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

Laulin, Jean-Paul PhD*,; Maurette, Pierre MD†,; Corcuff, Jean-Benoît MD, PhD‡,; Rivat, Cyril GS‡,; Chauvin, Marcel MD§,; Simonnet, Guy PhD

doi: 10.1097/00000539-200205000-00040
PAIN MEDICINE: Research Report

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.

*Université Bordeaux 1, France; †Département d’Anesthésie-Réanimation III, Hôpital Pellegrin, Bordeaux, France; ‡Université Bordeaux 2, France; and §Département d’Anesthésie-Réanimation, Hôpital Ambroise Paré, Paris, France

Supported, in part, by grants from the Institut National de la Santé et de la Recherche Médicale (INSERM, Paris, France), the Université Bordeaux 2 (Bordeaux, France), the Conseil Régional d’Aquitaine, the Institut Union Pharmacologique Scientifique Appliquée (UPSA) de la Douleur (Paris, France), and the Ministère de l’Education Nationale, de l’Enseignement Supérieur et de la Recherche (Paris, France).

December 20, 2001.

Address correspondence and reprint requests to Guy Simonnet, PhD, INSERM U259, rue Camille Saint-Saëns, 33077 Bordeaux, France. Address e-mail to

© 2002 International Anesthesia Research Society