PLASMA AND CEREBROSPINAL-FLUID CONCENTRATIONS OF MORPHINE AND MORPHINE GLUCURONIDES AFTER ORAL MORPHINE - THE INFLUENCE OF RENAL-FAILURE

Background: In patients with renal failure, morphine may cause prolong ed narcosis and respiratory depression. Accumulation of the pharmacolo gically active metabolite morphine-6-glucuronide (M-6G) may explain th is effect of morphine in patients with renal failure. After a single o ral dose, morphine and its conjugates were measured in the plasma and the cerebrospinal fluid (CSF) in patients with renal failure. Methods: Eight patients with normal renal function and six patients with renal failure requiring dialysis were studied after operation under spinal anesthesia. Plasma and CSF concentrations of morphine, morphine-3-gluc uronide (M-3G), and M-6G were measured by high-pressure liquid chromat ography every 4 h for 24 h after an oral dose of 30 mg morphine. Resul ts: The area under morphine plasma concentration-time curve from 0 to 24 h increased from 38 +/- 4 ng.ml(-1) X h in patients with normal ren al function to 110 ng.ml(-1) X h in those with renal failure (P < 0.01 ). In patients with renal failure, plasma concentrations of M-3G and M -6G were higher at 4 h and remained at an increased level until the en d of the study. The peak CSF concentration of morphine at 8 h was simi lar in those with renal failure or normal renal function, 1.8 +/- 0.4 and 2.0 +/- 0.6 ng ml(-1) respectively. M-3G and M-6G in CSF reached a maximum at 12 h in patients with normal renal function, whereas in th ose with renal failure the concentrations gradually increased so that the highest concentrations were observed at 24 h. At 24 h, CSF M-6G co ncentration was 15 times greater in patients with renal failure than i n those with normal renal function. Conclusions: We conclude that M-3G and M-6G readily cross the blood-brain barrier in patients with norma l renal function or with renal failure. In patients with renal failure , the retention of plasma M-6G induces a progressive accumulation of t his active metabolite in CSF; this accumulation may explain the increa sed susceptibility to morphine in patients with renal failure.