Background and Objectives: Lidocaine, a local anesthetic and antiarrhythmic drug that alters depolarization in neurons by blocking the fast voltage-gated sodium (Na+) channels in the cell membrane, is used for regional anesthesia, as antiarrhythmic drug, and as analgesic for various painful conditions. It is unclear whether monotherapy with intravenous lidocaine has an analgesic effect in healthy individuals. To address this important question, we studied pain perception before, during, and after the administration of intravenous lidocaine in 16 human volunteers. Our hypothesis was that lidocaine, administered as a short intravenous infusion, does not have an analgesic effect in healthy volunteers. Methods: Sixteen healthy human volunteers received systemic lidocaine at plasma concentration 2 mg/mL using a computer-assisted infusion. Participants underwent a series of sensory tests-thermal, electrical, and ischemic pain and normal pinprick sensation-at baseline, during, and 30 mins after administration of a 20-min lidocaine infusion at a 2 mg/mL effect site concentration. Results: We found a sustained decrease in ischemic pain ratings and a limited analgesic effect for electrical pain, whereas thermal pain and normal sensation did not change. Conclusions: The observed sustained analgesic effect of systemic lidocaine in the ischemic pain model suggests that lidocaine may be used to treat acute pain. Copyright © 2010 by American Society of Regional Anesthesia and Pain Medicine.