title: Acute decreases in cerebrospinal fluid glutathione levels after intracerebroventricular morphine for cancer pain.
abstract: 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 cistemal 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Anesthesia, New England Medical Center and Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
authors.forename: L C
authors.initials: LC
authors.lastname: Goudas
authors.forename: A
authors.initials: A
authors.lastname: Langlade
authors.forename: A
authors.initials: A
authors.lastname: Serrie
authors.forename: W
authors.initials: W
authors.lastname: Matson
authors.forename: P
authors.initials: P
authors.lastname: Milbury
authors.forename: C
authors.initials: C
authors.lastname: Thurel
authors.forename: P
authors.initials: P
authors.lastname: Sandouk
authors.forename: D B
authors.initials: DB
authors.lastname: Carr
mesh_terms: D002851:Chromatography, High Pressure Liquid; D005978:Glutathione / Q000134:cerebrospinal fluid*; D006801:Humans; D007276:Injections, Intraventricular; D009020:Morphine / Q000008:administration & dosage*; D009022:Morphine Derivatives / Q000134:cerebrospinal fluid; D009369:Neoplasms / Q000150:complications*; D010148:Intractable Pain / Q000188:drug therapy* / Q000209:etiology
chemical_list: D009022:Morphine Derivatives; C035349:morphine-6-glucuronide; D009020:Morphine; D005978:Glutathione