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Reduced side-effect liability of opioids may enhance the patient's quality of life and decrease the incidence of opioid-insensitive pain. Literature offers few comparative data between different opioids at equianalgesic doses. Therefore morphine, fentanyl, buprenorphine, codeine, hydrocodone and oxycodone were compared for analgesic properties and side-effect profiles in rats. Analgesic efficacy was analysed using a tail withdrawal test for acute thermal nociception, a formalin test for chemically induced inflammatory pain and a von Frey test for mechanical hypersensitivity. For side-effect profiling inhibition of gastrointestinal activity was evaluated in a charcoal and ricinus oil test, arterial PCO(2) was determined for measuring respiratory depression, the discriminative stimulus properties linked to the narcotic cue were assessed using a drug discrimination learning test, and motor coordination was tested through rotarod performance. ED(50)'s for the occurrence of side-effects were compared to ED(50)'s in behavioural pain tests. Fentanyl had a strong analgesic potency and, compared to other opioids, an acceptable side-effect profiling at analgesic ED(50)'s. Also consistent was the ceiling effect of buprenorphine implying an increased safety margin for side-effects, but a decreased analgesic efficacy. Differences between opioids as observed in this study can have important indications for their use in acute as well as in the onset of chronic treatments.

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 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.

Background: Opiate receptors have been argued to differentially regulate analgesia and respiratory depression. In order to validate possible interactions between the opiate mu- and kappa-receptors, interactions between sufentanil and U-50488H were studied in rats., Methods: Rats equipped with an arterial catheter were tested in the tail flick latency (TFL) test after intravenous treatment with sulentanil (a mu-agonist), U-50488H (a kappa-agonist) or fixed ratio combinations of both drugs. Simultaneously, respiratory changes were monitored by blood gas analysis., Results: The ED50s of sufentanil for a TFL > 6.0 and > or = 10.0 s were 0.0002 and 0.00059 mg/kg. For U-50488H the corresponding values were 1.53 and 8.11 mg/kg. Using a fixed dose ratio of 1/10,000, an additivity was demonstrated between sufentanil and U-50488H in terms of antinociception. With regard to respiratory parameters, PaCO2 significantly increased after all doses of sufentanil early after treatment. At the higher doses tested, there was also a decrease in PaO2 and O2 saturation. For U-50488H only the highest doses resulted in an early and small shift in PaCO2. The combination of sufentanil/U-50488H resulted in only a small increase in PaCO2 at the highest dose regimen tested., Conclusion: The results presented here demonstrate that drug mixtures of sufentanil and U-50488H can be additive with respect to antinociception with additionally less risk for respiratory side-effects, as compared with sufentanil alone. Therefore, a combination of mu- and kappa-opiate-receptor agonists might be more beneficial than each agent alone.

Background: Data on the analgesic properties of alpha 2 agonists and their interactions with opioids are conflicting. Experiments were conducted in rats to evaluate whether various available alpha 2 agonists can potentiate the analgesic properties of opioids and to determine the route of administration needed for optimal interaction., Methods: The tail-withdrawal reaction test was used as an analgesia assay. In separate experiments, the interactions between systemic (subcutaneous, intravenous, and intraperitoneal) and spinally (epidural and intrathecal) administered alpha 2 agonists and opioids were evaluated. The antagonism of medetomidine plus fentanyl with naloxone and/or idazoxan also was studied., Results: All alpha 2 agonists tested, when injected subcutaneously with fentanyl, potentiated the opioid-induced analgesia. In terms of a reduction of the amount of fentanyl needed to produce a deep surgical analgesia (tail-withdrawal reaction latency > or = 10 s) over more than 2 h, the relative order of potency of the alpha 2 agonists tested was: medetomidine > dexmedetomidine > xylazine > clonidine > detomidine. For some of these alpha 2 agonists there was a biphasic effect: at the larger doses tested, a reduction in the fentanyl potentiation was present. The potentiation of the opioid activity with alpha 2 agonists was also demonstrated in terms of a longer duration of analgesia after combined treatment with fixed doses of opioids. The interaction between the alpha 2 agonists and the opioids remained present when a more profound criterion of analgesia (tail-withdrawal reaction latency > or = 30 s) was used. Furthermore, the interactions between the alpha 2 agonists tested and fentanyl or sufentanil appeared to be independent of the route of administration. Potentiations were observed after simultaneous subcutaneous injections of both groups of compounds, after the combination of intraperitoneal (alpha 2 agonist) plus subcutaneous (opioid), intravenous (alpha 2 agonist) plus epidural (opioid) and simultaneous epidural or intrathecal administrations. With regard to antagonism of the analgesic activity of combined treatment with alpha 2 agonists plus opioids, naloxone provided total antagonism, whereas the alpha 2 antagonist idazoxan overcame only the alpha 2 agonist-induced potentiation of fentanyl., Conclusions: The tested alpha 2 agonists can potentiate the analgesic properties of opioids, but they have no intrinsic antinociceptive effects on spinal reflexes on their own. The potentiating activities of the alpha 2 agonists could be measured both in terms of a reduction of the amount of opioid needed to reach a particular level of analgesia and in terms of a longer duration of analgesia with a fixed dose of the opioid. The potentiations were observed with various alpha 2 agonists and opioids and appeared independent of the routes of administration.

The interaction between inactive doses of the opioid sufentanil and the local anesthetic bupivacaine after complexation in various concentrations of hydroxypropyl-beta-cyclodextrin (HP-B-CD) were studied after epidural and intrathecal administration in the rat. Whereas 0.125 microgram sufentanil and 80 micrograms bupivacaine produced only limited effects, a combination of the two compounds resulted in a profound surgical analgesia in all rats tested after epidural administration. Also intrathecally, a clear potentiation was present. The complexation of the same doses of sufentanil plus bupivacaine in HP-B-CD increased the duration of analgesia. Epidurally, a maximal potentiation of analgesia was present at 0.125 microgram sufentanil plus 80 micrograms bupivacaine in 20% HP-B-CD. Intrathecally, maximal potentiation of the analgesic activity was present starting from a complexation of both drugs in 10% hydroxypropyl-beta-cyclodextrin. Higher concentrations of hydroxypropyl-beta-cyclodextrin did not significantly further increase the duration of analgesia. These results indicate that for both routes of spinal administration, the complexation of sufentanil plus bupivacaine in HP-B-CD can produce a longer analgesia than either plain sufentanil, sufentanil combined with bupivacaine or sufentanil alone in HP-B-CD. The complexation of sufentanil plus bupivacaine in HP-B-CD did not diminish the increased safety observed to occur after complexation of sufentanil in HP-B-CD and after combination of sufentanil plus bupivacaine.