The synergistic effect of combined treatment with systemic ketamine and morphine on experimentally induced windup-like pain in humans.

Unlabelled: In this study, we evaluated whether combined treatment with ketamine (KET), an N-methyl-D-aspartate receptor antagonist, and morphine (MO) results in positive analgesic effects. Eleven volunteers were exposed to a skin burn injury on the leg. The effects of IV KET (9 microg. kg(-1). min(-1); 45 min) and MO (10 microg. kg(-1). min(-1); 10 min) alone and in combination, as well as placebo (saline; 10 min), were studied in a randomized, crossover, double-blinded design. The area of secondary hyperalgesia (SH) for mechanical stimulation was diminished by KET as compared with placebo. Mechanical pain thresholds were increased severalfold with KET and with KET plus MO, both in the primary hyperalgesic (PH; burn injury) and SH area. MO infusion showed no effect on the SH area or pain threshold. Windup-like pain was evaluated by continuous assessment on a visual analog scale during 30 s of repetitive stimulation (40-g load at 3 Hz) and analyzed as a sum of pain scores. The combined treatment (KET plus MO) almost abolished windup-like pain both in the PH and the SH areas, an effect that was not present with monotherapy with KET or MO. This study provides experimental support for a positive analgesic interaction between an N-methyl-D-aspartate receptor antagonist and an opioid on central summation of pain.

Implications: This is the first experimental study in humans to find synergistic analgesic effects with coadministration of the N-methyl-D-aspartate receptor antagonist ketamine and morphine on pain involving central sensitization phenomena.