Ketamine, an NMDA receptor antagonist, suppresses spatial and temporal properties of burn-induced secondary hyperalgesia in man: a double-blind, cross-over comparison with morphine and placebo

Pain. 1997 Aug;72(1-2):99-106. doi: 10.1016/s0304-3959(97)00006-7.


Effects of morphine and ketamine (NMDA receptor antagonist) on temporally summated pain ('wind-up-like pain') and spatial aspects of secondary hyperalgesia were investigated in 12 healthy volunteers. Hyperalgesia was produced by a local 1 degree burn injury covering 12.5 cm2 on the medial surface of the calf. Primary hyperalgesia was determined by measuring heat pain detection threshold (HPDT) within the site of injury. Spatial aspects of secondary hyperalgesia present outside the site of injury were quantitated by determination of the areas in which a mechanical punctate (von Frey hair, 50.6 mN), or brush stimuli elicited pain sensation. Temporal aspects of secondary hyperalgesia were determined by repetitively pricking the skin with a standard von Frey hair (834 mN) inducing a 'wind-up-like pain'. Morphine 0.15 mg/kg, ketamine 0.15 mg/kg or placebo (NaCl 0.9%) were administrated i.v. on 3 separate days 50 min after the burn injury in a double-blind, placebo controlled, randomised and cross-over design. In all subjects HPDT was significantly reduced within the injured area compared to the pre-injury threshold (primary hyperalgesia). All subjects developed areas of allodynia and hyperalgesia to punctate stimuli and brush stimuli outside the injured area (secondary hyperalgesia). HPDT was not reduced in the area of secondary hyperalgesia. In 95% of the measurements we found a sudden appearance of pain to repeated pricking with a von Frey hair (834 mN) in the area of secondary hyperalgesia ('wind-up-like pain'). Ketamine significantly reduced the area of secondary hyperalgesia both for punctate and brush stimuli in the first measurement 15 min after injection and eight of the 11 subjects reported that the 'wind-up-like pain' disappeared. On the measurements 45 and 75 min after ketamine injection, secondary hyperalgesia and 'wind-up-like pain' reappeared. Morphine did not significantly change the size of the area of secondary hyperalgesia and did not affect 'wind-up-like pain'. Ketamine or morphine did not change thermal detection thresholds. We conclude that spatial and temporal mechanisms, underlying secondary hyperalgesia, are mediated by glutamatergic transmission via NMDA receptors.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Analgesics, Opioid / adverse effects
  • Analgesics, Opioid / therapeutic use*
  • Burns / complications*
  • Cross-Over Studies
  • Depression, Chemical
  • Double-Blind Method
  • Excitatory Amino Acid Antagonists / adverse effects
  • Excitatory Amino Acid Antagonists / therapeutic use*
  • Female
  • Humans
  • Hyperalgesia / drug therapy*
  • Hyperalgesia / etiology
  • Ketamine / adverse effects
  • Ketamine / therapeutic use*
  • Male
  • Morphine / adverse effects
  • Morphine / therapeutic use*
  • Placebos
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Temperature
  • Time Factors
  • Touch / physiology


  • Analgesics, Opioid
  • Excitatory Amino Acid Antagonists
  • Placebos
  • Receptors, N-Methyl-D-Aspartate
  • Ketamine
  • Morphine