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REGIONAL ANESTHESIA AND PAIN MANAGEMENT

Acute Decreases in Cerebrospinal Fluid Glutathione Levels after Intracerebroventricular Morphine for Cancer Pain

Leonidas C. Goudas, MD, PhD^*, Agnes Langlade, MD, PhD, Alain Serrie, MD, PhD, Wayne Matson^§, Paul Milbury, ^§, Claude Thurel, MD, Pierre Sandouk, MD^||, and Daniel B. Carr, MD, FABPM^*,

Departments of *Anesthesia and Medicine, New England Medical Center and Tufts University School of Medicine, Boston, Massachusetts; Centre de Traitement de la Douleur, Hopital Lariboisiere, Paris, France; §ESA Corporation, Chelmsford, Massachusetts; and ||INSERM, Paris, France

Address correspondence and reprint requests to Daniel B. Carr, MD, FABPM, Department of Anesthesiology, New England Medical Center, 750 Washington St., Boston, MA 02111. Address e-mail to dcarr02{at}emerald.tufts.edu

Intracerebroventricular (ICV) morphine administration is effective for the management of refractory cancer pain. Recent preclinical observations of acute depletion of the major endogenous intracellular antioxidant glutathione (GSH) in brain and peripheral organs after ICV morphine in rodents led us to apply microchemical methods to profile the neurochemical effects of ICV morphine in three patients treated for intractable cancer pain. Assessment of morphine, morphine-6-glucuronide, and a panel of endogenous compounds and metabolites in ventricular and cisternal cerebrospinal fluid (CSF) demonstrated transient, postdose increases in morphine and morphine-6-glucuronide in ventricular and cisternal CSF, accompanied by acute decreases in CSF GSH levels. Significant changes were also observed in the CSF levels of 4-hydroxybenzoic acid, homovanillic acid, 5-hydroxyphenyllactic acid, and uric acid. These pilot clinical observations of acute central GSH depletion after ICV morphine suggest a novel mechanism for neuropsychiatric toxicity or preclinical findings, such as hyperalgesia or increased motoric activity observed in nonhuman species after central morphine administration. Because ICV morphine is a mainstay of treatment for refractory cancer pain, elucidation of a mechanism’s (or mechanisms’) mediating a potential pro-oxidant state in the central nervous system induced by ICV morphine is important.

Implications: We observed acute decreases in glutathione levels in cerebrospinal fluid sampled from patients after intracerebroventricular doses of morphine for intractable cancer pain. Such doses may, by depleting the antioxidant glutathione, render the central nervous system vulnerable to damage from oxidative stress.

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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