DISTRIBUTION, TOLERABILITY AND TISSUE COMPATIBILITY OF INTRATHECAL TIZANIDINE IN THE SHEEP

Background: Tizanidine (TZD) is an alpha-2-adrenergic drug with potent ial spinal analgesic action and could be a substitute or additive for intrathecal (i.t.) opiates in chronic pain treatment. However, long-te rm tolerability and tissue compatibility are not yet established. Meth ods: Three sheep were infused intrathecally with TZD up to 4000 mu g/d over a time period of up to 440 d using implantable drug administrati on devices; one control animal was infused with vehicle only; standard values were collected from untreated sheep. CSF samples and blood sam ples were analyzed to determine pharmacokinetics and systemic redistri bution. Behavioral effects were studied. The spinal cord tissue was in vestigated using standard laboratory histology. Results: Bolus kinetic s after i.t, injection of TZD are best described by a two-phase model. Elimination half-lives of TZD in CSF were 15 min and 152 min, respect ively. Clearance of TZD from lumbar CSF was 0.48 ml/min. Doses higher than 500 mu g i.t, caused dose-dependent motor inactivity and sleepine ss. Continuous i.t. TZD up to 4 mg/d was well tolerated regarding beha vior, physical activity, heart rate, muscle strength, and coordination . Minor elevations of CSF cell counts and total protein were detected both in saline and TZD-treated animals, presumably due to local irrita tion by the catheter and repeated sampling procedures. Histological ev aluation of the spinal cord and adjacent tissues showed no abnormaliti es. Conclusion: The long-term intrathecal infusion of TZD is well tole rated and non-toxic in the sheep. The data favor clinical tri als in p atients with chronic pain.