Acute decreases in cerebrospinal fluid glutathione levels after intracerebroventricular morphine for cancer pain

Intracerebroventricular (ICV) morphine administration is effective for the management of refractory cancer pain. Recent preclinical observations of ac ute 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 an d metabolites in ventricular and cisternal cerebrospinal fluid (CSF) demons trated transient, postdose increases in morphine and morphine-6-glucuronide in ventricular and cisternal CSF, accompanied by acute decreases in CSF GS H levels. Significant changes were also observed in the CSF levels of 4-hyd roxybenzoic acid, homovanillic acid, 5-hydroxyphenyllactic acid, and uric a cid. These pilot clinical observations of acute central GSH depletion after ICV morphine suggest a novel mechanism for neuropsychiatric toxicity or pr eclinical findings, such as hyperalgesia or increased motoric activity obse rved 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. Implica tions: We observed acute decreases in glutathione levels in cerebrospinal f luid sampled from patients after intracerebroventricular doses of morphine for intractable cancer pain. Such doses may, by depleting the anti-oxidant, glutathione, render the central nervous system vulnerable to damage from ox idative stress.