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Experimental evidence suggests that the antihyperalgesic effect of nonsteroidal anti-inflammatory drugs may include both peripheral (inflammatory site) and central sites of action. The aim of this study was to assess peripheral and central antihyperalgesic effects of diclofenac in a human experimental pain model.This was a randomized, double-blind, placebo-controlled study designed to compare the antihyperalgesic efficacy of topical (65 mg) and oral (93 mg) diclofenac via estimates of mechanical pain thresholds obtained at the site of induced inflammation with von Frey hairs. The dose of the 2 diclofenac formulations was calculated to achieve similar target concentrations, monitored in the inflammatory tissue by intradermal microdialysis. Simultaneous serial blood samples were collected to determine the systemic concentrations of the drug.Diclofenac was superior to placebo 1 hour after topical application (P < .002) and 1 to 3 hours after oral intake (P < .016). Topical diclofenac was more effective than oral diclofenac 1 hour after dosing and produced higher tissue concentrations (46.1 ng/mL versus 11.4 ng/mL, P < .02), whereas the compound was not detectable in plasma. Oral diclofenac had a higher antihyperalgesic efficacy at later observation periods (2-2.5 hours after dosing), when tissue concentrations of diclofenac for the 2 treatments did not differ significantly. The overall pain relief over a 3-hour postdose period was 1.7-fold greater with oral diclofenac than with topical diclofenac. However, the total tissue area under the curve after oral diclofenac did not exceed that for the topical formulation (32.2 ng · h · mL −1 versus 40.7 ng · h · mL −1 ).The higher antihyperalgesic efficacy of oral diclofenac as compared with topical diclofenac at comparable tissue concentrations suggests that not only peripheral but also central mechanisms are involved in the antihyperalgesic effects of systemically administered diclofenac.