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The present study was performed to evaluate the nature of the interaction between epidurally administered sufentanil and bupivacaine in producing antinociception in rats. Rats in which epidural catheters had been inserted received epidural injections with bupivacaine and sufentanil. Nociception was tested by use of the tail-withdrawal reaction (TWR) test and the hot-plate test. Isobolographic analyses were performed with fixed and variable dose ratio treatment schedules based on the ED50s and the highest inactive concentrations of the compounds in both tests. In the TWR test, a synergistic interaction was obtained between the two compounds independent of whether a variable dose ratio regimen (with either 0.08 microgram/rat sufentanil or 80 micrograms/rat bupivacaine as the preset component) or a fixed dose ratio of 1/1,000 sufentanil/bupivacaine (based on the individual ED50s) was used. In the hot-plate test, a synergistic interaction was observed only in the variable dose ratio regimen with 0.08 microgram/rat sufentanil as the preset component and in the fixed dose ratio regimen of 1/1,000 sufentanil/bupivacaine (a ratio based on the ED50 values of the TWR test) but not with a ratio of 1/200, as demonstrated by the ED50s of both drugs in the hot-plate test. The interaction between epidurally administered bupivacaine and sufentanil seems to be synergistic for both tests when variable and fixed dose ratios are used. The synergism could be more easily demonstrated in the TWR test. For drugs with a segmental action, the hot-plate test seems to be less optimal. The necessity of a minimal critical amount of bupivacaine to obtain synergism may have clinical implications.

Background: Alpha2-adrenoceptor agonists, such as clonidine, can potentiate the analgesic properties of spinal opioids. In order to further extend this observation to highly lipophilic and potent spinally acting opioids, we tested the interactions between clonidine and sufentanil after both epidural and intrathecal administration in rats., Methods: The rats were equipped with spinal catheters. Antinociceptive testing was performed with the Tail Withdrawal Reaction test. Dose-response functions of sufentanil, clonidine and combinations of clonidine plus sufentanil were determined., Results: These indicated that 1) sufentanil, but not clonidine alone, results in a dose-related antinociception after both the epidural and the intrathecal route of administration; 2) In combination with normally inactive doses of sufentanil, the addition of clonidine results in activity; 3) In a particular dose-range of sufentanil, there is a direct relationship between the doses of sufentanil and clonidine needed to produce antinociception; 4) Even at very high doses of clonidine, a minimal amount of sufentanil is needed to produce antinociception and 5) At the conditions tested here, the contribution of clonidine is minimal at high, intrinsic active doses of sufentanil.

Sixty patients, scheduled for Caesarean section were randomly allocated to receive by the epidural route in a double-blind fashion one of the following patient-controlled analgesia mixtures for the relief of postoperative pain: sufentanil 2 micrograms.ml-1 in 0.9% sodium chloride, sufentanil 2 micrograms.ml-1 + adrenaline 2.5 micrograms.ml-1, or sufentanil 2 micrograms.ml-1 + clonidine 3 micrograms.ml-1. Patient-controlled analgesia settings were a basal infusion rate of 2.5 ml.h-1, an incremental dose of 2.5 ml, a lockout interval of 10 min and a 1-h limit of 10 ml. Whereas patient demographics and pain scores between the groups were not different, the 24-h consumption of sufentanil was significantly lower in the groups receiving a combination (167.5 SD 45 and 139.1 SD 31.9 micrograms for the adrenaline and clonidine groups respectively) as compared to the plain sufentanil regimen (208.2 SD 38.9 micrograms). Although sufentanil requirements were the lowest in the clonidine admixture group, there were no differences with regard to sedation as compared to the plain sufentanil group. The quality of sleep appeared to be significantly better in the sufentanil/adrenaline group despite a significantly lower degree of sedation and higher incidence of pruritus. Treatment of pruritus with naloxone did not seem to influence the quality of analgesia.

Male Wistar rats were injected epidurally with various doses of sufentanil, bupivacaine or sufentanil combined with bupivacaine either 40 or 80 micrograms. Addition of 80 micrograms bupivacaine to sufentanil produced a 2.2- to 3-fold decrease of the lowest ED50 for a tail withdrawal reaction latency greater than 6 and greater than or equal to 10 s. The potentiation was already present at low doses. Whereas both 0.16 microgram sufentanil and 80 micrograms bupivacaine were inactive, the combination of the two drugs resulted in a deep analgesia in all animals. Because the addition of low doses of bupivacaine to sufentanil did not increase the ED50's for side-effects, higher specificity ratios were obtained as compared to sufentanil given alone. These results were discussed with regard to the potentiation of the analgesic properties of epidurally administered lipophilic opioids by local anaesthetics.

The effects of epidural fentanyl, sufentanil, carfentanil, lofentanil and alfentanil were compared in the rat. All five opiates produced analgesia with the relative order of potency being lofentanil greater than carfentanil greater than sufentanil greater than fentanyl greater than alfentanil, and the relative order of duration at comparative doses lofentanil greater than sufentanil greater than carfentanil greater than fentanyl greater than alfentanil. Because epidural administered opiates still exert some effects within the brain, specificity ratios (defined as the ratio between the ED50s for a prolongation of the tail-withdrawal reaction latency and a blockade of the pinna reflex) were calculated. The relative order of specificity between the five opiates was fentanyl greater than lofentanil greater than sufentanil greater than carfentanil greater than alfentanil. These results are discussed in the context of the search for a safe and sufficiently long-acting lipid soluble epidural analgesic. It is concluded that of these five opiates, sufentanil appears to be the best drug of choice for epidural analgesia.