Antinociceptive interaction of intrathecal alpha2-adrenergic agonists, tizanidine and clonidine, with lidocaine in rats.
BACKGROUND
The intrathecal alpha2-adrenergic agonist, clonidine, has been shown to have considerable antinociceptive effect, although clonidine causes hypotension and bradycardia. The combination of intrathecal clonidine and local anesthetics enhances analgesic effects, whereas the combination may cause marked hypotension and motor blockade, which may limit the clinical application of the combination. Tizanidine, another alpha2-adrenergic agonist, has also provided antinociception without producing pronounced hemodynamic changes. This study was designed to evaluate the antinociceptive and hemodynamic interactions of tizanidine and clonidine with lidocaine.


METHODS
Male Sprague Dawley rats were chronically implanted with lumbar intrathecal catheters. The tail-flick test was used to assess the thermal nociceptive threshold. The ability of intrathecal tizanidine, clonidine, lidocaine, or the combinations of alpha2-adrenergic agonist and lidocaine to alter the tail-flick latency was examined. To characterize the antinociceptive interaction, the isobolographic analysis was applied. Additionally, the motor function, blood pressure and heart rate after intrathecal administration of drugs and combinations were also monitored.


RESULTS
Intrathecal tizanidine, clonidine, or the combinations increased the tail-flick latency in dose- and time-dependent fashion without affecting motor function. The order potencies (dose producing a 50% of peak effect, in microg) of tizanidine and clonidine were 1.8 and 0.75, respectively. With isobolographic analysis, tizanidine with lidocaine and clonidine with lidocaine showed significantly synergistic antinociceptive interaction. Potency ratio analysis and fractional analysis also confirmed the synergistic interaction. At the doses in the combinations showing comparable antinociception, tizanidine with lidocaine, unlike clonidine with lidocaine, did not affect motor function or blood pressure.


CONCLUSIONS
The authors' results show that intrathecal tizanidine and clonidine synergistically interact with lidocaine so that the degree of antinociception to somatic noxious stimuli are enhanced. The antinociceptive synergistic interaction between tizanidine and lidocaine may be useful in clinical practice without affecting blood pressure, heart rate, or motor function.
Kawamata
T
T
Department of Anesthesiology, Sapporo Medical University School of Medicine, Hokkaido, Japan. kawamata@sapmed.ac.jp
Omote
K
K
Kawamata
M
M
Iwasaki
H
H
Namiki
A
A
D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003000:Clonidine / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D004347:Drug Interactions; D006339:Heart Rate / Q000187:drug effects; D007278:Injections, Spinal; D008012:Lidocaine / Q000008:administration & dosage*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010146:Pain / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015016:Yohimbine / Q000008:administration & dosage
D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists; D000700:Analgesics; D015016:Yohimbine; C023754:tizanidine; D008012:Lidocaine; D003000:Clonidine