Synergistic antinociceptive interaction after epidural coadministration of morphine and lidocaine in rats

Clinically, epidural coadministration of opioids and local anesthetics has provided excellent analgesia for various types of pain. However, information about the interaction of these drugs when administered epidurally is limited. Therefore, we evaluated the antinociceptive interaction between morphine and lidocaine on both somatic and visceral noxious stimuli in the rat.

Male Sprague-Dawley rats weighing 300-350 g had epidural catheters implanted at T13-L1. Every rat was tested with both the tail flick test, a somatic noxious stimulus, and the colorectal distension test, a visceral noxious stimulus. In the colorectal distension test, the response threshold was defined by the pressure within the intracolonic balloon required to trigger abdominal contraction. Tail flick latency and colorectal distension threshold were measured before and for 180 min after the administration of morphine, lidocaine, or combinations of those drugs. To characterize the interaction, isobolographic analysis was performed with a fixed morphine: lidocaine dose ratio of 1:1,000.

Epidural morphine (0.1-10 micrograms) and lidocaine (100-800 micrograms) increased the tail flick latency and colorectal distension threshold in a dose- and time-dependent fashion. The epidural injection of morphine (0.1-1 microgram) mixed with lidocaine (100 or 200 micrograms) significantly increased the peak effect and prolonged the duration of effects compared with each drug alone in both nociceptive tests. Areas under the curves, calculated to express overall magnitude and duration of antinociceptive effects, were significantly increased by combinations as compared with each drug alone, especially with morphine 0.1 microgram and lidocaine 100 or 200 micrograms, each of which alone produced no change in the area under the curve. Isobolographic analysis revealed that epidural morphine and lidocaine interact synergistically at 10, 20, and 30 min after injection in both somatic and visceral nociception tests. Both potency ratio analysis and fractional analysis confirmed the finding of the isobolographic analysis. Epidural naloxone antagonized the antinociceptive effects produced by the combination.

These data demonstrate that epidurally coadministered morphine and lidocaine produce synergistic analgesia and prolong the duration of analgesia in tests of somatic and of visceral nociception.