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Distribution, tolerability and tissue compatibility of intrathecal tizanidine in the sheep
Author(s) -
Ochs G.,
Loew M.,
Tonn J.,
Toyka K.
Publication year - 1998
Publication title -
acta anaesthesiologica scandinavica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.738
H-Index - 107
eISSN - 1399-6576
pISSN - 0001-5172
DOI - 10.1111/j.1399-6576.1998.tb05323.x
Subject(s) - medicine , pharmacokinetics , tolerability , anesthesia , spinal cord , bolus (digestion) , chronic pain , lumbar , pharmacology , surgery , adverse effect , psychiatry
Background : Tizanidine (TZD) is an alpha‐2‐adrenergic drug with potential spinal analgesic action and could be a substitute or additive for intrathecal (i.t.) opiates in chronic pain treatment. However, long‐term tolerability and tissue compatibility are not yet established. Methods : Three sheep were infused intrathecally with TZD up to 4000 μg/d over a time period of up to 440 d using implantable drug administration devices; one control animal was infused with vehicle only; standard values were collected from untreated sheep. CSF samples and blood samples were analyzed to determine pharmacokinetics and systemic redistribution. Behavioral effects were studied. The spinal cord tissue was investigated using standard laboratory histology. Results : Bolus kinetics 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, respectively. Clearance of TZD from lumbar CSF was 0.48 ml/min. Doses higher than 500 μg i.t. caused dose‐dependent motor inactivity and sleepiness. Continuous i.t. TZD up to 4 mg/d was well tolerated regarding behavior, 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 irritation by the catheter and repeated sampling procedures. Histological evaluation of the spinal cord and adjacent tissues showed no abnormalities. Conclusion : The long‐term intrathecal infusion of TZD is well tolerated and non‐toxic in the sheep. The data favor clinical trials in patients with chronic pain.