Differential modulation of remifentanil-induced analgesia and postinfusion hyperalgesia by S-ketamine and clonidine in humans

Anesthesiology. 2003 Jul;99(1):152-9. doi: 10.1097/00000542-200307000-00025.


Background: Experimental studies and clinical observations suggest a possible role for opioids to induce pain and hyperalgesia on withdrawal. The authors used a new experimental pain model in human skin to determine the time course of analgesic and hyperalgesic effects of the mu-receptor agonist remifentanil alone or in combination with the N-methyl-D-aspartate-receptor antagonist S-ketamine or the alpha(2)-receptor agonist clonidine.

Methods: Thirteen volunteers were enrolled in this randomized, double-blind, placebo-controlled study. Transcutaneous electrical stimulation at a high current density (2 Hz, 67.3 +/- 16.8 mA, mean +/- SD) induced acute pain (numerical 11-point rating scale: 5-6 out of 10) and stable areas of mechanical hyperalgesia to punctate stimuli and touch (allodynia). The magnitude of pain and area of hyperalgesia were assessed before, during, and after drug infusion (remifentanil at 0.1 microg x kg-1 x min-1 and S-ketamine at 5 microg x kg-1 x min-1 over a period of 30 min, respectively; clonidine infusion at 2 microg/kg for 5 min).

Results: Remifentanil reduced pain and areas of punctate hyperalgesia during infusion. In contrast, postinfusion pain and hyperalgesia were significantly higher than control. During infusion of S-ketamine, pain and hyperalgesia decreased and gradually normalized after infusion. When given in combination, S-ketamine abolished postinfusion increase of punctate hyperalgesia but did not reduce increased pain ratings. Clonidine alone did not significantly attenuate pain or areas of hyperalgesia. However, when given in combination with remifentanil, clonidine attenuated postinfusion increase of pain ratings.

Conclusions: Opioid-induced postinfusion hyperalgesia could be abolished by S-ketamine, suggesting an N-methyl-d-aspartate-receptor mechanism. In contrast, elevated pain ratings after infusion were not reduced by ketamine but were alleviated by the alpha(2)-receptor agonist clonidine. The results of this study suggest different mechanisms of opioid-induced postinfusion antianalgesia and secondary hyperalgesia.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic alpha-Agonists / therapeutic use*
  • Adult
  • Analgesics, Opioid / adverse effects*
  • Anesthetics, Dissociative / therapeutic use*
  • Blood Pressure / drug effects
  • Clonidine / therapeutic use*
  • Cross-Over Studies
  • Double-Blind Method
  • Electric Stimulation
  • Half-Life
  • Humans
  • Hyperalgesia / drug therapy*
  • Infusions, Intravenous
  • Ketamine / therapeutic use*
  • Male
  • Oxygen / blood
  • Pain Measurement / drug effects
  • Physical Stimulation
  • Piperidines / adverse effects*
  • Receptors, Opioid, mu / agonists
  • Remifentanil
  • Substance Withdrawal Syndrome / drug therapy*


  • Adrenergic alpha-Agonists
  • Analgesics, Opioid
  • Anesthetics, Dissociative
  • Piperidines
  • Receptors, Opioid, mu
  • Ketamine
  • Clonidine
  • Remifentanil
  • Oxygen