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 agonist, and clonidine, an alpha2-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 microg), or clonidine (0.1 to 3 microg) 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 microg (0.26 microg) to 0.29 g (0.05 microg) in the tail-flick test and from 1.34 microg (0.12 microg) and 1.21 microg (0.13 microg) to 0.05 microg (0.005 microg) and 0.13 microg (0.015 microg) 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.


CONCLUSIONS
Spinally-administered midazolam, a benzodiazepine, and clonidine, an alpha2-adrenergic receptor agonist, have significant synergistic effects on thermally-induced acute and formalin-induced inflammatory pain.
Nishiyama
T
T
Department of Surgical Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. nishiyam@ims.u-tokyo.ac.jp
Hanaoka
K
K
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000698:Analgesia; D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003000:Clonidine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005557:Formaldehyde; D006358:Hot Temperature; D007249:Inflammation / Q000473:pathology; D008297:Male; D008874:Midazolam / Q000494:pharmacology*; D010146:Pain / Q000188:drug therapy*; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000502:physiology*
D000316:Adrenergic alpha-Agonists; D018686:Anesthetics, Intravenous; D005557:Formaldehyde; D003000:Clonidine; D008874:Midazolam