Modulation of remifentanil-induced analgesia and postinfusion hyperalgesia by parecoxib in humans.
BACKGROUND
Numerous experimental and clinical studies suggest that brief opioid exposure can enhance pain sensitivity. It is suggested that spinal cyclooxygenase activity may contribute to the development and expression of opioid tolerance. The aim of the investigation was to determine analgesic and antihyperalgesic properties of the cyclooxygenase-2 inhibitor parecoxib on remifentanil-induced hypersensitivity in humans.


METHODS
Fifteen healthy male volunteers were enrolled in this randomized, double-blind, placebo-controlled study in a crossover design. Transcutaneous electrical stimulation at high current densities was used to induce spontaneous acute pain (numeric rating scale 6 of 10) and stable areas of pinprick hyperalgesia. Pain intensities and areas of hyperalgesia were assessed before, during, and after a 30-min intravenous infusion of remifentanil (0.1 microg x kg x min) or placebo (saline). Parecoxib (40 mg) was administered intravenously either with onset of electrical stimulation (preventive) or in parallel to the remifentanil infusion.


RESULTS
Remifentanil reduced pain and mechanical hyperalgesia during the infusion, but upon withdrawal, pain and hyperalgesia increased significantly above control level. Preventive administration of parecoxib led to an amplification of remifentanil-induced antinociceptive effects during the infusion (71.3 +/- 7 vs. 46.4 +/- 17% of control) and significantly diminished the hyperalgesic response after withdrawal. In contrast, parallel administration of parecoxib did not show any modulatory effects on remifentanil-induced hyperalgesia.


CONCLUSIONS
The results confirm clinically relevant interaction of mu opioids and prostaglandins in humans. Adequate timing seems to be of particular importance for the antihyperalgesic effect of cyclooxygenase-2 inhibitors.
Tröster
Andreas
A
Department of Anesthesiology, University Hospital Erlangen, Erlangen, Germany.
Sittl
Ruth
R
Singler
Boris
B
Schmelz
Martin
M
Schüttler
Jürgen
J
Koppert
Wolfgang
W
D000328:Adult; D000698:Analgesia / Q000009:adverse effects / Q000379:methods; D000701:Analgesics, Opioid / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage*; D004311:Double-Blind Method; D004347:Drug Interactions; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy* / Q000209:etiology; D007262:Infusions, Intravenous; D007555:Isoxazoles / Q000008:administration & dosage*; D007649:Ketamine / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D017288:Pain Threshold / Q000187:drug effects; D010880:Piperidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D000077208:Remifentanil
D000701:Analgesics, Opioid; D016861:Cyclooxygenase Inhibitors; D007555:Isoxazoles; D010880:Piperidines; D007649:Ketamine; C409945:parecoxib; D000077208:Remifentanil