Animal studies have suggested an altered response to opiate agonists and antagonists as well as an altered pain threshold in diabetic animals. In the studies reported herein, a 50 g glucose infusion in normal subjects resulted in a significant decrease in both the threshold level of pain and the maximal level of pain tolerated, as measured by responses to electrical pain induced by a Grass stimulator. In addition, patients with diabetes mellitus were hyperalgesic when compared with normal subjects. It is concluded that elevated glucose levels and/or rapid fluxes in glucose levels result in a decrease in pain tolerance. These findings have potential clinical implications in the pathophysiology and management of painful diabetic neuropathy and the use of narcotic agents in diabetes mellitus.