Preclinical studies have emphasized that persistent small afferent input will induce a state of central facilitation, which can be regulated by systemically administered sodium channel blockers. We have extended these preclinical studies to the human volunteers by examining the effects of lamotrigine and 4030W92, two structurally related voltage-sensitive sodium channel antagonists, on acute sensory thresholds and facilitated processing induced by intradermal capsaicin. Fifteen healthy subjects received 4030W92, lamotrigine, and placebo in a randomized order using double-blinded crossover design methodology in three sessions each separated by a 7-day washout period. In each session, baseline neurosensory testing was performed on the volar aspect of the subject's left forearm. Subjects were then dosed with either lamotrigine (300 mg), 4030W92 (100 mg), or placebo, followed 2 h later by capsaicin (100 microg) injected intradermally on the volar aspect of the left forearm. Pain scores, blood pressure, heart rate, and respiratory rate were measured at the time of injection and every 5 min for 15 min. Fifteen minutes after the capsaicin injection, the hyperalgesic area was determined by von Frey hair, stroking, and heat; the flare response was outlined; and neurosensory testing again was performed halfway between the edge of the hyperalgesic area and the capsaicin injection site. While capsaicin significantly decreased the hot pain and VF pain thresholds, oral lamotrigine and 4030W92 failed to alter this response to capsaicin, relative to placebo treatment. Similarly, oral lamotrigine or 4030W92 did not alter the pain scores reported from mechanical pain stimuli at any time postcapsaicin. This study showed a lack of effect of two structurally similar sodium channel antagonists on a human experimental pain model using intradermal capsaicin, which is consistent with other studies on the effects of sodium channel antagonists of capsaicin-induced pain and hyperalgesia. This lack of effect stands in contrast to reported effects of sodium channel antagonists on preclinical models of cutaneous hyperalgesia or effects of lamotrigine on clinical neuropathic pain.