The synergistic interaction between midazolam and clonidine in spinally-mediated analgesia in two different pain models of rats

Both midazolam, a benzodiazepine gamma -aminobutyric acid type A receptor a gonist, and clonidine, an alpha (2)-adrenergic receptor agonist, induce spi nally-mediated analgesia. We investigated the analgesic interaction of spin ally-administered midazolam and clonidine in their effects on acute and inf lammatory nociception. Rats implanted with lumbar intrathecal catheters wer e injected intrathecally with saline (control), midazolam (1 to 100 mug), o r clonidine (0.1 to 3 mug) to test for their responses to thermal stimulati on to the tail (tail-flick test) and subcutaneous formalin injection into t he hind paw (formalin test). The effects of the combination of midazolam an d clonidine on both stimuli were tested by isobolographic analysis by using the 50% effective doses. The general behavior and motor function were exam ined as side effects. When combined, the 50% effective doses of midazolam ( clonidine) decreased from 1.57 mug (0.26 mug) to 0.29g (0.05 mug) in the ta il-flick test and from 1.34 mug (0.12 mug) and 1.21 mug (0.13 mug) to 0.05 mug (0.005 mug) and 0.13 mug (0.015 mug) in Phase 1 and 2 of the formalin t est, respectively. Side effects did not increase by using the combination. These results suggest a favorable combination of intrathecal midazolam and clonidine in the management of acute and inflammatory pain after proper neu rotoxicologic studies.