Sodium channel blockers are approved for intravenous administration in the treatment of neuropathic pain states. Preclinical studies have suggested antihyperalgesic effects on the peripheral as well as the central nervous system. The objective of this study was to determine mechanisms of action of low-dose lidocaine in experimental induced, secondary hyperalgesia. In a first experimental trial, participants (n=12) received lidocaine systemically (a bolus injection of 2 mg/kg in 10 min followed by an intravenous infusion of 2 mg kg(-1)h(-1) for another 50 min). In a second trial, a modified intravenous regional anesthesia (IVRA) was administered to exclude possible central analgesic effects. In one arm, patients received an infusion of 40 ml lidocaine, 0.05%; in the other arm 40 ml NaCl, 0.9%, served as a control. In both trials capsaicin, 20 microgram, was injected intradermally and time course of capsaicin-induced pain, allodynia and hyperalgesia as well as axon reflex flare was determined. The capsaicin-induced pain was slightly reduced after systemic and regional application of the anesthetic. The area of pin-prick hyperalgesia was significantly reduced by systemic lidocaine, whereas the inhibition of hyperalgesia was absent during regional administration of lidocaine. In contrast, capsaicin-induced flare was significantly decreased after both treatments. We conclude that systemic lidocaine reduces pin-prick hyperalgesia by a central mode of action, which could involve blockade of terminal branches of nociceptors. A possible role for tetrodotoxin resistant sodium channels in the antihyperalgesic effect of low-dose lidocaine is discussed.