Morphine, morphine-6-glucuronide, and morphine-3-glucuronide in cerebrospinal fluid and plasma after epidural administration of morphine

Abstract

It has been suggested that the potency of epidural morphine might be explained by spinal metabolism to the active and potent metabolite morphine-6-glucuronide (M6G). The main objective of this study was to describe the early pharmacokinetics of epidurally administered, morphine with special attention to the appearance of the glucuronated metabolites in cerebrospinal fluid (CSF). Morphine was administered epidurally to eight patients scheduled for major abdominal surgery. The concentrations of morphine and its 6-glucuronide and 3-glucuronide metabolites were monitored in blood and CSF at 10, 30, 60, and 120 minutes and 10 and 24 hours. Postoperative pain was estimated on a visual analog scale, and analgesia requirements (administered by a patient-controlled technique) were recorded. Only traces of the metabolites were found in CSF and in only two patients throughout the 24 hours. Both metabolites appeared rapidly (within 30 minutes) in plasma in all patients and were found in plasma throughout the study period. Morphine concentration peaked in CSF within 30 minutes at a very high level; in plasma, it peaked at 10 minutes. No correlation was seen between initial or later concentrations of morphine in CSF and postoperative pain or morphine requirements. No evidence of spinal metabolism of morphine could be found. Rapid distribution of morphine to CSF and plasma occurred after epidural administration. No value of initial CSF morphine concentrations for prediction of analgesic requirements could be demonstrated.