Effects of NMDA receptor antagonists on opioid-induced respiratory depression and acute antinociception in rats.

Although exogenous opioids alter the responses of animals to tissue-damaging stimuli and therefore are the cornerstone in the treatment of acute antinociception, they have profound side effects on ventilation. To diminish ventilatory effects, combination therapies have been advocated. Recent studies reported the effectiveness of the addition of N-methyl-D-aspartate (NMDA) receptor antagonists such as ketamine to morphine in the treatment of acute pain. However, NMDA receptors, together with non-NMDA receptors are known to be involved in the neurotransmission of inspiratory drive to phrenic motoneurons. Co-administration of NMDA and non-NMDA receptor antagonists has been shown to be deleterious to respiratory function. The present study investigated the hypothesis that the association of opioids and NMDA receptor antagonists may add to the impairment of respiratory parameters. In male Wistar rats, combinations of opioids (fentanyl or morphine) at antinociceptive doses and NMDA receptor antagonists (ketamine, 40 mg/kg, or dextromethorphan, 10 mg/kg) at subanesthetic doses were administered intraperitoneally. Antinociception was tested with the tail-withdrawal reaction (TWR) test, while the effect on respiratory parameters was investigated with blood-gas analysis. We found that, in rats, co-administration of NMDA receptor antagonists and opioids may result in an increased respiratory depression as compared to the opioids alone. The effect of the NMDA receptor antagonists on opioid-induced antinociception was limited.

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.

Dextromethorphan and ketamine potentiate the antinociceptive effects of mu- but not delta- or kappa-opioid agonists in a mouse model of acute pain.

Animal and clinical studies have reported potentiation of opioid antinociception by NMDA receptor antagonists such as ketamine and dextromethorphan. The aim of this study was to compare these clinically available NMDA antagonists in combination with classical morphine, mu-selective fentanyl-like opioids, the delta-opioid agonist SNC80 and the kappa-opioid agonist U50,488H. Using a mouse hot-plate test, dose-response relationships were first determined for all compounds individually and then for opioids co-administered with fixed doses of ketamine or dextromethorphan. All compounds were administered intraperitoneally ED(50) values were calculated from the proportion of animals failing to exhibit any response within a fixed cut-off criterion of 30 s. To varying degrees, all compounds produced increases in response latencies over time. Dextromethorphan produced lower ED(50) values for morphine, fentanyl and sufentanil but exerted no effect on the potency of SNC80 or U50,488H. Similarly, ketamine potentiated the antinociceptive potency of morphine, fentanyl and sufentanil but not SNC80 or U50,488H. In summary, these results support the use of mu-opioid agonists in combination with NMDA antagonists, but suggest that there may be no advantage in combining dextromethorphan or ketamine with delta- or kappa-opioids in the management of acute pain.