We reviewed randomized controlled trials to determine the efficacy and safety of systemically administered local anesthetics compared with placebo or active drugs. Of 41 retrieved studies, 27 trials of diverse quality were included in the systematic review. Ten lidocaine and nine mexiletine trials had data suitable for meta-analysis (n = 706 patients total). Lidocaine (most commonly 5 mg/kg IV over 30-60 min) and mexiletine (median dose, 600 mg daily) were superior to placebo (weighted mean difference on a 0-100 mm pain intensity visual analog scale = -10.60; 95% confidence interval: -14.52 to -6.68; P < 0.00001) and equal to morphine, gabapentin, amitriptyline, and amantadine (weighted mean difference = -0.60; 95% confidence interval: -6.96 to 5.75) for neuropathic pain. The therapeutic benefit was more consistent for peripheral pain (trauma, diabetes) and central pain. The most common adverse effects of lidocaine and mexiletine were drowsiness, fatigue, nausea, and dizziness. The adverse event rate for systemically administered local anesthetics was more than for placebo but equivalent to morphine, amitriptyline, or gabapentin (odds ratio: 1.23; 95% confidence interval: 0.22 to 6.90). Lidocaine and mexiletine produced no major adverse events in controlled clinical trials, were superior to placebo to relieve neuropathic pain, and were as effective as other analgesics used for this condition.