Epidural ketamine potentiates epidural morphine but not fentanyl in acute nociception in rats.

Epidural opioids have been reported to provide superior analgesia in acute pain management. Despite the fact that the required doses are low, major side effects such as respiratory depression may still occur. In an effort to maximize analgesia and to minimize the rate of side effects, epidural NMDA receptor antagonists, especially ketamine, may be co-administered with opioids. This study investigated whether ketamine had beneficial effects on fentanyl- or morphine-induced antinociception in an acute pain model in rats. In male Wistar rats, an epidural catheter was placed under general anaesthesia. After 1 week the animals were subjected to the tail withdrawal reaction (TWR) test. After determination of the basal reaction latencies, fentanyl, morphine, ketamine or combinations of an opioid with ketamine were administered epidurally. TWR latencies were measured for up to 2h after treatment. Both opioids showed a dose related antinociceptive effect. Fentanyl had a fast onset and a short duration of action whereas the reverse was true for morphine. Ketamine exhibited only limited antinociceptive properties. In the combinations, ketamine improved morphine-induced antinociception both in terms of maximal possible effect (MPE) as well as in duration of action. The combination of fentanyl with ketamine did not result in any improvement, neither in terms of MPE nor in duration of action. Moreover, increasing doses of ketamine tended to decrease the MPE of various doses of fentanyl. These data confirm that ketamine, contrary to opioids, does not possess important antinociceptive properties in an acute test such as the TWR test. Furthermore, these data indicate that additive drugs such as ketamine may have different effects on different opioids.