Lack of secondary hyperalgesia and central sensitization in an acute sheep model.
OBJECTIVE
We aimed to determine the following in an experimental acute pain model in sheep: (1) whether multimodal analgesia with intravenous fentanyl and ketorolac was more effective than fentanyl alone; (2) whether secondary hyperalgesia (central sensitization) occurred in adjacent (foreleg) dermatomes after thoracic surgery; (3) whether ketorolac used preemptively influenced the development of secondary hyperalgesia after surgery.


METHODS
Changes in primary nociception were measured by increases to tolerated pressure, applied to the foreleg by a blunt pin, before foreleg withdrawal occurred. Changes to breath-to-breath interval and estimated end-tidal CO2 were used as indices of respiratory effects. Study 1 (n = 6) compared the paired responses to acute nociception after ketorolac (90 mg) or saline (control) pretreatment, followed by fentanyl (graded, 0 mg to 1.5 mg). Study 2 (n = 6) used a cross-over of ketorolac (90 mg) or saline (control) 24 hours and 1 hour, respectively, before a standardized thoracotomy incision, followed by antinociceptive testing with ketorolac (90 mg) and fentanyl (0.6 mg) daily over 4 days.


RESULTS
In study 1, fentanyl produced naloxone-antagonizable antinociception and respiratory depression. Ketorolac did not affect fentanyl antinociception, except for prolonging antinociception at the highest dose; it did not affect the respiratory effects. In study 2, preemptive ketorolac had no effect on the postoperative antinociceptive or respiratory effects of fentanyl. The pharmacokinetics of fentanyl were unaltered by ketorolac.


CONCLUSIONS
The results obtained in this acute pain model found no significant evidence of a fentanyl-ketorolac interaction, of central sensitization as shown by secondary hyperalgesia, or of a preemptive analgesic effect.
Mather
L E
LE
Department of Anaesthesia and Pain Management, University of Sydney at Royal North Shore Hospital, St Leonards, NSW, Australia. lmather@med.usyd.edu.au
Cousins
M J
MJ
Huang
Y F
YF
Pryor
M E
ME
Barratt
S M
SM
D000208:Acute Disease; D000698:Analgesia / Q000379:methods; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D000704:Analysis of Variance; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000627:therapeutic use; D019540:Area Under Curve; D002245:Carbon Dioxide / Q000032:analysis; D004195:Disease Models, Animal; D004338:Drug Combinations; D005283:Fentanyl / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D006930:Hyperalgesia / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D007275:Injections, Intravenous; D020910:Ketorolac / Q000008:administration & dosage / Q000627:therapeutic use; D009270:Naloxone / Q000627:therapeutic use; D009292:Narcotic Antagonists / Q000627:therapeutic use; D010149:Postoperative Pain / Q000503:physiopathology / Q000517:prevention & control*; D011292:Premedication; D011312:Pressure; D012119:Respiration / Q000187:drug effects; D012756:Sheep; D018709:Statistics, Nonparametric; D013908:Thoracotomy; D013990:Tidal Volume
D000701:Analgesics, Opioid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004338:Drug Combinations; D009292:Narcotic Antagonists; D002245:Carbon Dioxide; D009270:Naloxone; D005283:Fentanyl; D020910:Ketorolac