title: Antihyperalgesic and side effects of intrathecal clonidine and tizanidine in a rat model of neuropathic pain.
abstract: 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.
authors.affiliation: Department of Anesthesiology, Sapporo Medical University School of Medicine, Hokkaido, Japan. kawamata@sapmed.ac.jp
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Kawamata
authors.forename: Keiichi
authors.initials: K
authors.lastname: Omote
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Masaki
authors.initials: M
authors.lastname: Toriyabe
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Wada
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Namiki
mesh_terms: 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
chemical_list: D000316:Adrenergic alpha-Agonists; D000700:Analgesics; C023754:tizanidine; D003000:Clonidine