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Increased opioidergic neurotransmission in the brain appears to contribute to the pruritus that complicates cholestasis and certain non-cholestatic chronic liver diseases. Opiate antagonists have been shown to decrease scratching activity in patients with the pruritus of cholestasis. Initiation of oral administration of an orally bioavailable opiate antagonist may precipitate a florid opioid-withdrawal-like reaction in patients with pruritus complicating cholestasis. Such reactions can be minimized, or avoided completely, by cautiously infusing naloxone before giving small oral doses of an orally bioavailable opiate antagonist. The infusion rate of naloxone should initially be very low; it should be increased gradually and stopped when a rate known to be associated with opioid antagonist effects has been attained. Oral therapy with an opiate antagonist can then be initiated.

Findings consistent with the hypothesis that increased central opioidergic tone contributes to the pruritus of cholestasis provide a rationale for treating this form of pruritus with opiate antagonists. However, initiation of therapy with an opiate antagonist in a cholestatic patient may precipitate a transient opioid withdrawal-like reaction. A woman with chronic cholestasis and disabling pruritus experienced severe transient opioid withdrawal-like reactions after oral administration of 12.5 and 2 mg naltrexone. Subsequently, naloxone was administered by intravenous infusion. Initially, the infusion rate was low and subtherapeutic. It was gradually increased to a rate known to be effective in inducing opioid antagonism. Oral naltrexone was then reintroduced without any reaction occurring. During the ensuing 12 months, while taking naltrexone, 25 mg daily, the patient has been completely free from pruritus. These observations strongly support the hypothesis that increased central opioidergic tone is a component of the pathophysiology of cholestasis.

The site of the pathogenic events responsible for initiating the pruritus of cholestasis has been assumed to be the skin. This assumption cannot be excluded but is not supported by convincing data. Empirical therapies such as anion exchange resins and rifampicin often appear to be partially efficacious. Recent evidence suggests that altered neurotransmission in the brain may contribute to this form of pruritus. In particular, the hypothesis that increased central opioidergic tone is involved is supported by three observations: opiate agonists induce opioid receptor-mediated scratching activity of central origin, central opioidergic tone is increased in cholestasis and opiate antagonists reduce scratching activity in cholestatic patients. Apparent subjective ameliorations of pruritus following intravenous administration of ondansetron to cholestatic patients suggest that altered serotoninergic neurotransmission may also contribute to this form of pruritus.

Background: Intravenous naloxone frequently ameliorates the pruritus of cholestasis, but its low oral bioavailability precludes its use as a long-term therapy. Nalmefene is an orally bioavailable opiate antagonist., Objective: We assessed the efficacy of oral nalmefene in ameliorating the pruritus of cholestasis., Methods: In a prospective controlled study conducted in a tertiary referral hospital, 11 patients with generalized pruritus complicating chronic liver disease were randomized to receive either nalmefene or placebo in a double-blinded fashion for 2-month periods. Scratching activity was measured continuously for 24-hour periods at baseline and at the end of each treatment period., Results: Data on 8 patients who received at least 1 course of nalmefene were available for comparison with corresponding control data, which consisted of observations obtained during a course of placebo and/or at baseline. Nalmefene therapy was associated with a 75% reduction in the geometric mean hourly scratching activity (P <.01) and a decrease in the mean of a visual analogue score of the perception of pruritus in all 8 patients (mean decrease 77%, P <.01)., Conclusion: Oral administration of nalmefene can ameliorate pruritus complicating chronic liver disease.

Pruritus is a distressing symptom experienced by a large proportion of patients with cholestasis. The cause of this form of pruritus is unknown, and therapy tends to be empirical and unsatisfactory. This article discusses the emerging role of the brain and neurotransmitter systems in the pathogenesis of the pruritus of cholestasis and emphasizes the importance of the application of quantitative methodology in clinical trials of therapies for the pruritus of cholestasis.

The aims of this study were to determine whether long-term oral administration of the opiate antagonist nalmefene is associated with any beneficial effects in patients with pruritus secondary to cholestatic liver disease and to assess the safety of long-term administration of this drug to these patients. Fourteen patients with unrelieved chronic pruritus of cholestasis were studied. Scratching activity, independent of limb movements, was recorded continuously for 24-hour periods before and during treatment with an initial ameliorating dose of nalmefene. Simultaneously, during these periods, visual analogue scores (VASs) of pruritus were recorded every 4 hours while patients were awake. The dose of nalmefene, which initially was 2 mg orally twice daily, was increased during the study, usually until a satisfactory clinical response was achieved. Five patients experienced a transient opioid withdrawal-like reaction that did not preclude continuing with nalmefene therapy. Serum biochemical indices of cholestasis did not change appreciably during treatment. Thirteen patients reported amelioration of the perception of pruritus on nalmefene. In 5 patients, exacerbations of pruritus occurred approximately 4 weeks after an initial ameliorating dose had been reached; these exacerbations were managed by increasing the dose. Baseline mean values for VAS and scratching activity were higher than corresponding means during nalmefene therapy in 13 (P = .002) and 12 (P = .013) patients, respectively. Possible tolerance to nalmefene occurred in 3 patients. Three patients experienced marked exacerbation of pruritus after nalmefene therapy was suddenly discontinued. Blood levels of nalmefene were consistent with normal pharmacokinetics of the drug. These results suggest that nalmefene may have a favorable risk-to-benefit ratio when it is administered orally long-term to patients with the pruritus of cholestasis.

Objective: To determine whether endogenous opioids contribute to the pruritus of cholestasis by studying the effect of the opiate antagonist naloxone on the perception of pruritus and on scratching activity in patients with this form of pruritus., Design: Double-blind, placebo-controlled, crossover trial with four periods., Setting: Clinical research referral center., Patients: 29 pruritic patients with liver diseases of various causes., Intervention: Each patient received as many as two naloxone and two placebo solution infusions consecutively in random order. Each infusion lasted 24 hours., Measurements: During the infusions, visual analog scores of pruritus were recorded every 4 hours while patients were awake; scratching activity independent of limb movements was recorded continuously., Results: One patient had a mild reaction consistent with a naloxone-precipitated syndrome similar to opiate withdrawal. A significant 24-hour rhythm of scratching activity was seen in 7 of 11 patients for whom complete 96-hour data were collected. The mean of a visual analog score of the perception of pruritus (maximum, 10.0) recorded during naloxone infusions was 0.582 lower than that recorded during placebo infusions (95% CI, 0.176 to 0.988; P < 0.01). Furthermore, the ratio of the geometric mean hourly scratching activity during naloxone infusions to that during placebo infusions was 0.727 (CI, 0.612 to 0.842; P < 0.001) and was greater than 1.0 in only five patients., Conclusions: Naloxone administration is associated with amelioration of the perception of pruritus and reduction of scratching activity in cholestatic patients. Because of the opioid receptor specificity of the action of naloxone, these findings support the hypothesis that a mechanism underlying the pruritus of cholestasis is modulated by endogenous opioids and suggest that opiate antagonists may have a role in the management of this complication of cholestasis.

Cholestatic liver disease is associated with clinical and experimental findings consistent with increased opioidergic neuromodulation, increased plasma total opioid activity, and elevated plasma enkephalin concentrations. In contrast to the normal adult rat liver, preproenkephalin mRNA was detected by Northern blotting in livers of adult rats with cholestasis due to bile duct resection and not in the sham-resected controls. Preprodynorphin mRNA was not detected in livers of either group, while preproopiomelanocortin mRNA was found in very low levels in both groups. Preproenkephalin mRNA was not expressed in the livers of rats with acute hepatocellular necrosis induced by thioacetamide. Hybridization histochemistry of cholestatic livers demonstrated the presence of preproenkephalin mRNA primarily over cells in the periportal areas, some of which appeared to be proliferating bile ductular cells. Immunohistochemical staining of cholestatic liver indicated the production of at least Met-enkephalin in association with preproenkephalin gene expression. These findings suggest that the liver itself, by synthesizing enkephalins, contributes directly to the abnormalities of the opioid system reported in cholestasis.

The adrenal gland is known to produce and release endogenous opioids into the circulation. Bovine adrenal medulla docosapeptide (BAM-22P) is a potent opioid agonist, derived from the proenkephalin A gene, which is present in the adrenal medulla. This study was undertaken to determine whether BAM-22P is released into plasma during acute cholestatic liver injury, which increases plasma total opioid activity. Acute cholestasis was induced by bile duct ligation or administration of the hepatotoxin alpha-naphthylisothiocyanate. Plasma levels of BAM-22P were determined by a sensitive radioimmunoassay, and the specificity of the assay was confirmed using high-performance liquid chromatography. Plasma BAM-22P levels was cholestatic rats were significantly higher than those in control rats. This increase in plasma BAM-22P levels was completely prevented by adrenalectomy. Adrenal steady-state levels of proenkephalin mRNA, as determined by Northern blot hybridization analyses, were also increased significantly in cholestatic rats. These increases in proenkephalin mRNA levels were not paralleled by changes in adrenal BAM-22P peptide levels, which were similar in cholestatic rats and their respective controls. Similar levels of proenkephalin mRNA expression were observed in innervated and denervated adrenal glands from cholestatic rats, suggesting that the increase in adrenal proenkephalin mRNA levels in acute cholestasis is not due to splanchnic nerve activation. Thus acute cholestasis in the rat is associated with adrenal secretion and accumulation in plasma of the highly potent opioid peptide BAM-22P and an augmentation of adrenal proenkephalin mRNA expression. The increase in plasma BAM-22P levels may contribute substantially to the increase in total circulating opioid activity documented in cholestatic rats.

Clinical observations have suggested that cholestasis is associated with increased neurotransmission mediated by the opioid system in the central nervous system. As opiate agonists (e.g. morphine) mediate analgesia, increased opioidergic tone in cholestasis should be associated with a decreased response to pain. To test this hypothesis, the response of rats with acute cholestasis to a nociceptive stimulus was measured by the use of the tail-flick test, an extensively validated assay for measuring opiate-induced antinociception. Five and 7 days after bile-duct resection, the mean tail-flick latency was longer than before surgery (p < 0.05), whereas the corresponding means for unoperated and sham-resected controls were not significantly different from their respective baseline values. The increase in the mean tail-flick latency in the bile-duct resection group was reversed by (-)-naloxone (1 mg/kg subcutaneously), but not by its enantiomer (+)-naloxone (10 mg/kg subcutaneously) (p < 0.001). The stereoselective reversal of antinociception in cholestasis by naloxone indicates that this phenomenon is opioid-receptor mediated. In contrast, prolongation of the mean TFL found in the rat model of thioacetamide-induced acute hepatocellular necrosis was not reversed by (-)-naloxone, indicating that antinociception in this model is not opioid mediated. These findings provide support for the hypothesis that cholestasis is associated with increased opioidergic tone.

Endopeptidase 24.11 (enkephalinase), an enzyme known to be present in plasma and liver, is capable of metabolizing a substantial number of bioactive peptides. We measured plasma endopeptidase 24.11 activity in normal subjects and in patients with chronic hepatocellular disease or chronic cholestatic liver disease. The mean level of plasma endopeptidase 24.11 activity was 13 times higher in cholestatic patients than in controls or patients with hepatocellular disease (p < 0.01). Plasma endopeptidase 24.11 activity in patients correlated closely with traditional serum markers of cholestasis, including levels of alkaline phosphatase, gamma-glutamyltranspeptidase and aminopeptidase (p < 0.01 for all). However, plasma endopeptidase 24.11 activity correlated poorly with serum ALT aminotransferase level (p = NS), indicating that it is not a marker of hepatocellular disease. The lack of overlap between plasma endopeptidase 24.11 activity in cholestatic patients and noncholestatic liver disease controls suggests that this enzyme activity is a useful biochemical marker of cholestasis. In addition, because of the broad spectrum of peptides metabolized by endopeptidase 24.11, increased plasma endopeptidase 24.11 activity may contribute to the pathophysiology of the syndrome of cholestasis.

The blood-brain-barrier plays an essential role in regulating the entrance of substances into the brain. To date, permeability of the blood-brain barrier has not been studied in models of cholestatic liver injury, although levels of substances known to enhance vascular permeability (bile acids, substance P, histamine) are elevated in cholestasis. Two rat models of cholestasis were studied: bile duct resection (5 days after surgery) and alpha-naphthylisothiocyanate treatment (45 mg/kg/day for 7 days). The mean value for whole brain blood-to-brain transfer constant in bile duct resection rats was about 50% less than corresponding values in sham-operated and unoperated control rats (p < or = 0.05, respectively). Reductions in blood-to-brain transfer constant of similar magnitude were found in the caudate nuclei, cortexes and hippocampi of bile duct-resected rats. Blood-to-brain transfer constant values in alpha-naphthylisothiocyanate-treated rats were also about 50% less in whole brain and specific brain regions than corresponding control values. A precedent for a decrease in blood-to-brain transfer constant is the dexamethasone-treated rat, in which the phenomenon has been attributed to a decrease in cerebral capillary endothelial cell membrane fluidity. We confirmed that blood-to-brain transfer constant values are reduced by about 50% in dexamethasone-treated rats. A decrease in membrane fluidity affords a rational explanation for a decrease in blood-to-brain transfer constant in cholestasis as a consequence of the dynamic equilibrium between elevated plasma levels of cholesterol in cholestasis and cell membranes exposed to the circulation.

Cholestatic patients undergoing surgery have increased mortality and demonstrate clinical features suggestive of adrenal insufficiency. To examine whether cholestasis influences the status of the hypothalamic-pituitary-adrenal axis, we evaluated rats with acute cholestasis caused by bile duct resection (BDR) and sham-operated and unoperated controls. Basal unstressed plasma concentrations of ACTH and corticosterone were similar in BDR and sham-operated and unoperated control rats. However, exposure of BDR rats to saturated ether vapor resulted in significantly less ACTH and corticosterone release in plasma than in the control animals. To understand the mechanism(s) of decreased HPA axis responsiveness to ether stress in cholestasis, we administered corticotropin-releasing factor (CRF) and measured hypothalamic content, mRNA levels and in vitro secretion of CRF and arginine vasopressin (AVP), the two principal secretagogues of ACTH. In BDR animals, ACTH responses to CRF were decreased and hypothalamic content of CRF and CRF mRNA expression in the paraventricular nucleus were decreased by 25 and 37%, respectively. Furthermore, CRF release from hypothalamic explants of BDR rats was 23% less than that of controls. In contrast to CRF, hypothalamic content of AVP was 35% higher, AVP mRNA in the paraventricular nucleus was increased by 6.6-fold, and hypothalamic explant release of AVP was 24% higher in BDR rats than in control animals. Pituitary ACTH contents were similar in BDR and sham resected rats, but higher than unoperated controls. These findings demonstrate that acute cholestasis in the rat is associated with suppression of hypothalamic-pituitary-adrenal axis responsiveness to stress and demonstrate a dissociation between mechanisms of ACTH regulation mediated by CRF and AVP.

The medullary dorsal horn is a site of action of opiates in producing facial scratching. Extracts of plasma (0.4 microliter) from 4 patients with the pruritus of cholestasis induced facial scratching when microinjected into the medullary dorsal horn of monkeys. This extract-induced scratching could be abolished or prevented by administering the opioid receptor antagonist, naloxone. Neither saline nor an extract of plasma from a nonpruritic cholestatic patient induced scratching when similarly administered. We infer that plasma of patients with the pruritus of cholestasis contains a factor which induces pruritus by a central opioid receptor-mediated mechanism.

To obtain data on the degree to which the opioid system is changed in cholestasis, endogenous opioid activity in plasma of rats with acute cholestasis was determined 5 days after bile duct resection. Total plasma opioid activity was determined using a radioreceptor technique that measured the displacement of the opiate receptor ligand [3H]-DAMGO from lysed synaptosomal fractions of normal rat brain. Plasma total opioid activity was threefold greater in bile duct-resected rats than in sham-operated and unoperated controls (P less than or equal to 0.05). Plasma levels of the individual endogenous opioid, methionine-enkephalin, were determined using a sensitive radioimmunoassay, and the specificity of the assay was confirmed using high-performance liquid chromatography. In cholestatic rats, plasma methionine-enkephalin levels were more than six-fold greater than in sham-operated controls (P less than or equal to 0.001) and more than 17-fold greater than in unoperated controls (P less than or equal to 0.001). However, plasma methionine-enkephalin levels accounted for less than 5% of total plasma opioid activity after bile duct resection. Plasma methionine-enkephalin levels in both cholestatic plasma and plasma from sham-operated animals were stable when incubated in vitro despite the presence of undiminished activity of the major enkephalin-degrading enzymes. Thus, protection of methionine-enkephalin from degradation may be a factor contributing to the elevated plasma levels of methionine-enkephalin found in cholestasis. The magnitude of the increase in plasma endogenous opioid activity in bile duct-resected rats provides support for the hypothesis that endogenous opioids contribute to the pathophysiology of cholestasis.

Ameliorations of the pruritus of cholestasis by opioid antagonists are consistent with this form of pruritus being centrally mediated by the opioid system. To determine whether the central opioid system is altered in cholestasis, the specific binding of a selective mu-opioid receptor ligand, 3H-DAMGO, to mu-opioid receptors was studied in rats with acute cholestasis due to bile duct resection. Using whole brain membranes and subcellular mitochondrial-synaptosomal fractions the density of mu-receptor sites was 30% (p less than 0.01) and 22% (p = 0.03) less in bile-duct-resected rats than in sham-resected rats. Using membranes from individual brain regions specific binding of 3H-DAMGO was reduced by 43-53% in the cerebral cortex, hippocampus and caudate nucleus of bile-duct-resected rats. Thus mu-opioid receptors in the brain are down-regulated in a classical model of cholestasis. This alteration of the central opioid system could be a consequence of increased exposure of opioid receptors to endogenous opioids in cholestasis and may reflect an important mechanism in the pathogenesis of the pruritus of cholestasis.

A patient who developed chronic cholestatic jaundice during the 1st year of life and eventually died of liver cell failure at the age of 18 years is described. During the terminal illness Kayser-Fleischer-like rings were observed and the serum concentrations of total copper and ceruloplasmin were elevated. At autopsy, a mixed macronodular and micronodular cirrhosis was found and cholangiography and dissection of bile ducts revealed no obstructive lesion of the biliary tract. There was no family history of hepatobiliary disease. Liver biopsies obtained at the ages of 5 and 7 years showed accumulation of bile droplets in hepatocytes, normal-appearing bile ducts, no significant fibrosis, and intact lobular architecture. Striking features of the terminal cirrhosis were the presence of Mallory bodies and a marked excess of copper in the liver (2,175 mug per g dry weight). The latter two findings, as well as the elevated serum concentrations of total copper and ceruloplasmin, may be attributable to chronic cholestasis per se. This study emphasizes the clinical and therapeutic problems posed by chronic cholestasis of unknown etiology in childhood.