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

Abstract

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. 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. 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. 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.