Cerebrospinal fluid distribution of opioids after intraventricular & lumbar subarachnoid administration in sheep

The study of opioid distribution in blood and cerebrospinal fluid (CSF) is required to understand pharmacokinetic-pharmacodynamic relationships following lumbar intrathecal (it) and intracerebroventicular (i.c.v.) administration, and to investigate the contributions of spinal or supraspinal sites of action. The sheep model developed for pharmacokinetic study of analgesics allows atraumatic sampling of plasma and CSF after drug administration by the intravenous (i.v.), i.c.v., and it routes in an unanesthetized animal. Five adult female sheep were prepared with femoral vascular catheters, lumbar it and epidural cannulae, i.c.v. cannulae, and cisterna magna cannulae. Hydromorphone, methadone, naloxone, and [14C] sucrose were injected and collected by two methods: 1) injection into the i.c.v. cannula with lumbar CSF samples collected via the lumbar cannula and 2) injection into the lumbar cannula and cisternal CSF samples collected via ventriculocisternal cannula. Hydromorphone, morphine, and [14C] sucrose were detected at 90-105 min in lumbar CSF after i.c.v. injection. Hydromorphone and [14C] sucrose were detected in i.c.v. cerebrospinal fluid at 50 min after lumbar i.t. injection. Methadone was not detected in i.c.v. cerebrospinal fluid after i.t. injection, nor was methadone significantly detected in lumbar CSF after i.c.v. injection. These data indicate that i.c.v. and i.t. administration of lipophilic opioids produces CSF distributions different from those of hydrophilic opioids. This suggests that lipophilic opioids such as methadone or naloxone exert their effects predominantly on tissues near the site of injection. The study of i.t. and i.c.v. opiate administration and CSF pharmacokinetics may therefore have direct clinical implications.