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PAIN MEDICINE

The Synergistic Interaction Between Midazolam and Clonidine in Spinally-Mediated Analgesia in Two Different Pain Models of Rats

Tomoki Nishiyama, MD PhD^*, and Kazuo Hanaoka, MD PhD

*Department of Surgical Center, The Institute of Medical Science, and the Department of Anesthesiology, The University of Tokyo, Tokyo, Japan

Address correspondence and reprint requests to Tomoki Nishiyama, MD, PhD, Department of Surgical Center, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, 108-8639, Tokyo, Japan. Address e-mail to nishiyam{at}ims.u-tokyo.ac.jp

Both midazolam, a benzodiazepine -aminobutyric acid type A receptor agonist, and clonidine, an ₂-adrenergic receptor agonist, induce spinally-mediated analgesia. We investigated the analgesic interaction of spinally-administered midazolam and clonidine in their effects on acute and inflammatory nociception. Rats implanted with lumbar intrathecal catheters were injected intrathecally with saline (control), midazolam (1 to 100 µg), or clonidine (0.1 to 3 µg) to test for their responses to thermal stimulation to the tail (tail-flick test) and subcutaneous formalin injection into the hind paw (formalin test). The effects of the combination of midazolam and clonidine on both stimuli were tested by isobolographic analysis by using the 50% effective doses. The general behavior and motor function were examined as side effects. When combined, the 50% effective doses of midazolam (clonidine) decreased from 1.57 µg (0.26 µg) to 0.29g (0.05 µg) in the tail-flick test and from 1.34 µg (0.12 µg) and 1.21 µg (0.13 µg) to 0.05 µg (0.005 µg) and 0.13 µg (0.015 µg) in Phase 1 and 2 of the formalin test, 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 neurotoxicologic studies.

IMPLICATIONS: Spinally-administered midazolam, a benzodiazepine, and clonidine, an ₂-adrenergic receptor agonist, have significant synergistic effects on thermally-induced acute and formalin-induced inflammatory pain.

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999