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Chronic morphine therapy for cancer pain

Plasma and cerebrospinal fluid morphine and morphine-6-glucuronide concentrations

Pain Service, Department of Neurology (Dr. Portenoy, E. Khan, M. Layman, J. Lapin, and Dr. Foley), the Department of Neurology (Drs. Portenoy, Malkin, and Foley) and the Department of Biostatistics and Epidemiology (Dr. Thaler), Memorial Sloan-Kettering Cancer Center, New York, NY, and the Department of Pharmacology (Dr. Foley, D.J. Cerbone, and Dr. Inturrisi), Cornell University Medical College, New York, NY.

Morphine-6-glucuronide (M-6-G) is an active metabolite that may contribute to the clinical effects produced by systemic administration of morphine. To help clarify the extent to which M-6-G may cross the blood-brain barrier and exert effects, we employed high-performance liquid chromatography with electrochemical detection to measure the concentrations of M-6-G and morphine in the plasma and either ventricular (three patients) or lumbar (eight patients) CSF of cancer patients receiving chronic morphine therapy. The mean ratio of morphine in ventricular CSF: morphine in plasma was 0.71; the same ratio for M-6-G was only 0.077. The average molar ratio of M-6-G: morphine in ventricular CSF was 0.207, and the average molar ratio in plasma was 1.89. Although sampling problems render the lumbar CSF results less reliable, they were very similar. Thus, plasma contained approximately twice as much M-6-G as morphine, whereas CSF contained only one-fifth to one- third as much. These data confirm that M-6-G in plasma is distributed into CSF, but to a far lesser extent than morphine. They help explain animal data demonstrating much higher potency of M-6-G on administration into CSF than systemic administration and indicate that the degree to which M-6-G contributes to morphine effects in humans remains an unresolved question.

Address correspondence and reprint requests to Dr. Russell K. Portenoy, Pain Service, Department of Neurology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021.

Supported in part by grant CA-32897 from the National Cancer Institute. Dr. Portenoy's research is supported by grant JFRA-244 of the American Cancer Society.

Received July 17, 1990. Accepted for publication in final form February 18, 1991.

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