Lack of Secondary Hyperalgesia and Central Sensitization in an Acute Sheep Model

Background and Objectives 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.