Antihyperalgesic and side effects of intrathecal clonidine and tizanidine in a rat model of neuropathic pain.
BACKGROUND
Although intrathecal clonidine produces pronounced analgesia, antinociceptive doses of intrathecal clonidine produce several side effects, including hypotension, bradycardia, and sedation. Intrathecal tizanidine, another alpha(2)-adrenergic agonist, has provided antinociception without producing pronounced hemodynamic changes in animal studies. However, it has been unclear whether antihyperalgesic doses of intrathecal clonidine and tizanidine produce hypotension and bradycardia in a neuropathic pain state. This study was designed to evaluate the antihyperalgesic effects and side effects of intrathecal clonidine and tizanidine in a rat model of neuropathic pain.


METHODS
Male Sprague-Dawley rats were chronically implanted with lumbar intrathecal catheters, and the sciatic nerve was loosely ligated. After 21-28 days after surgery, the rats received intrathecal clonidine (0.3, 1.0, and 3.0 microg) and tizanidine (1.0, 2.0, and 5.0 microg), and the antihyperalgesic effects of thermal and mechanical stimuli were examined. In addition, the changes in blood pressure and heart rate, sedation level, and other side effects after intrathecal administration of drugs were recorded.


RESULTS
The administration of 3.0 microg intrathecal clonidine or 5.0 microg tizanidine significantly reversed both thermal and mechanical hyperalgesia. The administration of 3.0 microg intrathecal clonidine, but not 5.0 microg tizanidine, significantly decreased mean blood pressure and heart rate and produced urinary voiding. A greater sedative effect was produced by 3.0 microg intrathecal clonidine than by 5.0 microg tizanidine.


CONCLUSIONS
The antihyperalgesic dose of intrathecal clonidine and the antinociceptive doses produced several side effects. Intrathecal tizanidine at the dose that reversed hyperalgesia would be preferable for neuropathic pain management because of absence of hypotension and bradycardia and lower incidence of sedation.
Kawamata
Tomoyuki
T
Department of Anesthesiology, Sapporo Medical University School of Medicine, Hokkaido, Japan. kawamata@sapmed.ac.jp
Omote
Keiichi
K
Yamamoto
Hiroki
H
Toriyabe
Masaki
M
Wada
Kohsuke
K
Namiki
Akiyoshi
A
D000316:Adrenergic alpha-Agonists / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D000700:Analgesics / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D001919:Bradycardia / Q000209:etiology / Q000503:physiopathology; D003000:Clonidine / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D006339:Heart Rate / Q000187:drug effects; D006358:Hot Temperature; D006930:Hyperalgesia / Q000188:drug therapy* / Q000209:etiology* / Q000503:physiopathology; D007022:Hypotension / Q000209:etiology / Q000503:physiopathology; D007278:Injections, Spinal; D008297:Male; D010147:Pain Measurement / Q000187:drug effects; D010523:Peripheral Nervous System Diseases / Q000150:complications*; D010812:Physical Stimulation; D051381:Rats; D017207:Rats, Sprague-Dawley
D000316:Adrenergic alpha-Agonists; D000700:Analgesics; C023754:tizanidine; D003000:Clonidine