SYNERGISTIC ANTINOCICEPTIVE INTERACTION AFTER EPIDURAL COADMINISTRATION OF MORPHINE AND LIDOCAINE IN RATS

Background: Clinically, epidural coadministration of opioids and local anesthetics has provided excellent analgesia for various types of pai n. However, information about the interaction of these drugs when admi nistered epidurally is limited. Therefore, we evaluated the antinocice ptive interaction between morphine and lidocaine on both somatic and v isceral noxious stimuli in the rat. Methods: Male Sprague-Dawley rats weighing 300-350 g had epidural catheters implanted at T13-L1. Every r at was tested with both the tail flick test, a somatic noxious stimulu s, 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 abdo minal contraction. Tail flick latency and colerectal distension thresh old were measured before and for 180 min after the administration of m orphine, lidocaine, or combinations of those drugs. To characterize th e interaction, isobolographic analysis was performed with a fixed morp hine: lidocaine dose ratio of 1:1,000.Results: Epidural morphine (0.1- 10 mu g) and lidocaine (100-800 mu g) increased the tail flick latency and colorectal distension threshold in a dose- and time-dependent fas hion. The epidural injection of morphine (0.1-1 mu g) mixed with lidoc aine (100 or 200 mu g) significantly increased the peak effect and pro longed the duration of effects compared with each drug alone in both n ociceptive tests. Areas under the curves, calculated to express overal l magnitude and duration of antinociceptive effects, were significantl y increased by combinations as compared with each drug alone, especial ly with morphine 0.1 mu g and lidocaine 100 or 200 mu g, each of which alone produced no change in the area under the curve. Isobolographic analysis revealed that epidural morphine and lidocaine interact syn er gistically at 10, 20, and 30 min after injection in both somatic and v isceral nociception tests. Both potency ratio analysis and fractional analysis confirmed the finding of the isobolographic analysis. Epidura l naloxone antagonized the antinociceptive effects produced by the com bination. Conclusion: These data demonstrate that epidurally coadminis tered morphine and lidocaine produce synergistic analgesia and prolong the duration of analgesia in tests of somatic and of visceral nocicep tion.