Aside from temporary chemodenervation of skeletal muscle and potential anti-inflammatory effects, a genuine peripheral antinociceptive effect of Botulinum Neurotoxin Type A (BoNT/A) has been suspected. To evaluate the effect of BoNT/A on cutaneous nociception in humans, 50 healthy volunteers received subcutaneous injections of 100 mouse units (MU) BoNT/A (Dysport) and placebo. Both forearms of each subject were treated in a double-blind fashion, one with verum, one with placebo. Heat and cold pain thresholds within the treated skin areas were measured with quantitative sensory testing (QST) and pain thresholds were evaluated with local electrical stimulation (ES). The tests were done before treatment, and after 4 and 8 weeks. No major side effects were noted. All participants completed the study. Heat and cold pain thresholds increased from baseline to week 4 by 1.4 degrees C for verum and by 1.1 degrees C for placebo. From baseline to week 8, the thresholds increased by 2.7 degrees C for verum and by 1.2 degrees C for placebo. Electrically induced pain thresholds shifted from baseline to week 4 by -0.07 mA for verum and by 0.01 mA for placebo. From baseline to week 8, the thresholds increased by 0.10 mA for verum and by 0.11 mA for placebo. None of these differences was statistically significant. The study shows that there is no direct peripheral antinociceptive effect of BoNT/A in humans. The efficacy of BoNT/A in various pain syndromes must be explained by other pathways such as chemodenervation or anti-inflammatory effects.