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Mexiletine is a sodium channel blocker that has been used for the treatment of a variety of neuropathic pain syndromes. A recent double-blinded placebo-controlled study concluded that it was ineffective in the treatment of allodynia associated with neuropathic pain. However, this study failed to achieve adequate plasma levels of mexiletine. This was a study in healthy volunteers that sought to push the drug to dose-limiting side effects and then evaluate the effects on human experimental pain.Twelve healthy volunteers were studied using a randomized, double-blind, placebo-controlled crossover study. The subjects were titrated to a maximum dose of 1,350 mg/d or dose-limiting side effects, whichever occurred first. At baseline and day 10 and 17, neurosensory testing, train-of-three thermal pulses, and side-effect measurements were performed and on day 17, intradermal capsaicin was injected on the volar aspect of the forearm and the pain and secondary hyperalgesia to von Frey hair, stroking, and thermal stimuli were measured.Peak plasma levels occurred on day 10 and were 0.36 ± 0.21 μg/mL. All subjects experienced dose-limiting side effects. The mean maximum tolerable daily dose achieved was 859 mg (range, 300 to 1,350 mg). The side effects reported by the subjects included nausea, lightheadedness, muscle twitching and weakness, blurred vision, headache, tremors, difficulty concentrating, dysphoria, sedation, pruritis, and rash. These side effects occurred at an average daily dose of 993 mg (range, 600 to 1,350 mg). Compared with placebo, mexiletine had no significant effects on any of the neurosensory thresholds and pain scores after intradermal capsaicin. There was a significant reduction in the area of secondary hyperalgesia to von Frey hair stimulation only. There was a significant correlation between plasma mexiletine level and flare response.Mexiletine has minimal effects on human experimental pain. It is severely limited by side effects and tolerable doses seem to be void of effects on normal neurosensation and facilitated pain induced by capsaicin and thermal heat pulses.