Cerebrospinal fluid pharmacokinetics of intrathecal morphine sulfate and D‐Ala²‐D‐Leu⁵‐enkephalin

Abstract

Using an implantable pump system to deliver drugs and sample cerebrospinal fluid (CSF), we assessed rostral redistribution and systemic uptake after intrathecal bolus injection and steady-state infusion of morphine sulfate and the opioid peptide D-Ala2-D-Leu5-enkephalin (DADL) in two patients. Following bolus injection, the mean CSF elimination half-lives for morphine sulfate and DADL were 94 and 115 minutes, respectively. With the catheter tip at L2, the ratio of lumbar to cisternal (L/C) concentrations of morphine sulfate was about 7:1, and with the catheter tip at T10, the L/C ratios of morphine sulfate and DADL were approximately 2:1, indicating that this ratio is dependent in part on the level of intrathecal drug administration. CSF levels of morphine sulfate at steady state were three orders of magnitude higher than those in plasma. The CSF pharmacokinetics of morphine sulfate and DADL are similar, with supraspinal redistribution of these opioids via the CSF likely playing an important role in the generation of analgesia and central nervous system side effects.

Pharmacokinetics and Pharmacodynamics of Intrathecal Ziconotide in Chronic Pain Patients

“…The clearance of hydrophilic opiates has been reported to fall between 0.27 and 0.54 mL/min 10 . The CSF clearance of rhCNTF (0.25 mL/min 13 ), DADL‐enkephalin (0.27–0.66 mL/min 15 ), and thyrotropin‐releasing hormone (0.73 mL/min 16 ) in humans has been reported to be quite similar to ziconotide. CSF is formed (and therefore cleared) at a rate of 0.35 to 0.37 mL/min in adults 17 .…”

Implantable drug delivery systems with morphine in fibromyalgia -A case report-

“…Moulin et al [15] demonstrated that the ratio of the lumbar to cisternal (L/C) concentration of morphine sulfate with the catheter tip at L2 was higher than that at T10. Because of these pharmacokinetic characteristics of morphine sulfate, the level of the catheter tip, pain lesion, and occurrence of complication due to morphine sulfate must be considered when an IDDS is performed.…”

Intrathecal Drug Administration

“…Coombs et al (1985) measured the cisternal and lumbar CSF morphine concentration in a patient receiving continuous intrathecal infusion and obtained a lumbar-to-cisternal ratio of 4.6 : 1. Some investigators have also suggested that this supraspinal redistribution of opiates accounts for much of the analgesia seen in patients (Moulin et al 1986). Therefore, there is the potential at high doses to get supraspinal side effects, even with intrathecal infusion, since the cisternal CSF concentration is not insignificant.…”

“…Some investigators have also suggested that this supraspinal redistribution of opiates accounts for much of the analgesia seen in patients (Moulin et al 1986). Plasma morphine concentrations were 1000 times less than lumbar CSF concentrations (Moulin et al 1986), so drug redistribution to the brain by the circulatory system is probably not an issue in the analgesia produced by the intrathecal administration of morphine. It is also unlikely that body position influences the rostral spread of drug when low volume infusions of essentially isotonic solutions are used, since with spinal anaesthetics position has no effect on the level of anaesthesia when isobaric solutions are used (Greene 1985).…”