Distribution, tolerability and tissue compatibility of intrathecal tizanidine in the sheep.
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 micrograms/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 microgram i.t. caused dose-dependent motor inactivity and sleepiness. Continuous i.t. TZD up to 4 micrograms/d was well tolerated regarding behavioral, physical activity, heart rate, muscle 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.


CONCLUSIONS
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.
Department of Neurology, Julius-Maximilians-Universität Würzburg, Germany.
G
G
Ochs
M
M
Loew
J
J
Tonn
K
K
Toyka
D000316:Adrenergic alpha-Agonists / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015360:Analgesia, Epidural; D000700:Analgesics / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000627:therapeutic use; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002908:Chronic Disease; D003000:Clonidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006339:Heart Rate / Q000187:drug effects; D015918:Infusion Pumps, Implantable; D007278:Injections, Spinal; D008657:Metabolic Clearance Rate; D009043:Motor Activity / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects; D010146:Pain / Q000188:drug therapy; D014677:Pharmaceutical Vehicles; D012756:Sheep; D012894:Sleep Stages / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology; D014018:Tissue Distribution
D000316:Adrenergic alpha-Agonists; D000700:Analgesics; D000701:Analgesics, Opioid; D014677:Pharmaceutical Vehicles; C023754:tizanidine; D003000:Clonidine