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Effect of Oral Ketamine on Secondary Hyperalgesia, Thermal and Mechanical Pain Thresholds, and Sedation in Humans
  1. Søren Mikkelsen, M.D.,
  2. Henrik Jørgensen, M.D.,
  3. Pia S. Larsen,
  4. Jannick Brennum, M.D., Ph.D. and
  5. Jørgen B. Dahl, M.D., D.MSc.
  1. From the Laboratory of Pain Physiology, Department of Anesthesiology, Copenhagen University Hospital (S.M., H.J. P.S.L., J.B.D.), Herlev, Copenhagen; and the Department of Neurosurgery, Copenhagen University Hospital (J.B.), Rigshospitalet, Copenhagen.
  1. Reprint requests: Søren Mikkelsen, M.D., Department of Anesthesiology 4132, Copenhagen University Hospital, Rigshospitalet, DK-2100 Copenhagen, Denmark. E-mail: mikkelsen{at}


Background and Objectives Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist, and has been proven effective in alleviating secondary hyperalgesia in human subjects when injected intravenously. After oral ingestion, ketamine is metabolized into norketamine, which in vitro possesses NMDA receptor antagonistic effect. The aim of this study was to investigate the effects of oral administration of ketamine on secondary hyperalgesia evoked by standardized tissue injury.

Methods Twenty-four male volunteers were included in the study. Each volunteer received the following treatment regimen, in randomized, double-blind, 3-way cross-over fashion: (A) placebo; (B) ketamine, 0.5 mg/kg; and (C) ketamine, 1.0 mg/kg. Standardized tissue injury was induced after study medication by heating the right calf with a rectangular thermode. The temperature was 47°C, and heating time was 7 minutes. The following parameters were investigated: Pain during induction of the burn injury; heat-pain detection thresholds in the injured area and a corresponding noninjured area; secondary hyperalgesia surrounding the injured area on the calf; secondary hyperalgesia induced by heating an area on the thigh with 45°C in 3 minutes; pressure-pain detection thresholds measured on the middle phalanx of the 4th left finger; pain during a 60-second thermal stimulation of 46°C on undamaged skin on the left thigh; and side effects.

Results Some degree of sedation was observed after oral administration of ketamine. No effects on any of the other investigated parameters were observed.

Conclusion Oral ketamine 0.5 or 1.0 mg/kg has no effect on secondary hyperalgesia or thermal or mechanical pain thresholds in human volunteers.

  • Oral ketamine
  • Hyperalgesia

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  • Supported by grants from the following foundations: Danish Medical Research Council, Copenhagen, Denmark (Reg. no. 28809); Novo Nordisk Foundation, Bagsvaerd, Denmark; Danish Foundation for the Advancement of Medical Science, Copenhagen, Denmark; and Agnes and Poul Friis' Foundation, Copenhagen, Denmark. No conflicts of interest exist between any of the authors and the foundations supporting this study.