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Oral nalmefene therapy reduces scratching activity due to the pruritus of cholestasis: A controlled study
THERAPY
Oral nalmefene therapy reduces scratching activity due to the pruritus of cholestasis: A controlled study Nora V. Bergasa, MD,a David W. Alling, MD, PhD,b† Thomas L. Talbot, BA,c Mary C. Wells, RN,d and E. Anthony Jones, MD, DSce Bethesda, Maryland, and Amsterdam, The Netherlands 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. (J Am Acad Dermatol 1999;41:431-4.)
R
elief of pruritus complicating chronic cholestatic liver diseases remains a major unsolved clinical problem. When unrelieved, this complication of cholestasis can lead to severe sleep deprivation and even suicidal ideation. Its pathogenesis is unknown and conventional therapies are empirical and are usually, at best, only partially efficacious.1 Recent evidence has suggested that increased neurotransmission mediated by endogenous opioids contributes to the pruritus of cholestasis.2,3 In parFrom the Liver Diseases Section, Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases,a the Clinical Center,b the Applied Clinical Engineering Section, Biomedical Engineering and Instrumentation Program, National Center for Research Resources,c and the Department of Nursing, Clinical Center,d National Institutes of Health, Bethesda, and the Department of Gastrointestinal and Liver Diseases, Academic Medical Center, Amsterdam.e Reprint requests: Nora V. Bergasa, MD, Department of Gastroenterology and Liver Disease, Beth Israel Medical Center, 1st Ave at 16th St, 18 Baird Hall, New York, NY 10003. †Deceased. Copyright © 1999 by the American Academy of Dermatology, Inc. 0190-9622/99/$8.00 + 0 16/1/98972
ticular, 2 controlled trials in cholestatic patients have shown that intravenous infusions of the opiate antagonist naloxone are associated subjectively with an apparent decrease in the perception of pruritus and objectively with a decrease in its behavioral consequence, scratching activity.4,5 Naloxone, however, has a short plasma half-life (about 1.5 hours) and low oral bioavailability (2%),6 precluding its use as a longterm therapy. Nevertheless, the findings in these 2 trials4,5 suggest that long-term relief from this form of pruritus may be possible by administering an opiate antagonist that is bioavailable when given orally. Indeed, in an open label uncontrolled study,7 oral administration of the opiate antagonist nalmefene (6-deoxy-6-methylene-naltrexone)8-10 appeared to be associated with subjective improvements in the perception of pruritus in patients with chronic cholestasis. Our initial uncontrolled experience with open label oral nalmefene for this indication11 demonstrated that it has an acceptable safety profile in cholestatic patients and also suggested that it may be efficacious in ameliorating the pruritus of cholestasis. We report herein controlled observations that indicate that oral treatment with nalme431
432 Bergasa et al
fene is efficacious in ameliorating, not only the perception of pruritus, but also associated scratching activity in patients with cholestasis.
METHODS The protocol of this study was approved by the Clinical Research Subpanel of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH). Highly purified nalmefene was generously provided by Mallinckrodt Inc, St Louis, Missouri. Tablets containing nalmefene for human administration and placebo tablets were prepared by the Pharmaceutical Development Branch, Pharmacy Department, Clinical Center, NIH. Adult patients with unrelieved incapacitating generalized pruritus, complicating well-characterized stable chronic liver disease, were entered into the study. Nonhepatic causes of pruritus were excluded. Narcotic use within 1 month of entry into the study was an exclusion criterion. However, none of our patients gave a history of any ingestion of narcotic medications. Conventional antipruritic medications, specifically antihistamines and cholestyramine, were discontinued at least 1 week before entry into the study. The study design consisted of 2 double-blind 2-month courses of treatment. In course 1, patients were randomized to receive either nalmefene tablets (67%) or placebo tablets (33%). In course 2, all patients were rerandomized to receive either nalmefene (50%) or placebo (50%). After completion of each course of treatment and recording symptoms and data for that period, the code for that course was broken and patients were told what they had been receiving. To minimize the possibility of nalmefene precipitating an opiate withdrawal-like reaction in cholestatic patients,7 initial doses of trial medication (nalmefene or placebo) in each course of treatment were low (for nalmefene: only 2 mg twice daily on day 1), and subsequent doses were gradually increased over 3 days (for nalmefene: 5 mg twice daily on day 2, 10 mg twice daily on day 3, and 20 mg twice daily on day 4). The dose of trial medication was cautiously increased further if pruritus did not appear to be relieved. Scratching activity was measured continuously for 24hour periods while the patient was hospitalized, immediately before the first randomization (baseline), and at the end of each of the 2-month courses of treatment (while the patient was still taking the trial medication for that course). Each patient was an inpatient at the Clinical Center during the first 3 days after the introduction of nalmefene or placebo; subsequently, each patient was seen in the outpatient department within 2 weeks of initiation of therapy, and every 2 weeks thereafter until the next hospital admission for reevaluation at the end of a course of treatment. The measurements of scratching activity, which were independent of arm movements, were obtained for each 30 seconds of the recording period by application of piezofilm technology using a monitoring system specifically designed to quantitate this activity.12 This monitoring system had been previously validated and had been applied successfully to quantitate scratching
J AM A C A D D ERMATOL SEPTEMBER 1999
activity in trials of the efficacy of naloxone infusions in ameliorating the pruritus of cholestasis.4,5 The perception of pruritus was assessed every 4 hours while patients were awake during recordings of scratching activity, using a visual analogue scale (0 to 10 cm) to generate a visual analogue score (VAS).4 The trial was terminated after 11 patients had been studied according to protocol. Of these, 8 had received at least 1 course of nalmefene. The liver diseases in these 8 patients were primary biliary cirrhosis (PBC) in 5, precirrhotic chronic hepatitis C in 2, and hepatic sarcoidosis in 1. Four of the 5 patients with PBC were being treated for their underlying liver disease with ursodeoxycholic acid only, without perceptible relief of pruritus, and this medication for the underlying liver disease was not discontinued. None of the patients was treated with any other specific therapy for the underlying liver disease. To maximize the amount of useful information that could be derived from the data in this group of patients, we applied statistical methods that differed from those described in the protocol. Specifically, baseline data on scratching activity and VAS were included in the analysis. Data from individual patients were reduced to control-nalmefene differences, the significance of which was tested by the paired sample t test.
RESULTS No serious adverse events or logistical problems with the conduct of the study occurred. Trial medication was discontinued prematurely (before completion of course 2) in 4 patients, in 2 because of possible progression of disease and consideration of liver transplantation and in another 2 because of the attending physician’s concern about adverse events. One of the latter patients experienced generalized discomfort, chest tightness, and lack of appetite at a low dose of nalmefene (2 mg twice a day). The other, 3 weeks after entering the second phase of the study and while reporting no pruritus, had insomnia and joint stiffness associated with low-grade fever, peripheral blood eosinophilia, and an increase in total serum bilirubin from 0.9 to 1.6 mg/dL; the study drug was nalmefene at a dose of 20 mg twice a day. After breaking the treatment code for all patients, we found that maintenance doses of nalmefene varied between 20 and 120 mg twice daily. Data on 8 patients who had baseline measurements taken and who had received at least 1 course of nalmefene were available for analysis. Four of these patients did not receive a course of placebo. Among the 4 who did, log10 mean hourly scratching activity while taking placebo agreed closely with corresponding baseline values (1.69 vs 1.69, 1.37 vs 1.39, 2.47 vs 2.48, 1.46 vs 1.20), whereas the VAS of pruritus was worse on placebo than at baseline in 2 patients (3.3 vs 8.3, 5.4 vs 5.15, 4.49 vs 4.05, 3.5 vs 6.18). These findings led us to use the baseline data
Bergasa et al 433
J AM A C A D D ERMATOL V OLUME 41, NUMBER 3, PART 1
Fig 1. Geometric mean hourly scratching activity during control periods (baseline and/or placebo) and during nalmefene therapy in 8 patients with chronic cholestasis.
for comparative purposes in the 4 patients who had no course of placebo. Thus, in 2 patients who did not cross over, data obtained during nalmefene therapy were compared with corresponding baseline data, and in 2 patients who received 2 courses of nalmefene, the data obtained during nalmefene therapy were averaged and compared with corresponding baseline data. In the 4 patients who did cross over, data during nalmefene treatment were compared with the average of corresponding data collected at baseline and during placebo therapy. Control (baseline and/or placebo) versus nalmefene differences for both log10 mean hourly scratching activity and VAS were derived for each of these 8 patients. Of the 8 patients who had received nalmefene, 7 reported a greater feeling of well-being while taking the drug than before treatment or during placebo treatment. In 6 of these patients, nalmefene therapy was associated with transient symptoms (lasting less than 3 days) consistent with a mild opiate withdrawal-like reaction.7 The symptoms included abdominal
Fig 2. Mean visual analogue scores of the perception of pruritus during control periods (baseline and/or placebo) and during nalmefene therapy in 8 patients with chronic cholestasis.
pain, palpitations, anorexia, and apprehension in 1 patient, anorexia in 1, and nightmares in 1. Two patients had “goose bumps” that persisted throughout the period of nalmefene therapy. These symptoms were not sufficiently severe to necessitate any adjustment of the dose of trial medication. Nalmefene therapy was associated with an overall decrease in the geometric mean hourly scratching activity of 75% (P < .01, 7 d.f.) (Fig 1). The VAS decreased during therapy in all of the patients receiving nalmefene, the overall mean decrease being 77% (P < .01) (Fig 2).
DISCUSSION The hypothesis that increased neurotransmission/neuromodulation mediated by endogenous opioids in the central nervous system contributes to the pruritus of cholestasis3 is currently supported by 3 lines of evidence: (1) Administration of morphine or other opiate agonist drugs induces opiate antagonist-reversible pruritus, particularly if the drug is given centrally rather than peripherally13,14; (2) the
434 Bergasa et al
syndrome of cholestasis is associated with phenomena consistent with increased opioidergic tone (eg, opiate antagonist-reversible antinociception, opiate antagonist-induced opiate withdrawal-like syndrome7,15); and (3) the pruritus of cholestasis can be ameliorated by the parenteral administration of the opiate antagonist naloxone.4,5 The results obtained in this study further support the previous suggestion based on observations from open-label studies that were not controlled,7,11 that oral administration of nalmefene can ameliorate pruritus complicating chronic liver disease. This inference is supported not only by subjective (VAS) data on the perception of pruritus, but also by data from continuous 24-hour measurements of scratching activity that constituted an objective quantitative efficacy end point.12 The results also supplement analogous findings in controlled trials of intravenous infusions of naloxone for pruritus in patients with cholestatic liver diseases4,5 and, consequently, are consistent with the conclusion that a specific class of drugs, opiate antagonists, is efficacious in ameliorating the pruritus of cholestasis. Furthermore, our findings provide additional support for the hypothesis that increased opioidergic neurotransmission contributes to the pathogenesis of the pruritus of cholestasis.3 The potency of nalmefene as an opiate antagonist,8 its long plasma half-life (relative to naloxone),9 and its oral bioavailability10 enable opioid antagonism to be readily achieved by twice-daily oral dosing with this drug.11 Consequently, oral nalmefene therapy appears to be an appropriate means to reduce increased opioidergic neurotransmission in the long-term management of the pruritus of cholestasis. In this context, the potency of nalmefene as an opiate antagonist may be particularly important because a relatively greater degree of opioid antagonism appears to be required to reverse the effects of endogenous opioids, rather than exogenous opiates such as morphine.16 In contrast to a previous study in which oral administration of nalmefene (5 mg) consistently precipitated florid transient opiate withdrawal-like reactions in patients with chronic cholestasis,7 such reactions were either mild or absent in this study, presumably because the initial dose of nalmefene was lower and the dose was only gradually increased. Subjective observations have been reported, suggesting that oral administration of the opiate antagonist naltrexone may also ameliorate the pruritus of cholestasis.17 However, naltrexone may be hepatotoxic,18 and it appears to be less well tolerated than nalmefene by some cholestatic patients (Jones EA, unpublished observations). It seems theoretically possible that another, as yet unidentified, opiate antagonist may have properties
J AM A C A D D ERMATOL SEPTEMBER 1999
that are superior to those of nalmefene in ameliorating the pruritus that complicates chronic liver disease. However, until such an alternative drug is identified, the oral administration of nalmefene appears to be a potential therapeutic option in the long-term management of patients with the pruritus of cholestasis. The authors are most grateful to Mallinckrodt Inc for supplying the nalmefene. They also wish to thank S. Chia, H. Coonjeevaram, R. Sallie, and C. Yurdaydin for their valuable contributions to the clinical care of the patients studied and M. Souppaya for technical help with the scratching activity monitoring system. REFERENCES 1. Raiford DS. Pruritus of chronic cholestasis. Q J Med 1995;88:603-7. 2. Jones EA, Bergasa NV.The pruritus of cholestasis and the opioid system. JAMA 1992;268:3359-62. 3. Bergasa NV, Jones EA. The pruritus of cholestasis: potential pathogenic and therapeutic implications of opioids. Gastroenterology 1995;108:1582-8. 4. Bergasa NV, Talbot TL, Alling DW, Schmitt JM, Walker EC, Baker BL, et al. A controlled trial of naloxone infusions for the pruritus of chronic cholestasis. Gastroenterology 1992;102:544-9. 5. Bergasa NV, Alling DW, Talbot TL, Swain MG, Yurdaydin C, Turner ML, et al. Effects of naloxone infusions in patients with the pruritus of cholestasis: a double-blind, randomized, controlled trial. Ann Intern Med 1995;123:161-7. 6. Speight TM, Holford NHG. Avery’s drug treatment. 4th ed. Auckland NZ: Adis International; 1997. p. 1642. 7. Thornton JR, Losowsky MS. Opioid peptides and primary biliary cirrhosis. Br Med J 1988;297:1501-4. 8. Michel M, Bolger G, Weissman B-A. Binding of a new opiate antagonist, nalmefene, to rat brain membranes. Methods Find Exp Clin Pharmacol 1985;7:175-7. 9. Dixon R, Howes J, Gentile J, Hsu H-B, Hsiao J, Garg D, et al. Nalmefene: intravenous safety and kinetics of a new opioid antagonist. Clin Pharmacol Ther 1986;39:49-53. 10. Gal TJ, DiFarzio C, Dixon R. Prolonged blockade of opioid effect with oral nalmefene. Clin Pharmacol Ther 1986;40:537-42. 11. Bergasa NV, Schmitt JM, Talbot TL, Alling DW, Swain MG, Turner M, et al. Open label trial of oral nalmefene therapy for the pruritus of cholestasis. Hepatology 1998;27:679-84. 12. Talbot TL, Schmitt JM, Bergasa NV, Jones EA, Walker EC. Application of piezo film technology for the quantitative assessment of pruritus. Biomed Instrum Technol 1991;25:400-3. 13. Koenigstein H. Experimental study of itch stimuli in animals. Arch Dermatol Syphylol 1948;57:828-49. 14. Thomas DA, Williams GM, Iwata K, Kenshalo DJ, Dubner R. Effects of central administration of opioids on facial scratching in monkeys. Brain Res 1992;585:315-7. 15. Bergasa NV, Alling DW, Vergalla J, Jones EA. Cholestasis in the male rat is associated with naloxone-reversible antinociception. J Hepatol 1994;20:85-90. 16. Morley JE, Levine AS. Stress-induced eating is mediated through endogenous opiates. Science 1980;209:1259-61. 17. Wolfhagen FHJ, Sternieri E, Hop WCJ, Vitale G, Bertolotti M, van Buuren HR. Oral naltrexone treatment for cholestatic pruritus: a double-blind, placebo-controlled study. Gastroenterology 1997;113:1264-9. 18. Mitchell JE. Naltrexone and hepatotoxicity [letter]. Lancet 1986;1:1215.
Oral nalmefene therapy reduces scratching activity due to the pruritus of cholestasis: A controlled study Nora V. Bergasa, MD,a David W. Alling, MD, PhD,b† Thomas L. Talbot, BA,c Mary C. Wells, RN,d and E. Anthony Jones, MD, DSce Bethesda, Maryland, and Amsterdam, The Netherlands 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. (J Am Acad Dermatol 1999;41:431-4.)
R
elief of pruritus complicating chronic cholestatic liver diseases remains a major unsolved clinical problem. When unrelieved, this complication of cholestasis can lead to severe sleep deprivation and even suicidal ideation. Its pathogenesis is unknown and conventional therapies are empirical and are usually, at best, only partially efficacious.1 Recent evidence has suggested that increased neurotransmission mediated by endogenous opioids contributes to the pruritus of cholestasis.2,3 In parFrom the Liver Diseases Section, Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases,a the Clinical Center,b the Applied Clinical Engineering Section, Biomedical Engineering and Instrumentation Program, National Center for Research Resources,c and the Department of Nursing, Clinical Center,d National Institutes of Health, Bethesda, and the Department of Gastrointestinal and Liver Diseases, Academic Medical Center, Amsterdam.e Reprint requests: Nora V. Bergasa, MD, Department of Gastroenterology and Liver Disease, Beth Israel Medical Center, 1st Ave at 16th St, 18 Baird Hall, New York, NY 10003. †Deceased. Copyright © 1999 by the American Academy of Dermatology, Inc. 0190-9622/99/$8.00 + 0 16/1/98972
ticular, 2 controlled trials in cholestatic patients have shown that intravenous infusions of the opiate antagonist naloxone are associated subjectively with an apparent decrease in the perception of pruritus and objectively with a decrease in its behavioral consequence, scratching activity.4,5 Naloxone, however, has a short plasma half-life (about 1.5 hours) and low oral bioavailability (2%),6 precluding its use as a longterm therapy. Nevertheless, the findings in these 2 trials4,5 suggest that long-term relief from this form of pruritus may be possible by administering an opiate antagonist that is bioavailable when given orally. Indeed, in an open label uncontrolled study,7 oral administration of the opiate antagonist nalmefene (6-deoxy-6-methylene-naltrexone)8-10 appeared to be associated with subjective improvements in the perception of pruritus in patients with chronic cholestasis. Our initial uncontrolled experience with open label oral nalmefene for this indication11 demonstrated that it has an acceptable safety profile in cholestatic patients and also suggested that it may be efficacious in ameliorating the pruritus of cholestasis. We report herein controlled observations that indicate that oral treatment with nalme431
432 Bergasa et al
fene is efficacious in ameliorating, not only the perception of pruritus, but also associated scratching activity in patients with cholestasis.
METHODS The protocol of this study was approved by the Clinical Research Subpanel of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH). Highly purified nalmefene was generously provided by Mallinckrodt Inc, St Louis, Missouri. Tablets containing nalmefene for human administration and placebo tablets were prepared by the Pharmaceutical Development Branch, Pharmacy Department, Clinical Center, NIH. Adult patients with unrelieved incapacitating generalized pruritus, complicating well-characterized stable chronic liver disease, were entered into the study. Nonhepatic causes of pruritus were excluded. Narcotic use within 1 month of entry into the study was an exclusion criterion. However, none of our patients gave a history of any ingestion of narcotic medications. Conventional antipruritic medications, specifically antihistamines and cholestyramine, were discontinued at least 1 week before entry into the study. The study design consisted of 2 double-blind 2-month courses of treatment. In course 1, patients were randomized to receive either nalmefene tablets (67%) or placebo tablets (33%). In course 2, all patients were rerandomized to receive either nalmefene (50%) or placebo (50%). After completion of each course of treatment and recording symptoms and data for that period, the code for that course was broken and patients were told what they had been receiving. To minimize the possibility of nalmefene precipitating an opiate withdrawal-like reaction in cholestatic patients,7 initial doses of trial medication (nalmefene or placebo) in each course of treatment were low (for nalmefene: only 2 mg twice daily on day 1), and subsequent doses were gradually increased over 3 days (for nalmefene: 5 mg twice daily on day 2, 10 mg twice daily on day 3, and 20 mg twice daily on day 4). The dose of trial medication was cautiously increased further if pruritus did not appear to be relieved. Scratching activity was measured continuously for 24hour periods while the patient was hospitalized, immediately before the first randomization (baseline), and at the end of each of the 2-month courses of treatment (while the patient was still taking the trial medication for that course). Each patient was an inpatient at the Clinical Center during the first 3 days after the introduction of nalmefene or placebo; subsequently, each patient was seen in the outpatient department within 2 weeks of initiation of therapy, and every 2 weeks thereafter until the next hospital admission for reevaluation at the end of a course of treatment. The measurements of scratching activity, which were independent of arm movements, were obtained for each 30 seconds of the recording period by application of piezofilm technology using a monitoring system specifically designed to quantitate this activity.12 This monitoring system had been previously validated and had been applied successfully to quantitate scratching
J AM A C A D D ERMATOL SEPTEMBER 1999
activity in trials of the efficacy of naloxone infusions in ameliorating the pruritus of cholestasis.4,5 The perception of pruritus was assessed every 4 hours while patients were awake during recordings of scratching activity, using a visual analogue scale (0 to 10 cm) to generate a visual analogue score (VAS).4 The trial was terminated after 11 patients had been studied according to protocol. Of these, 8 had received at least 1 course of nalmefene. The liver diseases in these 8 patients were primary biliary cirrhosis (PBC) in 5, precirrhotic chronic hepatitis C in 2, and hepatic sarcoidosis in 1. Four of the 5 patients with PBC were being treated for their underlying liver disease with ursodeoxycholic acid only, without perceptible relief of pruritus, and this medication for the underlying liver disease was not discontinued. None of the patients was treated with any other specific therapy for the underlying liver disease. To maximize the amount of useful information that could be derived from the data in this group of patients, we applied statistical methods that differed from those described in the protocol. Specifically, baseline data on scratching activity and VAS were included in the analysis. Data from individual patients were reduced to control-nalmefene differences, the significance of which was tested by the paired sample t test.
RESULTS No serious adverse events or logistical problems with the conduct of the study occurred. Trial medication was discontinued prematurely (before completion of course 2) in 4 patients, in 2 because of possible progression of disease and consideration of liver transplantation and in another 2 because of the attending physician’s concern about adverse events. One of the latter patients experienced generalized discomfort, chest tightness, and lack of appetite at a low dose of nalmefene (2 mg twice a day). The other, 3 weeks after entering the second phase of the study and while reporting no pruritus, had insomnia and joint stiffness associated with low-grade fever, peripheral blood eosinophilia, and an increase in total serum bilirubin from 0.9 to 1.6 mg/dL; the study drug was nalmefene at a dose of 20 mg twice a day. After breaking the treatment code for all patients, we found that maintenance doses of nalmefene varied between 20 and 120 mg twice daily. Data on 8 patients who had baseline measurements taken and who had received at least 1 course of nalmefene were available for analysis. Four of these patients did not receive a course of placebo. Among the 4 who did, log10 mean hourly scratching activity while taking placebo agreed closely with corresponding baseline values (1.69 vs 1.69, 1.37 vs 1.39, 2.47 vs 2.48, 1.46 vs 1.20), whereas the VAS of pruritus was worse on placebo than at baseline in 2 patients (3.3 vs 8.3, 5.4 vs 5.15, 4.49 vs 4.05, 3.5 vs 6.18). These findings led us to use the baseline data
Bergasa et al 433
J AM A C A D D ERMATOL V OLUME 41, NUMBER 3, PART 1
Fig 1. Geometric mean hourly scratching activity during control periods (baseline and/or placebo) and during nalmefene therapy in 8 patients with chronic cholestasis.
for comparative purposes in the 4 patients who had no course of placebo. Thus, in 2 patients who did not cross over, data obtained during nalmefene therapy were compared with corresponding baseline data, and in 2 patients who received 2 courses of nalmefene, the data obtained during nalmefene therapy were averaged and compared with corresponding baseline data. In the 4 patients who did cross over, data during nalmefene treatment were compared with the average of corresponding data collected at baseline and during placebo therapy. Control (baseline and/or placebo) versus nalmefene differences for both log10 mean hourly scratching activity and VAS were derived for each of these 8 patients. Of the 8 patients who had received nalmefene, 7 reported a greater feeling of well-being while taking the drug than before treatment or during placebo treatment. In 6 of these patients, nalmefene therapy was associated with transient symptoms (lasting less than 3 days) consistent with a mild opiate withdrawal-like reaction.7 The symptoms included abdominal
Fig 2. Mean visual analogue scores of the perception of pruritus during control periods (baseline and/or placebo) and during nalmefene therapy in 8 patients with chronic cholestasis.
pain, palpitations, anorexia, and apprehension in 1 patient, anorexia in 1, and nightmares in 1. Two patients had “goose bumps” that persisted throughout the period of nalmefene therapy. These symptoms were not sufficiently severe to necessitate any adjustment of the dose of trial medication. Nalmefene therapy was associated with an overall decrease in the geometric mean hourly scratching activity of 75% (P < .01, 7 d.f.) (Fig 1). The VAS decreased during therapy in all of the patients receiving nalmefene, the overall mean decrease being 77% (P < .01) (Fig 2).
DISCUSSION The hypothesis that increased neurotransmission/neuromodulation mediated by endogenous opioids in the central nervous system contributes to the pruritus of cholestasis3 is currently supported by 3 lines of evidence: (1) Administration of morphine or other opiate agonist drugs induces opiate antagonist-reversible pruritus, particularly if the drug is given centrally rather than peripherally13,14; (2) the
434 Bergasa et al
syndrome of cholestasis is associated with phenomena consistent with increased opioidergic tone (eg, opiate antagonist-reversible antinociception, opiate antagonist-induced opiate withdrawal-like syndrome7,15); and (3) the pruritus of cholestasis can be ameliorated by the parenteral administration of the opiate antagonist naloxone.4,5 The results obtained in this study further support the previous suggestion based on observations from open-label studies that were not controlled,7,11 that oral administration of nalmefene can ameliorate pruritus complicating chronic liver disease. This inference is supported not only by subjective (VAS) data on the perception of pruritus, but also by data from continuous 24-hour measurements of scratching activity that constituted an objective quantitative efficacy end point.12 The results also supplement analogous findings in controlled trials of intravenous infusions of naloxone for pruritus in patients with cholestatic liver diseases4,5 and, consequently, are consistent with the conclusion that a specific class of drugs, opiate antagonists, is efficacious in ameliorating the pruritus of cholestasis. Furthermore, our findings provide additional support for the hypothesis that increased opioidergic neurotransmission contributes to the pathogenesis of the pruritus of cholestasis.3 The potency of nalmefene as an opiate antagonist,8 its long plasma half-life (relative to naloxone),9 and its oral bioavailability10 enable opioid antagonism to be readily achieved by twice-daily oral dosing with this drug.11 Consequently, oral nalmefene therapy appears to be an appropriate means to reduce increased opioidergic neurotransmission in the long-term management of the pruritus of cholestasis. In this context, the potency of nalmefene as an opiate antagonist may be particularly important because a relatively greater degree of opioid antagonism appears to be required to reverse the effects of endogenous opioids, rather than exogenous opiates such as morphine.16 In contrast to a previous study in which oral administration of nalmefene (5 mg) consistently precipitated florid transient opiate withdrawal-like reactions in patients with chronic cholestasis,7 such reactions were either mild or absent in this study, presumably because the initial dose of nalmefene was lower and the dose was only gradually increased. Subjective observations have been reported, suggesting that oral administration of the opiate antagonist naltrexone may also ameliorate the pruritus of cholestasis.17 However, naltrexone may be hepatotoxic,18 and it appears to be less well tolerated than nalmefene by some cholestatic patients (Jones EA, unpublished observations). It seems theoretically possible that another, as yet unidentified, opiate antagonist may have properties
J AM A C A D D ERMATOL SEPTEMBER 1999
that are superior to those of nalmefene in ameliorating the pruritus that complicates chronic liver disease. However, until such an alternative drug is identified, the oral administration of nalmefene appears to be a potential therapeutic option in the long-term management of patients with the pruritus of cholestasis. The authors are most grateful to Mallinckrodt Inc for supplying the nalmefene. They also wish to thank S. Chia, H. Coonjeevaram, R. Sallie, and C. Yurdaydin for their valuable contributions to the clinical care of the patients studied and M. Souppaya for technical help with the scratching activity monitoring system. REFERENCES 1. Raiford DS. Pruritus of chronic cholestasis. Q J Med 1995;88:603-7. 2. Jones EA, Bergasa NV.The pruritus of cholestasis and the opioid system. JAMA 1992;268:3359-62. 3. Bergasa NV, Jones EA. The pruritus of cholestasis: potential pathogenic and therapeutic implications of opioids. Gastroenterology 1995;108:1582-8. 4. Bergasa NV, Talbot TL, Alling DW, Schmitt JM, Walker EC, Baker BL, et al. A controlled trial of naloxone infusions for the pruritus of chronic cholestasis. Gastroenterology 1992;102:544-9. 5. Bergasa NV, Alling DW, Talbot TL, Swain MG, Yurdaydin C, Turner ML, et al. Effects of naloxone infusions in patients with the pruritus of cholestasis: a double-blind, randomized, controlled trial. Ann Intern Med 1995;123:161-7. 6. Speight TM, Holford NHG. Avery’s drug treatment. 4th ed. Auckland NZ: Adis International; 1997. p. 1642. 7. Thornton JR, Losowsky MS. Opioid peptides and primary biliary cirrhosis. Br Med J 1988;297:1501-4. 8. Michel M, Bolger G, Weissman B-A. Binding of a new opiate antagonist, nalmefene, to rat brain membranes. Methods Find Exp Clin Pharmacol 1985;7:175-7. 9. Dixon R, Howes J, Gentile J, Hsu H-B, Hsiao J, Garg D, et al. Nalmefene: intravenous safety and kinetics of a new opioid antagonist. Clin Pharmacol Ther 1986;39:49-53. 10. Gal TJ, DiFarzio C, Dixon R. Prolonged blockade of opioid effect with oral nalmefene. Clin Pharmacol Ther 1986;40:537-42. 11. Bergasa NV, Schmitt JM, Talbot TL, Alling DW, Swain MG, Turner M, et al. Open label trial of oral nalmefene therapy for the pruritus of cholestasis. Hepatology 1998;27:679-84. 12. Talbot TL, Schmitt JM, Bergasa NV, Jones EA, Walker EC. Application of piezo film technology for the quantitative assessment of pruritus. Biomed Instrum Technol 1991;25:400-3. 13. Koenigstein H. Experimental study of itch stimuli in animals. Arch Dermatol Syphylol 1948;57:828-49. 14. Thomas DA, Williams GM, Iwata K, Kenshalo DJ, Dubner R. Effects of central administration of opioids on facial scratching in monkeys. Brain Res 1992;585:315-7. 15. Bergasa NV, Alling DW, Vergalla J, Jones EA. Cholestasis in the male rat is associated with naloxone-reversible antinociception. J Hepatol 1994;20:85-90. 16. Morley JE, Levine AS. Stress-induced eating is mediated through endogenous opiates. Science 1980;209:1259-61. 17. Wolfhagen FHJ, Sternieri E, Hop WCJ, Vitale G, Bertolotti M, van Buuren HR. Oral naltrexone treatment for cholestatic pruritus: a double-blind, placebo-controlled study. Gastroenterology 1997;113:1264-9. 18. Mitchell JE. Naltrexone and hepatotoxicity [letter]. Lancet 1986;1:1215.