals]: 1.3 degrees C [0.07,2.53], P=0.019). Following capsaicin sensitisation, the heat pain threshold and tolerance were similar between SB-705498 and placebo. However, SB-705498 increased heat pain tolerance at the site of UVB-evoked inflammation (estimated difference from placebo: 0.93 degrees C [0.25,1.6], P=0.0054). The magnitude of the pharmacodynamic effects of SB-705498 appeared to be related to plasma concentration. These results indicate that SB-705498, at a clinically safe and well-tolerated dose, has target-specific pharmacodynamic activity in humans. These data provide the first clinical evidence that a TRPV1 antagonist may alleviate pain and hyperalgesia associated with inflammation and tissue injury.

Background & Aims: Experimental pain models are important for understanding pain mechanisms and for analgesic development. Hyperalgesia and allodynia are hallmarks of sensitisation underlying chronic pain states, and can be invoked in the electrical hyperalgesia and UVB inflammation models. They are quantified by mapping out areas of cutaneous hypersensitivity using pinprick or dynamic touch stimuli applied along systems of radials. We investigated the potential of using various 4-radial systems as opposed to 8, to calculate areas of hyperalgesia and allodynia. Methods: This work retrospectively analysed internal data, currently collected from 1 electrical hyperalgesia and 2 UVB studies. Areas of hyperalgesia and allodynia were measured using a 260mN von Frey filament and cotton bud, respectively, using an 8 point gridline system; the analyses were by mixed model repeated measures ANOVA. The point estimates and corresponding 95% confidence intervals for the difference "active treatment-placebo" were constructed for both 4-radial (circle, diamond and ellipse approximations) and 8-radial measurements and then compared. Results: Of the 3 types of 4-radial approximation, the circle one appeared to best replicate the results of the 8-spoke approximation for all the studies analysed. Under this 4-radial method the conclusions from each of the studies remained unchanged with the magnitude of difference being small. Conclusions: Four-radial quantification of areas of experimental hyperalgesia and allodynia yields results similar to the more involved 8-radial method. As these tests require subject and operator concentration, reducing the number of assessments is likely to reduce the risk of experimental error and variability. This work was carried out by GlaxoSmithKline

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