Continuous intrathecal clonidine and tizanidine in conscious dogs: analgesic and hemodynamic effects.
Alpha-2-adrenergic agonists, such as clonidine, produce antinociception in animal pain models after intrathecal administration. However, clinical usage is limited by cardiovascular side effects. To investigate alternative alpha(2)-adrenergic agonists as analgesics, we implanted six dogs with an intrathecal catheter and infusion pump. After baseline saline infusion, animals received clonidine or tizanidine (crossover study) each week at escalating doses of 125-750 microg/h. Analgesia, blood pressure, heart rate, respiratory rate, sedation, and coordination were evaluated. A 28-day safety study was performed with another nine dogs receiving intrathecal tizanidine (3 or 6 mg/d) or saline. Equal doses of clonidine and tizanidine produce the same antinociception in thermal withdrawal tests. Blood pressure was reduced with 125-500 microg/h of clonidine, but not with tizanidine at any dose. Clonidine 250 microg/h reduced heart rate by 45.8%, and five of six animals had bradyarrhythmias (marked bradycardia), whereas tizanidine decreased heart rate by 15.1% without arrhythmias, even at the largest dose. Respiratory rate decreased with 250 microg/h of clonidine and larger doses. Sedation or incoordination occurred only at the largest dose for either drug. The safety study indicated that 3 mg/d of tizanidine in dogs produced no side effects or histopathologic changes. Tizanidine may be a useful alternative in patients experiencing cardiovascular side effects with intrathecal infusion of clonidine.


CONCLUSIONS
Clonidine is an effective spinal analgesic, but it is dose-limited by cardiovascular side effects. We compared the analgesic properties and side effects of clonidine with those of a similar drug, tizanidine. Continuous spinal infusion of tizanidine produced similar analgesia as clonidine, but with fewer adverse effects on blood pressure and heart rate.
Kroin
Jeffrey S
JS
Departments of *Anesthesiology and †Neurosurgery, Rush Medical College, Chicago, Illinois.
McCarthy
Robert J
RJ
Penn
Richard D
RD
Lubenow
Timothy J
TJ
Ivankovich
Anthony D
AD
D000316:Adrenergic alpha-Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D000700:Analgesics; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003000:Clonidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D006993:Hypnotics and Sedatives; D007278:Injections, Spinal; D008297:Male; D011597:Psychomotor Performance / Q000187:drug effects; D015656:Respiratory Mechanics / Q000187:drug effects
D000316:Adrenergic alpha-Agonists; D000700:Analgesics; D006993:Hypnotics and Sedatives; C023754:tizanidine; D003000:Clonidine