STUDIES OF THE OPIATE SYSTEM IN CHOLESTATIC LIVER DISEASE

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The hypothesis that increased functional activity of the opioid system contributes to the pathophysiology of cholestasis is being tested in animal models and man. Using an objective monitoring system naloxone infusions have been shown to decrease scratching activity independent of gross body movements by 26-96% in 8 patients with pruritus due to primary biliary cirrhosis in a single blinded controlled-trial. In a double blind controlled trial naloxone infusions were associated with a decrease in scratching activity in 24 of 29 patients with pruritus due to chronic cholestasis (p less than 0.003). These findings confirm a role for the opioid system in the pathogenesis of the pruritus of cholestasis and suggest that not only opiates, like morphine, but also endogenuous opioids mediate pruritus. The ability of the orally bioavailable opiate antagonist nalmefene to provide long-term control of the pruritus of chronic cholestasis is being evaluated. An open label study in 16 patients has been completed with encouraging results and a double-blind placebo-controlled study has been initiated. Increased opiatergic tone in cholestasis is strongly suggested by anti-nociception that is stereoselectively reversed by naloxone and down regulation of brain mu-opioid receptors in bile duct resected (BDR) rats, but no rats with acute hepatocellular necrosis. Using Northern blots preproenekephalin mRNA has been shown to be unequivocally expressed in livers of BDR rats but not controls. This expression was shown by the hybridization histochemistry to be in the nuclei of proliferating bile ductular cells and was associated with positive immunohistochemical staining for met-enkephalin. These findings indicate that the fetal ability of the liver to synthesize opioid peptides is regained during cholestasis.