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The pruritus of cholestasis: Potential pathogenic and therapeutic implications of opioids
GASTROENTEROLOGY 1995;108:1582-1588
VIEWPOINTS ON DIGESTIVE DISEASES The Pruritus of Cholestasis: Potential Pathogenic and Therapeutic Implications of Opioids NORA VALERIA B E R G A S A * a n d E. A N T H O N Y JONES t *Laboratory of the Biology of Addictive Diseases, Rockefeller University, New York, New York; and tDepartment of Gastrointestinal and Liver Diseases, Academic Medical Centre, Amsterdam, The Netherlands
Upon any attempt obstinately to renew the old doses, there arose a new symptom.., viz., an irritation on the surface of the s k i n . . . which soon became unsupportable, and tended to distraction. --Thomas de Quincy, 1821 Confessions of an English Opium Eater 1
he impressive march of progress in the field of hepatology in recent years has had minimal impact on the problems posed by patients with the pruritus that frequently complicates the syndrome of cholestasis. This form of pruritus remains one of the most challenging management problems with which gastroenterologists and hepatologists are commonly confronted. Because the pathogenesis of the pruritus of cholestasis is unknown, therapies used in its management have tended to be empirical. The number and diversity of these therapies reflect the frustration and impotence of clinicians attempting to provide patients with substantial relief from this maddening condition. Unrelieved pruritus of cholestasis not only can interfere with normal activities but may lead to severe sleep deprivation and even suicidal ideation. Intractable pruritus attributable to cholestasis is considered to be an indication for liver transplantation. There are several reasons why progress has been so slow in understanding the pathogenesis of the pruritus of cholestasis and in developing more effective therapies. Because the symptom of pruritus is inherently subjective, it has not been obvious to clinical investigators whether application of any objective quantitative methods would provide meaningful data in clinical trials. There has been a tendency to base hypotheses of pathogenesis on correlations between subjective assessments of pruritus and levels of specific substances. In this context, data on levels of a substance in plasma may be less relevant than corresponding levels elsewhere (e.g., interstitial fluid of skin). To determine whether a correlation has pathogenic relevance, it is necessary to show a causal relationship between increased levels of the substance and the mediation of pruritus, and this requirement has not been fulfilled
T
for putative pruritogens (e.g., bile acids) in cholestatic patients] There must be a logical reason for implicating a specific class of substance in the pathogenesis of the pruritus of cholestasis, and such a reason currently appears to be lacking for most of the putative pruritogens that have been implicated in this syndrome. In clinical trials of potential therapies for the pruritus of cholestasis, it is essential to distinguish between therapeutic effects and placebo responses or spontaneous fluctuations in the intensity of pruritus. This requirement makes it necessary to evaluate any new form of therapy in double-blind, randomized, controlled trials, but few such trials with a rigorous design have been undertaken. The pathogenesis of the pruritus of cholestasis has long been a popular topic for speculative hypotheses, which have reflected the profound ignorance relating to this topic. Of the treatments tried, virtually all have been empirical. Some have the potential for decreasing levels of a variety of substances in plasma. The aim implicit in such treatments seems to be to decrease the plasma concentrations of one or more unspecified and unknown pruritogens. This concept seems to be the rationale for the oral administration of anion exchange resins, such as cholestyramine, and the use of drugs that induce hepatic enzymes, such as phenobarbital and rifampicin. Although reports of therapies of this type associate their administration with amelioration of the pruritus of cholestasis, such reports do not implicate a specific class of substances in pathogenesis and consequently have not advanced understanding of the fundamental nature of the pruritus of cholestasis. More extreme examples of this approach are plasmapheresis, charcoal hemoperfusion, and partial external diversion of bile. The fact that such heroic measures have been tried implies that less cumbersome therapeutic modalities have not been effective. The empirical approach has not provided any valuable new insights into pathogenesis. © 1995 by the American Gastroenterological Association 0016-5085/95/$3.00
May 1995
It became evident that significant further progress in research on the pruritus of cholestasis depended on fulfilling two pressing needs. One was to develop new concepts of pathogenesis more soundly based on meaningful scientific data. The other was to devise methods for generating relevant objective quantitative data in clinical studies to evaluate the efficacy of therapies more definitively than had been possible using subjective methods. Clinical impressions of the apparent (but unproved) efficacy of one or more conventional treatments recounted by experienced and respected hepatologists must not be allowed to retard the momentum of the new initiatives that are necessary to make substantial progress in this field.
Evolution of a New Concept In 1979, Bernstein and Swift reported an apparent dramatic improvement of intractable pruritus associated with a subcutaneous injection of naloxone (but not saline) in a young woman with primary biliary cirrhosis. 3 This case report was the first study that raised the possibility not only of an involvement of the opioid system in the pathogenesis of the pruritus of cholestasis, but also of a potential role of opiate antagonists in its management. At about the time of this report, a limb-movement meter was applied to assess scratching activity in a doubleblind, controlled study of the effects of intravenous injections of naloxone in patients with chronic pruritus caused by cholestasis of various etiologies. In this study, about half of the patients seemed to have a placebo response and most of the others seemed to have a beneficial response to naloxone. Publication of this trial in 19804 did not seem to lead to a rapid stimulation of further studies of the opioid system in cholestasis, possibly because the data on limb movements did not adequately reflect scratching activity. It was not until 1988 that the next relevant report appeared, 5 an open-label trial of the experimental opiate antagonist nalmefene in 11 patients with chronic liver disease conducted by Thornton and Losowsky in the United Kingdom. Nine of the patients in this trial had primary biliary cirrhosis. Based on application of subjective assessments, oral administration of nalmefene seemed to be associated with sustained ameliorations of pruritus in cholestatic patients. Another observation in this study was that the first doses (5 rag) the patients received consistently precipitated a transient adverse reaction. These investigators were unable to continue with their studies of nalmefene in patients with liver disease when the drug became unavailable for experimental use in humans in the United Kingdom. Interest in research on the pruritus of cholestasis was rekindled by an appreciation of the potential significance
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of Thornton and Losowsky's landmark paper.2 Of particular interest was the similarity between the opiate antagonist-precipitated adverse reaction they observed in patients with chronic liver disease and the withdrawal reaction of opiate addiction. This similarity required explanation. By analogy with the pathophysiology of opiate addiction, the most likely explanation would seem to be that opioidergic tone (i.e., endogenous opioid-mediated neurotransmission/neuromodulation) is increased in patients with chronic liver disease. If this is so, could this phenomenon be related to the pruritus of cholestasis? The answer to this question would seem to be in the affirmative if increased opioidergic tone can mediate pruritus. Many reports indicate that morphine can induce pruritus. 2 In the 8th edition of Goodman and Gilman, "pruritus" is listed as an untoward effect of morphine. 6 The evidence for an association between the administration of opiates and pruritus consists largely of observations documented in the pain and anesthesiology literature. 2 Opiates with agonist properties at opioid receptors that have been implicated in the mediation of pruritus include not only morphine but also diamorphine, meperidine, methadone, fentanyl, hydromorphone, pethidine, and butorphanol. 2 Whereas opiate-induced pruritus may be well recognized by neurologists, anesthesiologists, and obstetricians, this phenomenon may not be familiar to gastroenterologists and hepatologists. However, it is common to see patients about to undergo an endoscopic procedure scratch the tip of their nose following the administration of meperidine (Demerol; Winthrop Pharmaceuticals) (personal observations), and opiate-induced "itching of the nose" is specifically mentioned in a pharmacology text] It is exceedingly common to associate itching with a large variety of drugs other than opiates. Accordingly, it seems likely that the association between opiates and pruritus is fortuitous and nonspecific. However, the pruritus associated with the administration of opiates seems to be reversible by naloxone, suggesting that opiate-induced pruritus is opioid receptor mediated. For example, the 8th edition of Goodman and Gilman states that "pruritus may, in part, involve effects of opioids on neurons, since it is provoked by opioids that do not release histamine and is quickly abolished by small doses of naloxone. ''6 It has been conventional to consider that pruritus arises peripherally in nerve endings in the skin. Indeed, for decades clinicians have considered that the pruritus of cholestasis is mediated by an accumulation in the skin of unspecified pruritogenic substances that are normally secreted into bile. However, the observation that opiates can mediate pruritus draws attention to the alternative possibility that pruritus can also arise centrally in the
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brain. This concept is supported by Koenigstein's seminal descriptions of the effects of administering a potent opiate centrally. In particular, when morphine (0.2-0.7 mg/kg) is injected intracisternally into cats, violent facial scratching activity is induced and lasts approximately 90 minutes. 8 Indeed, pruritus has been classified as a central nervous system (CNS) effect of opiates. For example, the Cecil Textbook of Medicine states that "central modulators of pruritus, such as systemic morphine, cause itch . . . by acting on central opiate receptors. ''9 Systemic effects of opiates must be distinguished from their local effects near injection sites, which include histamine release, urticaria, and local pruritus that is not reversed by naloxone and hence is not mediated by opioid receptors. 6 Only the systemic effects of opiates are of potential interest in relation to the pruritus of cholestasis. Both increased opioidergic tone and pruritus are systemic effects of opiates, and it is the association of increased opioidergic tone with pruritus that may have relevance to the pathogenesis of the pruritus of cholestasis.
Hypothesis Increased opioidergic neurotransmission/neuromodulation (tone) in the CNS contributes to the pruritus of cholestasis.
Testing the Validity of the Hypothesis The validity of the proposed hypothesis is testable. This hypothesis would be strongly supported if it could be shown that (1) opioid-receptor ligands with agonist properties mediate pruritus, (2) opioid-mediated neurotransmission/neuromodulation (tone) in the CNS is increased in cholestasis, and (3) the pruritus of cholestasis can be reversed (at least partially) by opiate antagonists.
Opioid-Receptor Agonists and Pruritus Some of the evidence that opiate drugs with agonist properties induce pruritus has been reviewed above. 2'8 This evidence has been supplemented recently by studies in monkeys (Macacafasdcularis) in which microinjections of morphine or the opioid agonist ligand (D-Ala2-N-Me-Phe4-Gly-ol)-enkephalin into the medullary dorsal horn induced facial scratching that was abolished by naloxone. *° These findings indicate that opiate-agonist ligands in the brain can mediate scratching activity. Opioidergic Tone in Cholestasis
Five lines of evidence are consistent with opioidergic (neurotransmission/neuromodulation) tone being altered in cholestasis.
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Opiate antagonist-induced reaction in cholestatic patients. The reaction induced in patients with
chronic liver disease by the oral administration of the opiate antagonist nalmefene (5 mg) strongly suggests that opioidergic tone is increased in these patients. The reaction typically lasts 2 - 3 days despite continued administration of the drug. Features of the reaction include anorexia, nausea, colicky abdominal pain, constipation, pallor, cool skin, tremor, insomnia, perspiration, an increase in blood pressure, and a decrease in pulse rate. Changes in mood and auditory and visual hallucinations have been observed in some patients. A similar reaction was not observed when nalmefene was administered (even in high doses, e.g., 300 mg) to normal subjects) Although the reaction experienced by the patients with liver disease had features in common with the classical withdrawal reaction of opiate addiction, there were differences. In particular, in the patients with liver disease hallucinations occurred but rhinorrhea was not reported, whereas in classical opiate withdrawal rhinorrhea occurs but hallucinations do not. The interpretation of the differences between these two reactions may be facilitated by considering the following points: (1) the classical opiate withdrawal reaction in humans occurs after continuous use of opiates (e.g., morphine, heroin); (2) in patients with liver disease who have not been exposed to opiates, opioidergic phenomena would not be related to opiates, which are alkaloids, but to endogenous opioids, which are peptides; and (3) the opioid-receptor subtype specificity of opiate agonists, such as morphine-like alkaloids, may be different from that of opiate antagonists such as nalmefene (e.g., different affinities for bt and ~ opioid receptors). Opioid-mediated antinociception in a model of cholestasis. One of the principal functions of the opioid system is the mediation of analgesia. It is well established that exogenously administered opiate agonists such as morphine mediate analgesia by binding to opioid receptors in the nervous system. Thus, if cholestasis is associated with increased opioidergic tone, a component of the syndrome would be a state of antinociception (analgesia) that can be reversed by an opiate antagonist. To test this possibility, the effect of cholestasis on tail-flick latencies in the rat was investigated. A tail-flick latency is defined as the time interval (measured in tenths of a second) between the application of a standardized noxious stimulus to the animal's tail (e.g., a focused beam of radiant light) and the abrupt reflex-mediated removal of the tail from the site of the stimulus. The tail-flick assay is an extensively validated method for assaying the potency of opiates. Opiates that mediate analgesia, such as morphine, increase tail-flick latency. Accordingly, it was pos-
May 1995
THE PRURITUS OF CHOLESTASIS AND THE OPIOID SYSTEM
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Demonstration of increased opioidergic tone in a model of cholestasis. (A) Increased tail-flick latencies (TFLs) in rats with acute cholestasis caused by bile duct resection (BDR) and their reversibility by an opiate antagonist. UNOP, unoperated; SHAM, sham resected. (-)-Naloxone reversed the prolonged TFLs in the BDR group but had no significant effect on TFLs in the control groups. (B) Five days after BDR, prolonged TFLs were significantly decreased by (-)-naloxone but were increased slightly after the administration of the pharmacologically inert enantiomer (+)-naloxone. Data are means _+ SEM. Reprinted with permission. 11
tulated that increased opioidergic tone in cholestasis would be associated with opiate antagonist-reversible antinociception (in the absence of any exogenously administered opiate) and that an experimentally detectable manifestation of this phenomenon would be naloxonereversible prolongation of tail-flick latencies in cholestatic rats. Cholestatic rats did show a significant prolongation of tail-flick latencies, but rats with acute hepatocellular necrosis also had prolonged tail-flick latencies. However, (-)-naloxone reversed antinociception in cholestatic rats but had no effect on antinociception in rats with hepatocellular necrosis. Furthermore, whereas prolonged tail-flick latencies in cholestatic rats were reversed by (-)-naloxone, they were not reversed by its pharmacologically inert enantiomer (+)-naloxone (Figure 1). I1 These findings indicate not only that antinocicep-
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tion occurs in a model of cholestasis, but also that this phenomenon in cholestasis is stereoselectively reversed by naloxone and consequently is opioid receptor mediated. These findings also imply that increased opioidergic tone was demonstrable in a model of cholestasis but not in a model of hepatocellular necrosis. Opioid agonist levels in cholestasis. One of the possible factors contributing to increased opioidergic tone in cholestasis could be increased levels of endogenous opioid-agonist ligands. Of potential relevance to this possibility is the finding that total opioid activity in serum is significantly increased in cholestatic rats. 12 Moreover, the serum concentrations of immunoreactive Met-enkephalin are elevated not only in a model of cholestasis, 12 but also in cholestatic patients) However, immunoreactive Metenkephalin accounts for only a small proportion of total serum opioid activity in cholestatic rats. 12 Centrally mediated scratching induced by cholestatic p l a s m a . Plasma extracts from patients with the pruritus of cholestasis recently have been shown to induce naloxone-reversible facial scratching in monkeys when microinjected into the medullary dorsal horn; plasma extracts from cholestatic patients without pruritus did not have this property (Figure 2)) 3 These observations indicate that plasma of patients with the pruritus of cholestasis contains one or more substances, probably opioid in nature, that have the property of inducing central opioid receptor-mediated scratching activity. Opioid receptor changes in the CNS in a model o f c h o l e s t a s i s . Because opioid-agonist ligands exert a biological effect when bound to their receptors and the altered status of the opioid system in cholestasis may be the consequence of opioid ligand/receptor interactions, the effects of cholestasis on the binding of opioid ligands to brain membranes were studied. In cholestatic rats, the density of }.t-opioid receptors in the brain was significantly reduced, 14 suggesting changes in opioid-receptor kinetics and expression in the animal model.
Opiate Antagonists and the Pruritus of Cholestasis The need to apply objective quantitative methods in clinical trials is pertinent to the assessment of the effects of opiate antagonists in patients with the pruritus of cholestasis. The definitions of pruritus and scratching activity appear to be of particular relevance to this issue. Pruritus (or itching) is defined as the need to scratch and hence is an intrinsically subjective perception that cannot be quantitated. This point applies to the application of visual analogue scores of itching, which generate numerical data that, although satisfying to investigators, are inherently subjective. Visual analogue scores are influ-
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enced by interindividual variations in the abilities of patients to integrate the perception of itching over time, to conceptualize the visuospatial analogue scale, and to translate from the one to the other. Scratching activity, in the context of this article, can be defined as a behavioral manifestation of a complication of cholestasis. In contrast to pruritus, scratching activity can be quantitated. To fulfil the need for objective quantitative data, a monitoring system was developed that directly measures scratching activity independent of limb movements. 15 The validity of the index of scratching activity generated by this monitoring system was confirmed by independent observations as well as by the use of videotapes. 15 The availability of this device enabled definitive studies of the effects of opiate antagonists on scratching activity in patients with cholestasis to be undertaken.
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Initially, to determine more definitively whether an opiate antagonist can ameliorate the manifestations of the pruritus of cholestasis, a single-blind study comparing the effects of naloxone (0.2 ~tg" kg -1" rain -1) and placebo infusions was undertaken in eight patients with chronic unrelieved pruritus caused by primary biliary cirrhosis. Scratching activity was consistently less during naloxone infusions than during placebo infusions (mean, 50% less; range, 26%-96%; P < 0.001) (Figure 3). 15 Subsequently, the phenomenon observed in this study was confirmed by the results of a randomized, doubleblind, placebo-controlled trial in 29 patients with the pruritus of cholestasis (Bergasa et al., unpublished data). Thus, naloxone reduces scratching activity in patients with cholestatic liver disease. In these controlled trials, naloxone did not completely abolish scratching activity. Possible explanations for this observation include (1) the dose was insufficient; (2) the duration of infusion was too short; (3)the opioid-receptor subtype specificity of naloxone is not ideal for this indication; or (4) nonopioid mechanisms are also involved in the mediation of
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Figure 2. Facial scratching in monkeys (M. fascicularis) after microinjections (0.4 gL) into the medullary dorsal horn. (A) Effect of plasma extracts from a patient with the pruritus of cholestasis administered with (©) and without (e) naloxone (1 mg/kg intramuscularly). (B) Effects of a plasma extract from a patient with the pruritus of cholestasis (e), a plasma extract from a cholestatic patient without pruritus (A), and saline ((3). The pruritus of cholestasis is associated with the presence of a plasma factor that induces centrally mediated, naloxone-reversible scratching activity. Reprinted from Life Sciences; 53; Bergasa NV, Thomas DA, Vergalla J, Turner ML, Jones EA; Plasma from patients with the pruritus of cholestasis induces opioid receptormediated scratching in monkeys; 1 2 5 3 - 1 2 5 7 ; 1993, with kind permission from Elsevier Science Ltd., The Boulevard, Langford Lane, Kidlington OX5 1GB, United Kingdom. 13
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Figure 3. Mean indices of scratching activity in 8 patients with pruritus caused by primary biliary cirrhosis during placebo and naloxone infusions. The two breaks in the continuity of the vertical axis facilitated plotting the data. Mean scratching activity during naloxone infusions was 50% less than during placebo infusions (P < 0.001), indicating that an opiate antagonist can ameliorate scratching activity in patients with the pruritus of cholestasis. Reprinted with permission (JAMA 1992;268:3359-3362). 19 Copyright 1992, American Medical Association.
May 1995
scratching activity in cholestatic patients. Furthermore, in the double-blind study the mean value for a visual analogue score of the perception of pruritus during naloxone infusions was significantly less than that during placebo infusions. These findings provide further support for the hypothesis that the pruritus of cholestasis is mediated, at least in part, by the opioid system. However, amelioration of the pruritus of cholestasis is not invariable when an opiate antagonist is administered. Such treatment failures could imply that, at least in some patients, mechanisms other than those that involve opioid receptors may contribute to the pathogenesis of the pruritus of cholestasis.
Support for the Hypothesis The above section indicates that (1) opioid-receptor ligands with agonist properties can mediate pruritusS'l°; (2) altered opioidergic neurotransmission occurs in cholestasisS'11; and (3) the pruritus of cholestasis can be ameliorated by opiate antagonists. ~5 Taken together, the data on which these inferences are based provide strong support for the hypothesis that altered opioidergic tone in the CNS contributes to the pruritus ofcholestasis.
Potential Therapeutic Implications of the Hypothesis The results of the two controlled naloxone trials establish opiate antagonists as a therapeutic option for the management of the pruritus of cholestasis and indicate that naloxone infusions (or subcutaneous or intramuscular injections) may be useful for the emergency treatment of the pruritus of cholestasis. A major shortcoming of naloxone is that the preferred route of administration is parenteral because of its large first-pass extraction by the liver. 6 Thus, it would not be satisfactory for long-term control of this problem. What appears to be needed is an opiate antagonist with appreciable bioavailability when given by mouth. Nalmefene, which at present is not commercially available in the United States, is an opiate antagonist that is chemically related to naloxone.16 Compared with naloxone, nalmefene has three important properties: (1) greater bioavailability when given orally, (2) more potent antagonist action at opioid receptors, and (3) slower metabolism (more prolonged plasma half-life)) '16 In open-label trials of orally administered nalmefene in patients with unrelieved pruritus secondary to cholestatic liver disease, data on both the quantitative scratching activity index and a visual analogue score of pruritus strongly suggested that nalmefene induces sustained beneficial effects in a majority of patients 5 (Bergasa et al., unpublished data). An important aspect of a schedule for the oral administration
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of nalmefene to cholestatic patients is that the initial dose is small (2 mg twice daily), and the dose is gradually increased to a therapeutic maintenance dose over a period of weeks. In this way, precipitation of an opiate withdrawal-like reaction 5 should be avoided or at least markedly reduced. An intriguing observation in many cholestatic patients during nalmefene therapy was the occurrence of a "breakthrough" reappearance of pruritus after an apparently effective initial maintenance dose had been achieved. Such apparent relapses could usually be overcome by upward adjustment of the dose and suggests that in cholestasis, nalmefene therapy might lead to an increase in opioid receptors on the neuronal surface. Such a phenomenon could increase the sensitivity of neurons to the prevailing levels of pruritogenic opioid-agonist ligands. This line of reasoning affords a potential explanation for a "breakthrough" in the perception of pruritus during the early weeks of oral nalmefene therapy. 14 The ability of orally administered nalmefene to induce sustained beneficial responses in patients with hitherto unrelieved pruritus of cholestasis has been confirmed in a randomized, blinded, placebo-controlled trial (Bergasa et al., unpublished data). With the exception of an opiate withdrawal-like syndrome that can be prevented in most patients by using an appropriate dose schedule, adverse events reported to date following the administration of either naloxone or nalmefene to cholestatic patients appear to be rare and of no major clinical consequence) '15 In particular, no consistent changes in the abnormal serum biochemistry exhibited by cholestatic patients have been observed in association with the administration of either of these drugs. Both drugs appear to have favorable risk-benefit ratios with respect to the treatment of patients with the pruritus of cholestasis. Although additional controlled trials of nalmefene in the management of chronic pruritus in cholestatic patients are indicated, the available data indicate that orally administered nalmefene shows considerable promise for the long-term amelioration of pruritus in patients with chronic cholestatic liver diseases. Because opioid agonists appear to have a cholestasis-potentiating effect that is mediated via central opioid receptors, Iv it seems possible that in addition to ameliorating pruritus in cholestatic patients, opiate antagonists may also tend to decrease the severity of cholestasis.
Concluding Perspectives Evidence has been presented indicating that increased central opioidergic neurotransmission/neuromodulation (tone) is a component of the pathophysiology of cholestasis and contributes to the pruritus that complicates this syndrome. Thus, mechanisms involved in the
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pathogenesis of this form of pruritus appear to include the molecular events initiated by interactions between opioid receptors (glycoproteins) and endogenous ligands for these receptors with agonist properties (peptides). It would appear that supranormal opioid agonist-induced activation of neuronal G proteins and ion channels in the CNS can lead to the perception of pruritus and stimulation of motor pathways that mediate scratching activity. A contribution to the pruritus of cholestasis by opioid agonist-induced molecular events may be mediated by only certain (currently undefined) opioid agonists and by certain opioid receptor subtypes. Central opioid ligandreceptor interactions alone may adequately account for the pruritus of cholestasis; alternatively, other unknown factors may also be involved. The relationship between peripheral changes in opioid metabolism and increased opioidergic tone in the CNS in cholestasis is currently undefined. Because levels of opioids in plasma may not correlate with functionally significant levels of opioids at opioid receptors in the CNS, the hypothesis that increased opioidergic tone contributes to the pruritus of cholestasis is not dependent on data on plasma levels of individual opioids. However, it is theoretically possible that increased plasma-to-brain transfer of opioid peptides could contribute to enhanced opioidergic tone in the CNS in cholestasis. Furthermore, the sources of biologically active opioid peptides involved in the mediation of the pruritus of cholestasis are unknown but might include the cholestatic liver, which has been shown in a model to express the messenger RNA of the opioid-precursor gene preproenkephalin) 8 Whether peripheral opioid receptors are involved in the pathogenesis of the pruritus of cholestasis is unknown. Two recent experimental innovations should facilitate further research on the pathogenesis and treatment of the pruritus of cholestasis: (1) the development of a behavioral assay for scratching activity of central origin in the monkey M. fascicularis; and (2) the development of a method of quantitating scratching activity independent of limb movements in humans. The pruritus of cholestasis can be ameliorated by the administration of opiate antagonists. Nalmefene, a potent opiate antagonist that is bioavailable after oral administration, shows considerable promise for the long-term management of the pruritus of cholestasis.
References 1. de Quincy T. Confessions of an English opium eater. London Magazine 1821. London: Penguin, 1971.
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2. Jones EA, Bergasa NV. The pruritus of cholestasis. From bile acids to opiate agonists. Hepatology 1990; 1 1 : 8 8 4 - 8 8 7 . 3. Bernstein JE, Swift R. Relief of intractable pruritus with naloxone. Arch Dermatol 1979; 1 1 5 : 1 3 6 6 - 1 3 6 7 . 4. Summerfieid JA. Naloxone modulates the perception of itch in man. Br J Clin Pharmacol 1 9 8 0 ; 1 0 : 1 8 0 - 1 8 2 . 5. Thornton JR, Losowsky MS. Opioid peptides and primary biliary cirrhosis. BMJ 1 9 8 8 ; 2 9 7 : 1 5 0 1 - 1 5 0 4 . 6. Jaffe JH, Martin WR: Opioid analgesics and antagonists. In: Gilman AG, Rail TW, Nies AS, Taylor P, eds. Goodman and Gilman's the pharmacological basis of therapeutics. 8th ed. New York: Pergamon, 1 9 9 0 : 4 8 5 - 5 2 1 . 7. Graham-Smith DG, Aronson JK. Narcotic analgesics, in: GrahamSmith DG, Aronson JK, eds. Oxford textbook of clinical pharmacology and drug therapy. 2nd ed. New York: Oxford, 1 9 9 2 : 6 4 1 644. 8. Koenigstein H. Experimental study of itch stimuli in animals. Arch Dermatol Syph 1 9 4 8 ; 5 7 : 8 2 8 - 8 4 9 . 9. Parker F. Skin diseases. In: Wyngaarden J, Smith LH eds. Cecil textbook of medicine. Philadelphia: Saunders, 1 9 8 8 : 2 3 0 0 2353. 10. Thomas DA, Williams GW, Iwata K, Kenshalo DR Jr, Dubner R. Effects of central administration of opioids on facial scratching in monkeys. Brain Res 1 9 9 2 ; 5 8 5 : 3 1 5 - 3 1 7 . 11. Bergasa NV, Ailing DW, Vergalla J, Jones EA. Chotestasis in the male rat is associated with naloxone-reversibie antinociception. J Hepatol 1 9 9 4 ; 2 0 : 8 5 - 9 0 . 12. Swain MG, Rothman RB, Xu H, Vergalla J, Bergasa NV, Jones EA. Endogenous opioids accumulate in plasma in a rat model of acute cholestasis. Gastroenterology 1992; 1 0 3 : 6 3 0 - 6 3 5 . 13. Bergasa NV, Thomas DA, Vergalla J, Turner ML, Jones EA. Plasma from patients with the pruritus of cholestasis induces opioid receptor-mediated scratching in monkeys. Life Sci 1993;53: 1253-1257. 14. Bergasa NV, Rothman RB, Vergalla J, Xu H, Swain MG, Jones EA. Central mu-opioid receptors are down-regulated in a rat model of acute chotestasis. J Hepatol 1 9 9 2 ; 1 5 : 2 2 0 - 2 2 4 . 15. Bergasa NV, Talbot TL, Ailing DW, Schmit JM, Walker EC, Baker BL, Korenman JC, Park Y, Hoofnagle JH, Jones EA. A controlled trial of naloxone infusions for the pruritus of chronic chotestasis. Gastroenterology 1992; 1 0 2 : 5 4 4 - 5 4 9 . 16. Gal TJ, DiFarzio CA, Dixon R. Prolonged blockade of opioid effect with oral nalmefene. Clin Pharm Ther 1 9 8 6 ; 4 0 : 5 3 7 - 5 4 2 . 17. Hurwitz A, Looney G, Sullins M, Ben-Zvi Z. Hepatobiliary effects of morphine are mediated in the brain. Hepatology 1990; 1 2 : 1 4 0 6 1412. 18. Bergasa NV, Sabol SL, Young WS III, Kleiner DE, Jones EA. Cholestasis is associated with preproenkephalin mRNA expression in the adult rat liver. Am J Physiol 1995;268:G346-G354. 19. Jones EA, Bergasa NV. Pruritus of cholestasis and the opioid system. JAMA 1 9 9 2 ; 2 6 8 : 3 3 5 9 - 3 3 6 2 .
Received June 30, 1994. Accepted September 13, 1994. Address requests for reprints to: Nora V. Bergasa, M.D., Laboratory of the Biology of Addictive Diseases, Rockefeller University, Box 241, 1230 York Avenue, New York, New York 10021-6399. Dr. Jones's current address is: Department of Gastrointestinal and Liver Diseases, Academic Medical Center, Meiberdreef 9, 1105 AZ Amsterdam Zuidoost, The Netherlands. Dr. Bergasa was supported by grant P50-DA05130 from the National Institute of Drug Abuse, National Institutes of Health.
VIEWPOINTS ON DIGESTIVE DISEASES The Pruritus of Cholestasis: Potential Pathogenic and Therapeutic Implications of Opioids NORA VALERIA B E R G A S A * a n d E. A N T H O N Y JONES t *Laboratory of the Biology of Addictive Diseases, Rockefeller University, New York, New York; and tDepartment of Gastrointestinal and Liver Diseases, Academic Medical Centre, Amsterdam, The Netherlands
Upon any attempt obstinately to renew the old doses, there arose a new symptom.., viz., an irritation on the surface of the s k i n . . . which soon became unsupportable, and tended to distraction. --Thomas de Quincy, 1821 Confessions of an English Opium Eater 1
he impressive march of progress in the field of hepatology in recent years has had minimal impact on the problems posed by patients with the pruritus that frequently complicates the syndrome of cholestasis. This form of pruritus remains one of the most challenging management problems with which gastroenterologists and hepatologists are commonly confronted. Because the pathogenesis of the pruritus of cholestasis is unknown, therapies used in its management have tended to be empirical. The number and diversity of these therapies reflect the frustration and impotence of clinicians attempting to provide patients with substantial relief from this maddening condition. Unrelieved pruritus of cholestasis not only can interfere with normal activities but may lead to severe sleep deprivation and even suicidal ideation. Intractable pruritus attributable to cholestasis is considered to be an indication for liver transplantation. There are several reasons why progress has been so slow in understanding the pathogenesis of the pruritus of cholestasis and in developing more effective therapies. Because the symptom of pruritus is inherently subjective, it has not been obvious to clinical investigators whether application of any objective quantitative methods would provide meaningful data in clinical trials. There has been a tendency to base hypotheses of pathogenesis on correlations between subjective assessments of pruritus and levels of specific substances. In this context, data on levels of a substance in plasma may be less relevant than corresponding levels elsewhere (e.g., interstitial fluid of skin). To determine whether a correlation has pathogenic relevance, it is necessary to show a causal relationship between increased levels of the substance and the mediation of pruritus, and this requirement has not been fulfilled
T
for putative pruritogens (e.g., bile acids) in cholestatic patients] There must be a logical reason for implicating a specific class of substance in the pathogenesis of the pruritus of cholestasis, and such a reason currently appears to be lacking for most of the putative pruritogens that have been implicated in this syndrome. In clinical trials of potential therapies for the pruritus of cholestasis, it is essential to distinguish between therapeutic effects and placebo responses or spontaneous fluctuations in the intensity of pruritus. This requirement makes it necessary to evaluate any new form of therapy in double-blind, randomized, controlled trials, but few such trials with a rigorous design have been undertaken. The pathogenesis of the pruritus of cholestasis has long been a popular topic for speculative hypotheses, which have reflected the profound ignorance relating to this topic. Of the treatments tried, virtually all have been empirical. Some have the potential for decreasing levels of a variety of substances in plasma. The aim implicit in such treatments seems to be to decrease the plasma concentrations of one or more unspecified and unknown pruritogens. This concept seems to be the rationale for the oral administration of anion exchange resins, such as cholestyramine, and the use of drugs that induce hepatic enzymes, such as phenobarbital and rifampicin. Although reports of therapies of this type associate their administration with amelioration of the pruritus of cholestasis, such reports do not implicate a specific class of substances in pathogenesis and consequently have not advanced understanding of the fundamental nature of the pruritus of cholestasis. More extreme examples of this approach are plasmapheresis, charcoal hemoperfusion, and partial external diversion of bile. The fact that such heroic measures have been tried implies that less cumbersome therapeutic modalities have not been effective. The empirical approach has not provided any valuable new insights into pathogenesis. © 1995 by the American Gastroenterological Association 0016-5085/95/$3.00
May 1995
It became evident that significant further progress in research on the pruritus of cholestasis depended on fulfilling two pressing needs. One was to develop new concepts of pathogenesis more soundly based on meaningful scientific data. The other was to devise methods for generating relevant objective quantitative data in clinical studies to evaluate the efficacy of therapies more definitively than had been possible using subjective methods. Clinical impressions of the apparent (but unproved) efficacy of one or more conventional treatments recounted by experienced and respected hepatologists must not be allowed to retard the momentum of the new initiatives that are necessary to make substantial progress in this field.
Evolution of a New Concept In 1979, Bernstein and Swift reported an apparent dramatic improvement of intractable pruritus associated with a subcutaneous injection of naloxone (but not saline) in a young woman with primary biliary cirrhosis. 3 This case report was the first study that raised the possibility not only of an involvement of the opioid system in the pathogenesis of the pruritus of cholestasis, but also of a potential role of opiate antagonists in its management. At about the time of this report, a limb-movement meter was applied to assess scratching activity in a doubleblind, controlled study of the effects of intravenous injections of naloxone in patients with chronic pruritus caused by cholestasis of various etiologies. In this study, about half of the patients seemed to have a placebo response and most of the others seemed to have a beneficial response to naloxone. Publication of this trial in 19804 did not seem to lead to a rapid stimulation of further studies of the opioid system in cholestasis, possibly because the data on limb movements did not adequately reflect scratching activity. It was not until 1988 that the next relevant report appeared, 5 an open-label trial of the experimental opiate antagonist nalmefene in 11 patients with chronic liver disease conducted by Thornton and Losowsky in the United Kingdom. Nine of the patients in this trial had primary biliary cirrhosis. Based on application of subjective assessments, oral administration of nalmefene seemed to be associated with sustained ameliorations of pruritus in cholestatic patients. Another observation in this study was that the first doses (5 rag) the patients received consistently precipitated a transient adverse reaction. These investigators were unable to continue with their studies of nalmefene in patients with liver disease when the drug became unavailable for experimental use in humans in the United Kingdom. Interest in research on the pruritus of cholestasis was rekindled by an appreciation of the potential significance
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of Thornton and Losowsky's landmark paper.2 Of particular interest was the similarity between the opiate antagonist-precipitated adverse reaction they observed in patients with chronic liver disease and the withdrawal reaction of opiate addiction. This similarity required explanation. By analogy with the pathophysiology of opiate addiction, the most likely explanation would seem to be that opioidergic tone (i.e., endogenous opioid-mediated neurotransmission/neuromodulation) is increased in patients with chronic liver disease. If this is so, could this phenomenon be related to the pruritus of cholestasis? The answer to this question would seem to be in the affirmative if increased opioidergic tone can mediate pruritus. Many reports indicate that morphine can induce pruritus. 2 In the 8th edition of Goodman and Gilman, "pruritus" is listed as an untoward effect of morphine. 6 The evidence for an association between the administration of opiates and pruritus consists largely of observations documented in the pain and anesthesiology literature. 2 Opiates with agonist properties at opioid receptors that have been implicated in the mediation of pruritus include not only morphine but also diamorphine, meperidine, methadone, fentanyl, hydromorphone, pethidine, and butorphanol. 2 Whereas opiate-induced pruritus may be well recognized by neurologists, anesthesiologists, and obstetricians, this phenomenon may not be familiar to gastroenterologists and hepatologists. However, it is common to see patients about to undergo an endoscopic procedure scratch the tip of their nose following the administration of meperidine (Demerol; Winthrop Pharmaceuticals) (personal observations), and opiate-induced "itching of the nose" is specifically mentioned in a pharmacology text] It is exceedingly common to associate itching with a large variety of drugs other than opiates. Accordingly, it seems likely that the association between opiates and pruritus is fortuitous and nonspecific. However, the pruritus associated with the administration of opiates seems to be reversible by naloxone, suggesting that opiate-induced pruritus is opioid receptor mediated. For example, the 8th edition of Goodman and Gilman states that "pruritus may, in part, involve effects of opioids on neurons, since it is provoked by opioids that do not release histamine and is quickly abolished by small doses of naloxone. ''6 It has been conventional to consider that pruritus arises peripherally in nerve endings in the skin. Indeed, for decades clinicians have considered that the pruritus of cholestasis is mediated by an accumulation in the skin of unspecified pruritogenic substances that are normally secreted into bile. However, the observation that opiates can mediate pruritus draws attention to the alternative possibility that pruritus can also arise centrally in the
1584 BERGASAAND JONES
brain. This concept is supported by Koenigstein's seminal descriptions of the effects of administering a potent opiate centrally. In particular, when morphine (0.2-0.7 mg/kg) is injected intracisternally into cats, violent facial scratching activity is induced and lasts approximately 90 minutes. 8 Indeed, pruritus has been classified as a central nervous system (CNS) effect of opiates. For example, the Cecil Textbook of Medicine states that "central modulators of pruritus, such as systemic morphine, cause itch . . . by acting on central opiate receptors. ''9 Systemic effects of opiates must be distinguished from their local effects near injection sites, which include histamine release, urticaria, and local pruritus that is not reversed by naloxone and hence is not mediated by opioid receptors. 6 Only the systemic effects of opiates are of potential interest in relation to the pruritus of cholestasis. Both increased opioidergic tone and pruritus are systemic effects of opiates, and it is the association of increased opioidergic tone with pruritus that may have relevance to the pathogenesis of the pruritus of cholestasis.
Hypothesis Increased opioidergic neurotransmission/neuromodulation (tone) in the CNS contributes to the pruritus of cholestasis.
Testing the Validity of the Hypothesis The validity of the proposed hypothesis is testable. This hypothesis would be strongly supported if it could be shown that (1) opioid-receptor ligands with agonist properties mediate pruritus, (2) opioid-mediated neurotransmission/neuromodulation (tone) in the CNS is increased in cholestasis, and (3) the pruritus of cholestasis can be reversed (at least partially) by opiate antagonists.
Opioid-Receptor Agonists and Pruritus Some of the evidence that opiate drugs with agonist properties induce pruritus has been reviewed above. 2'8 This evidence has been supplemented recently by studies in monkeys (Macacafasdcularis) in which microinjections of morphine or the opioid agonist ligand (D-Ala2-N-Me-Phe4-Gly-ol)-enkephalin into the medullary dorsal horn induced facial scratching that was abolished by naloxone. *° These findings indicate that opiate-agonist ligands in the brain can mediate scratching activity. Opioidergic Tone in Cholestasis
Five lines of evidence are consistent with opioidergic (neurotransmission/neuromodulation) tone being altered in cholestasis.
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Opiate antagonist-induced reaction in cholestatic patients. The reaction induced in patients with
chronic liver disease by the oral administration of the opiate antagonist nalmefene (5 mg) strongly suggests that opioidergic tone is increased in these patients. The reaction typically lasts 2 - 3 days despite continued administration of the drug. Features of the reaction include anorexia, nausea, colicky abdominal pain, constipation, pallor, cool skin, tremor, insomnia, perspiration, an increase in blood pressure, and a decrease in pulse rate. Changes in mood and auditory and visual hallucinations have been observed in some patients. A similar reaction was not observed when nalmefene was administered (even in high doses, e.g., 300 mg) to normal subjects) Although the reaction experienced by the patients with liver disease had features in common with the classical withdrawal reaction of opiate addiction, there were differences. In particular, in the patients with liver disease hallucinations occurred but rhinorrhea was not reported, whereas in classical opiate withdrawal rhinorrhea occurs but hallucinations do not. The interpretation of the differences between these two reactions may be facilitated by considering the following points: (1) the classical opiate withdrawal reaction in humans occurs after continuous use of opiates (e.g., morphine, heroin); (2) in patients with liver disease who have not been exposed to opiates, opioidergic phenomena would not be related to opiates, which are alkaloids, but to endogenous opioids, which are peptides; and (3) the opioid-receptor subtype specificity of opiate agonists, such as morphine-like alkaloids, may be different from that of opiate antagonists such as nalmefene (e.g., different affinities for bt and ~ opioid receptors). Opioid-mediated antinociception in a model of cholestasis. One of the principal functions of the opioid system is the mediation of analgesia. It is well established that exogenously administered opiate agonists such as morphine mediate analgesia by binding to opioid receptors in the nervous system. Thus, if cholestasis is associated with increased opioidergic tone, a component of the syndrome would be a state of antinociception (analgesia) that can be reversed by an opiate antagonist. To test this possibility, the effect of cholestasis on tail-flick latencies in the rat was investigated. A tail-flick latency is defined as the time interval (measured in tenths of a second) between the application of a standardized noxious stimulus to the animal's tail (e.g., a focused beam of radiant light) and the abrupt reflex-mediated removal of the tail from the site of the stimulus. The tail-flick assay is an extensively validated method for assaying the potency of opiates. Opiates that mediate analgesia, such as morphine, increase tail-flick latency. Accordingly, it was pos-
May 1995
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Demonstration of increased opioidergic tone in a model of cholestasis. (A) Increased tail-flick latencies (TFLs) in rats with acute cholestasis caused by bile duct resection (BDR) and their reversibility by an opiate antagonist. UNOP, unoperated; SHAM, sham resected. (-)-Naloxone reversed the prolonged TFLs in the BDR group but had no significant effect on TFLs in the control groups. (B) Five days after BDR, prolonged TFLs were significantly decreased by (-)-naloxone but were increased slightly after the administration of the pharmacologically inert enantiomer (+)-naloxone. Data are means _+ SEM. Reprinted with permission. 11
tulated that increased opioidergic tone in cholestasis would be associated with opiate antagonist-reversible antinociception (in the absence of any exogenously administered opiate) and that an experimentally detectable manifestation of this phenomenon would be naloxonereversible prolongation of tail-flick latencies in cholestatic rats. Cholestatic rats did show a significant prolongation of tail-flick latencies, but rats with acute hepatocellular necrosis also had prolonged tail-flick latencies. However, (-)-naloxone reversed antinociception in cholestatic rats but had no effect on antinociception in rats with hepatocellular necrosis. Furthermore, whereas prolonged tail-flick latencies in cholestatic rats were reversed by (-)-naloxone, they were not reversed by its pharmacologically inert enantiomer (+)-naloxone (Figure 1). I1 These findings indicate not only that antinocicep-
1585
tion occurs in a model of cholestasis, but also that this phenomenon in cholestasis is stereoselectively reversed by naloxone and consequently is opioid receptor mediated. These findings also imply that increased opioidergic tone was demonstrable in a model of cholestasis but not in a model of hepatocellular necrosis. Opioid agonist levels in cholestasis. One of the possible factors contributing to increased opioidergic tone in cholestasis could be increased levels of endogenous opioid-agonist ligands. Of potential relevance to this possibility is the finding that total opioid activity in serum is significantly increased in cholestatic rats. 12 Moreover, the serum concentrations of immunoreactive Met-enkephalin are elevated not only in a model of cholestasis, 12 but also in cholestatic patients) However, immunoreactive Metenkephalin accounts for only a small proportion of total serum opioid activity in cholestatic rats. 12 Centrally mediated scratching induced by cholestatic p l a s m a . Plasma extracts from patients with the pruritus of cholestasis recently have been shown to induce naloxone-reversible facial scratching in monkeys when microinjected into the medullary dorsal horn; plasma extracts from cholestatic patients without pruritus did not have this property (Figure 2)) 3 These observations indicate that plasma of patients with the pruritus of cholestasis contains one or more substances, probably opioid in nature, that have the property of inducing central opioid receptor-mediated scratching activity. Opioid receptor changes in the CNS in a model o f c h o l e s t a s i s . Because opioid-agonist ligands exert a biological effect when bound to their receptors and the altered status of the opioid system in cholestasis may be the consequence of opioid ligand/receptor interactions, the effects of cholestasis on the binding of opioid ligands to brain membranes were studied. In cholestatic rats, the density of }.t-opioid receptors in the brain was significantly reduced, 14 suggesting changes in opioid-receptor kinetics and expression in the animal model.
Opiate Antagonists and the Pruritus of Cholestasis The need to apply objective quantitative methods in clinical trials is pertinent to the assessment of the effects of opiate antagonists in patients with the pruritus of cholestasis. The definitions of pruritus and scratching activity appear to be of particular relevance to this issue. Pruritus (or itching) is defined as the need to scratch and hence is an intrinsically subjective perception that cannot be quantitated. This point applies to the application of visual analogue scores of itching, which generate numerical data that, although satisfying to investigators, are inherently subjective. Visual analogue scores are influ-
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GASTROENTEROLOGY Vol. 108, No. 5
enced by interindividual variations in the abilities of patients to integrate the perception of itching over time, to conceptualize the visuospatial analogue scale, and to translate from the one to the other. Scratching activity, in the context of this article, can be defined as a behavioral manifestation of a complication of cholestasis. In contrast to pruritus, scratching activity can be quantitated. To fulfil the need for objective quantitative data, a monitoring system was developed that directly measures scratching activity independent of limb movements. 15 The validity of the index of scratching activity generated by this monitoring system was confirmed by independent observations as well as by the use of videotapes. 15 The availability of this device enabled definitive studies of the effects of opiate antagonists on scratching activity in patients with cholestasis to be undertaken.
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Initially, to determine more definitively whether an opiate antagonist can ameliorate the manifestations of the pruritus of cholestasis, a single-blind study comparing the effects of naloxone (0.2 ~tg" kg -1" rain -1) and placebo infusions was undertaken in eight patients with chronic unrelieved pruritus caused by primary biliary cirrhosis. Scratching activity was consistently less during naloxone infusions than during placebo infusions (mean, 50% less; range, 26%-96%; P < 0.001) (Figure 3). 15 Subsequently, the phenomenon observed in this study was confirmed by the results of a randomized, doubleblind, placebo-controlled trial in 29 patients with the pruritus of cholestasis (Bergasa et al., unpublished data). Thus, naloxone reduces scratching activity in patients with cholestatic liver disease. In these controlled trials, naloxone did not completely abolish scratching activity. Possible explanations for this observation include (1) the dose was insufficient; (2) the duration of infusion was too short; (3)the opioid-receptor subtype specificity of naloxone is not ideal for this indication; or (4) nonopioid mechanisms are also involved in the mediation of
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Figure 2. Facial scratching in monkeys (M. fascicularis) after microinjections (0.4 gL) into the medullary dorsal horn. (A) Effect of plasma extracts from a patient with the pruritus of cholestasis administered with (©) and without (e) naloxone (1 mg/kg intramuscularly). (B) Effects of a plasma extract from a patient with the pruritus of cholestasis (e), a plasma extract from a cholestatic patient without pruritus (A), and saline ((3). The pruritus of cholestasis is associated with the presence of a plasma factor that induces centrally mediated, naloxone-reversible scratching activity. Reprinted from Life Sciences; 53; Bergasa NV, Thomas DA, Vergalla J, Turner ML, Jones EA; Plasma from patients with the pruritus of cholestasis induces opioid receptormediated scratching in monkeys; 1 2 5 3 - 1 2 5 7 ; 1993, with kind permission from Elsevier Science Ltd., The Boulevard, Langford Lane, Kidlington OX5 1GB, United Kingdom. 13
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Figure 3. Mean indices of scratching activity in 8 patients with pruritus caused by primary biliary cirrhosis during placebo and naloxone infusions. The two breaks in the continuity of the vertical axis facilitated plotting the data. Mean scratching activity during naloxone infusions was 50% less than during placebo infusions (P < 0.001), indicating that an opiate antagonist can ameliorate scratching activity in patients with the pruritus of cholestasis. Reprinted with permission (JAMA 1992;268:3359-3362). 19 Copyright 1992, American Medical Association.
May 1995
scratching activity in cholestatic patients. Furthermore, in the double-blind study the mean value for a visual analogue score of the perception of pruritus during naloxone infusions was significantly less than that during placebo infusions. These findings provide further support for the hypothesis that the pruritus of cholestasis is mediated, at least in part, by the opioid system. However, amelioration of the pruritus of cholestasis is not invariable when an opiate antagonist is administered. Such treatment failures could imply that, at least in some patients, mechanisms other than those that involve opioid receptors may contribute to the pathogenesis of the pruritus of cholestasis.
Support for the Hypothesis The above section indicates that (1) opioid-receptor ligands with agonist properties can mediate pruritusS'l°; (2) altered opioidergic neurotransmission occurs in cholestasisS'11; and (3) the pruritus of cholestasis can be ameliorated by opiate antagonists. ~5 Taken together, the data on which these inferences are based provide strong support for the hypothesis that altered opioidergic tone in the CNS contributes to the pruritus ofcholestasis.
Potential Therapeutic Implications of the Hypothesis The results of the two controlled naloxone trials establish opiate antagonists as a therapeutic option for the management of the pruritus of cholestasis and indicate that naloxone infusions (or subcutaneous or intramuscular injections) may be useful for the emergency treatment of the pruritus of cholestasis. A major shortcoming of naloxone is that the preferred route of administration is parenteral because of its large first-pass extraction by the liver. 6 Thus, it would not be satisfactory for long-term control of this problem. What appears to be needed is an opiate antagonist with appreciable bioavailability when given by mouth. Nalmefene, which at present is not commercially available in the United States, is an opiate antagonist that is chemically related to naloxone.16 Compared with naloxone, nalmefene has three important properties: (1) greater bioavailability when given orally, (2) more potent antagonist action at opioid receptors, and (3) slower metabolism (more prolonged plasma half-life)) '16 In open-label trials of orally administered nalmefene in patients with unrelieved pruritus secondary to cholestatic liver disease, data on both the quantitative scratching activity index and a visual analogue score of pruritus strongly suggested that nalmefene induces sustained beneficial effects in a majority of patients 5 (Bergasa et al., unpublished data). An important aspect of a schedule for the oral administration
THE PRURITUS OF CHOLESTASIS AND THE OPIOID SYSTEM
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of nalmefene to cholestatic patients is that the initial dose is small (2 mg twice daily), and the dose is gradually increased to a therapeutic maintenance dose over a period of weeks. In this way, precipitation of an opiate withdrawal-like reaction 5 should be avoided or at least markedly reduced. An intriguing observation in many cholestatic patients during nalmefene therapy was the occurrence of a "breakthrough" reappearance of pruritus after an apparently effective initial maintenance dose had been achieved. Such apparent relapses could usually be overcome by upward adjustment of the dose and suggests that in cholestasis, nalmefene therapy might lead to an increase in opioid receptors on the neuronal surface. Such a phenomenon could increase the sensitivity of neurons to the prevailing levels of pruritogenic opioid-agonist ligands. This line of reasoning affords a potential explanation for a "breakthrough" in the perception of pruritus during the early weeks of oral nalmefene therapy. 14 The ability of orally administered nalmefene to induce sustained beneficial responses in patients with hitherto unrelieved pruritus of cholestasis has been confirmed in a randomized, blinded, placebo-controlled trial (Bergasa et al., unpublished data). With the exception of an opiate withdrawal-like syndrome that can be prevented in most patients by using an appropriate dose schedule, adverse events reported to date following the administration of either naloxone or nalmefene to cholestatic patients appear to be rare and of no major clinical consequence) '15 In particular, no consistent changes in the abnormal serum biochemistry exhibited by cholestatic patients have been observed in association with the administration of either of these drugs. Both drugs appear to have favorable risk-benefit ratios with respect to the treatment of patients with the pruritus of cholestasis. Although additional controlled trials of nalmefene in the management of chronic pruritus in cholestatic patients are indicated, the available data indicate that orally administered nalmefene shows considerable promise for the long-term amelioration of pruritus in patients with chronic cholestatic liver diseases. Because opioid agonists appear to have a cholestasis-potentiating effect that is mediated via central opioid receptors, Iv it seems possible that in addition to ameliorating pruritus in cholestatic patients, opiate antagonists may also tend to decrease the severity of cholestasis.
Concluding Perspectives Evidence has been presented indicating that increased central opioidergic neurotransmission/neuromodulation (tone) is a component of the pathophysiology of cholestasis and contributes to the pruritus that complicates this syndrome. Thus, mechanisms involved in the
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pathogenesis of this form of pruritus appear to include the molecular events initiated by interactions between opioid receptors (glycoproteins) and endogenous ligands for these receptors with agonist properties (peptides). It would appear that supranormal opioid agonist-induced activation of neuronal G proteins and ion channels in the CNS can lead to the perception of pruritus and stimulation of motor pathways that mediate scratching activity. A contribution to the pruritus of cholestasis by opioid agonist-induced molecular events may be mediated by only certain (currently undefined) opioid agonists and by certain opioid receptor subtypes. Central opioid ligandreceptor interactions alone may adequately account for the pruritus of cholestasis; alternatively, other unknown factors may also be involved. The relationship between peripheral changes in opioid metabolism and increased opioidergic tone in the CNS in cholestasis is currently undefined. Because levels of opioids in plasma may not correlate with functionally significant levels of opioids at opioid receptors in the CNS, the hypothesis that increased opioidergic tone contributes to the pruritus of cholestasis is not dependent on data on plasma levels of individual opioids. However, it is theoretically possible that increased plasma-to-brain transfer of opioid peptides could contribute to enhanced opioidergic tone in the CNS in cholestasis. Furthermore, the sources of biologically active opioid peptides involved in the mediation of the pruritus of cholestasis are unknown but might include the cholestatic liver, which has been shown in a model to express the messenger RNA of the opioid-precursor gene preproenkephalin) 8 Whether peripheral opioid receptors are involved in the pathogenesis of the pruritus of cholestasis is unknown. Two recent experimental innovations should facilitate further research on the pathogenesis and treatment of the pruritus of cholestasis: (1) the development of a behavioral assay for scratching activity of central origin in the monkey M. fascicularis; and (2) the development of a method of quantitating scratching activity independent of limb movements in humans. The pruritus of cholestasis can be ameliorated by the administration of opiate antagonists. Nalmefene, a potent opiate antagonist that is bioavailable after oral administration, shows considerable promise for the long-term management of the pruritus of cholestasis.
References 1. de Quincy T. Confessions of an English opium eater. London Magazine 1821. London: Penguin, 1971.
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Received June 30, 1994. Accepted September 13, 1994. Address requests for reprints to: Nora V. Bergasa, M.D., Laboratory of the Biology of Addictive Diseases, Rockefeller University, Box 241, 1230 York Avenue, New York, New York 10021-6399. Dr. Jones's current address is: Department of Gastrointestinal and Liver Diseases, Academic Medical Center, Meiberdreef 9, 1105 AZ Amsterdam Zuidoost, The Netherlands. Dr. Bergasa was supported by grant P50-DA05130 from the National Institute of Drug Abuse, National Institutes of Health.