The Role of Ketamine in Preventing Fentanyl-Induced Hyperalgesia and Subsequent Acute Morphine Tolerance

TLDR

Perioperative opioids increase postoperative pain and morphine requirement, indicating acute opioid tolerance, and they elicit NMDA‑dependent pain hypersensitivity. The study examined how ketamine pretreatment affects post‑fentanyl morphine analgesic efficacy. The authors measured rat nociceptive thresholds using a paw‑pressure vocalization test. Four fentanyl boluses produced dose‑dependent hyperalgesia and diminished subsequent morphine analgesia, but ketamine pretreatment enhanced fentanyl’s effect, suppressed both immediate and delayed hyperalgesia, and restored full morphine efficacy, suggesting that sustained NMDA blockade can improve postoperative morphine effectiveness.

Abstract

Perioperative opioids increase postoperative pain and morphine requirement, suggesting acute opioid tolerance. Furthermore, opioids elicit N-methyl-d-aspartate (NMDA)-dependent pain hypersensitivity. We investigated postfentanyl morphine analgesic effects and the consequences of NMDA-receptor antagonist (ketamine) pretreatment. The rat nociceptive threshold was measured by the paw-pressure vocalization test. Four fentanyl boluses (every 15 min) elicited a dose-dependent (a) increase followed by an immediate decrease of the nociceptive threshold and (b) reduction of the analgesic effect of a subsequent morphine administration (5 mg/kg): −15.8%, −46.6%, −85.1% (4 × 20, 4 × 60, 4 × 100 μg/kg of fentanyl, respectively). Ketamine pretreatment (10 mg/kg) increased the fentanyl analgesic effect (4 × 60 μg/kg), suppressed the immediate hyperalgesic phase, and restored the full effect of a subsequent morphine injection. Fentanyl also elicited a delayed dose-dependent long-lasting decrease of the nociceptive threshold (days) that was prevented by a single ketamine pretreatment before fentanyl. However, a morphine administration at the end of the fentanyl effects restored the long-lasting hyperalgesia. Repeated ketamine administrations were required to obtain a complete preventive effect. Although ketamine had no analgesic effect per se at the dose used herein, our results indicate that sustained NMDA-receptor blocking could be a fruitful therapy for improving postoperative morphine effectiveness.