Characteristics of distribution of morphine and metabolites in cerebrospinal fluid and plasma with chronic intrathecal morphine infusion in humans.

BACKGROUND: Despite widespread use of chronic intrathecal (IT) infusions of morphine, there is little systematic human work evaluating the steady state morphine concentrations or cerebrospinal (CSF) chemistry after long-term IT morphine delivery. We sought to address these issues in patients receiving chronic IT morphine infusion.
METHODS: Pain patients with implanted catheters and pumps (range: 127 to 2165 days), receiving a stable dosing (>1 week) of IT morphine by infusion, were entered into the study. The following sequence was performed: (1) estimation of pain score; (2) radiograph localization of catheter tip; (3) percutaneous sampling of lumbar CSF at the L4 to 5 or L5-S1 space. CSF/plasma samples were assayed for chemistry, and morphine and its 3/6 glucuronide metabolites (M3G, M6G) by liquid chromatography mass spectrometry.
RESULTS: Nineteen patients were enrolled. CSF samples were obtained from 16 subjects. Three patients were not included in the primary analysis because 1 catheter was epidural, 1 catheter was fractured, and 1 had a granuloma at the catheter tip. Of the 13 sampled patients, the range of daily doses, rates, and concentrations were 1.6 to 25 mg/d and 0.1 to 1 mL/d, 5 to 50 mg/mL, respectively. The principal observations were as follows: (i) morphine, M3G, and M6G were present in the CSF and plasma and showed a significant regression slope when plotted versus daily dose; (ii) in contrast, the regression slope of the group ratio morphine:M3G:M6G plotted versus daily dose in CSF or plasma was not different from zero; (iii) plotting "normalized" CSF analyte concentration (e.g., concentration at site/daily IT morphine dose) against the segmental distance of the sampling site from the catheter tip revealed a significant decline in concentration of morphine, but not of conjugates as a function of distance from the catheter tip; (iv) plotting CSF protein, glucose, and red and white cell counts versus daily morphine dose or morphine concentration at the sampling site revealed no significant regression; and (v) patients with a catheter failure or a granuloma showed reduced concentrations of morphine in their CSF.
CONCLUSION: Chronic infusion of morphine shows high concentrations, which correlate with the infusion dose and the proximity of the sampling site to the infusion site with no effects on CSF chemistry.