This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (10) Citing Articles via Google Scholar Google Scholar Articles by Nishiyama, T. Articles by Hanaoka, K. Search for Related Content PubMed PubMed Citation Articles by Nishiyama, T. Articles by Hanaoka, K. Related Collections Pain Pharmacology

---

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.

This article has been cited by other articles:

				S. Chiba, T. Nishiyama, and Y. Yamada The Antinociceptive Effects and Pharmacological Properties of JM-1232(-): A Novel Isoindoline Derivative Anesth. Analg., March 1, 2009; 108(3): 1008 - 1014. [Abstract] [Full Text] [PDF]

				M. J. Johansen, T. L. Gradert, W. C. Satterfield, W. B. Baze, K. Hildebrand, L. Trissel, and S. J. Hassenbusch Safety of Continuous Intrathecal Midazolam Infusion in the Sheep Model Anesth. Analg., June 1, 2004; 98(6): 1528 - 1535. [Abstract] [Full Text] [PDF]

				T. L. Yaksh and J. W. Allen The Use of Intrathecal Midazolam in Humans: A Case Study of Process Anesth. Analg., June 1, 2004; 98(6): 1536 - 1545. [Abstract] [Full Text] [PDF]

				T. Nishiyama, H. Tamai, and K. Hanaoka Serum and Cerebrospinal Fluid Concentrations of Midazolam After Epidural Administration in Dogs Anesth. Analg., January 1, 2003; 96(1): 159 - 162. [Abstract] [Full Text] [PDF]