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REGIONAL ANESTHESIA AND PAIN MANAGEMENT

Cerebrospinal Fluid and Plasma Concentrations of Morphine, Morphine-3-Glucuronide, and Morphine-6-Glucuronide in Patients Before and After Initiation of Intracerebroventricular Morphine for Cancer Pain Management

Maree T. Smith, PhD^*, Andrew W. E. Wright, MSc (Qual)^*, Bronwyn E. Williams, FRCA, Gordon Stuart, FRACS, and Tess Cramond, FRCA, FANZCA

*School of Pharmacy, The University of Queensland; and Multidisciplinary Pain Centre and Kenneth G Jamieson Neurosurgical Unit, Royal Brisbane Hospital, Brisbane, Queensland, Australia

Address correspondence and reprint requests to Dr. Maree T. Smith, School of Pharmacy, The University of Queensland, St. Lucia, Queensland, 4072 Australia. Address e-mail to maree.smith @pharmacy.uq.edu.au.

Twenty-three patients treated with intracerebroventricular (ICV) morphine in this study not only obtained excellent pain relief without rapid increases in dose, but also experienced a reduction in morphine-related side effects. By 24 h after initiation of ICV morphine, the mean trough cerebrospinal fluid (CSF) morphine concentration (approximately 20 µM) was 50-fold higher than the baseline concentration (approximately 0.4 µM), and the CSF concentration of morphine-6-glucuronide (M6G) was undetectable (<0.01 µM). The mean CSF concentration of morphine-3-glucuronide (M3G) decreased 90%, from a baseline concentration of 1 µM to 0.1 µM by Day 7 postventriculostomy. Thereafter, the mean trough CSF M3G concentration remained relatively constant while ICV morphine was continued, although the concomitant M3G plasma concentrations were undetectable (<0.01 µM). The large increase in the CSF morphine concentration in patients receiving ICV morphine strongly suggests that increased CSF morphine levels are unlikely to be the primary cause of analgesic tolerance or undesirable excitatory side effects (hyperalgesia, myoclonus, seizures) experienced by some patients receiving chronic large-dose systemic morphine.

Implications: After initiation of intracerebroventricular morphine, cancer patients experienced excellent pain relief. Although the mean morphine concentration in cerebrospinal fluid increased 50-fold relative to preventriculostomy levels, rapid dose increases did not occur, which suggests that increased cerebrospinal fluid morphine levels are unlikely to be the main cause of analgesic tolerance.

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				P. Klepstad, P. C Borchgrevink, O. Dale, K. Zahlsen, T. Aamo, P. Fayers, B. Fougner, and S. Kaasa Routine drug monitoring of serum concentrations of morphine, morphine-3-glucuronide and morphine-6-glucuronide do not predict clinical observations in cancer patients Palliative Medicine, December 1, 2003; 17(8): 679 - 687. [Abstract] [PDF]

				C. W. Vaughan and M. Connor In Search of a Role for the Morphine Metabolite Morphine-3-Glucuronide Anesth. Analg., August 1, 2003; 97(2): 311 - 312. [Full Text] [PDF]

				K. Hemstapat, G. R. Monteith, D. Smith, and M. T. Smith Morphine-3-Glucuronide's Neuro-Excitatory Effects Are Mediated via Indirect Activation of N-Methyl-D-Aspartic Acid Receptors: Mechanistic Studies in Embryonic Cultured Hippocampal Neurones Anesth. Analg., August 1, 2003; 97(2): 494 - 505. [Abstract] [Full Text] [PDF]

Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999