Efficacy and safety of oral naltrexone treatment for pruritus of cholestasis, a crossover, double blind, placebo-controlled study☆
Introduction
Pruritus is the most disabling symptom in chronic cholestatic liver disease. Many therapies have been used for the treatment of these patients with different outcomes [1], [2], [3]. Despite benefits from cholestyramine [4], ursodeoxycholic acid [5], [6], [7], or rifampin [8], [9], [10], [11], [12], there is an important number of patients who do not respond to medical treatment, in whom unconventional methods, like plasmapheresis, [13] have been tried. Moreover, unrelieved chronic pruritus can be an indication for liver transplantation after therapeutic failure [14], [15].
The mechanisms that explain this kind of itching are subject of controversy. Although it was classically thought to arise from retained bile acids [16], [17], recent studies have suggested that pruritus due of cholestasis could be mediated by endogenous opioid substances in the central nervous system [18], [19], [20]. The evidence that supports this hypothesis is the following: (a) patients with chronic cholestatic liver disease have increased plasma levels of endogenous opioids substances, such as enkephalin [21]; (b) opiates produce itching that can be reversed by an opiate antagonist (naloxone) [22], [23]; and (c) naloxone-reversible itching can be induced in monkeys by injecting plasma extracts from cholestatic patients with pruritus into the medullary dorsal horn [24]. Recently, several published trials have confirmed that administration of opiate antagonists (naloxone and nalmefene) in patients with primary biliary cirrhosis leads to a significant improvement in pruritus measured by a reduction in scratching activity [18], [25], [26], [27]. Unfortunately, the drugs investigated have important limitations. Naloxone has a short half-life and its oral bioavailability is low; so, it can only be administered parenterally [27], [28]. On the other hand, opiate antagonist treatment has been associated with a severe opiate withdrawal-like syndrome [29], [30].
Naltrexone, an oral opioid antagonist, has been recently released for use in the treatment of narcotic and alcohol dependence. It has bioavailability and half-life that lie between naloxone and nalmefene. This drug undergoes extensive (95%) first-pass metabolism and has high plasma levels in the first hour of ingestion. The clearance follows mainly the renal route [28], [31], [32]. It has also been proposed as a treatment for pruritus of cholestasis [33], [34].
We have performed a double-blind, crossover, placebo-controlled trial to assess the efficacy and safety of oral naltrexone in the treatment of pruritus due to cholestasis, and to evaluate its effects in the short and long term.
Section snippets
Patients
Twenty patients (36–70 years old) with pruritus associated with chronic intrahepatic cholestasis were included in this study. Fifteen patients had a diagnosis of primary biliary cirrhosis (PBC): three with negative antimitochondrial antibodies (AMA), two with chronic hepatitis C (one of them also had an hepatocellular carcinoma), one with primary sclerosing cholangitis (PSC), one with overlap syndrome (autoimmune hepatitis (AIH) and autoimmune cholangiopathy (AIC)) and one with cryptogenic
Effects of naltrexone on pruritus
The baseline characteristics of the patients are presented in Table 1. The mean basal VAS was similar when the first test period was either naltrexone (Group A) or placebo (Group B). One patient (no. 16) changed by mistake the sequence of the bottles with the medication; for this reason, Group A included 11 patients and Group B included nine patients.
At the end of naltrexone treatment, pruritus decreased significantly compared to basal (mean daytime pruritus VAS decreased from 6.29±2.28 to
Discussion
The results of the current study suggest that the administration of an oral opiate antagonist, naltrexone, relieves the pruritus associated with chronic cholestatic liver disease.
The decrease in values of VAS with naltrexone agrees with those found in two previously published reports [33], [34]. In the first one, an open-label trial including five patients, pruritus decreased significantly after a week of naltrexone treatment [33]. The second, a placebo-controlled study showed a significant
Acknowledgements
E.C. was recipient of a grant by FUNDHIG (Fundación Argentina para el Estudio del Hı́gado). Laboratorios Souberian Chobet, Buenos Aires, provided naltrexone.
References (41)
- et al.
Cholestyramine for long-term relief of the pruritus complicating intrahepatic cholestasis
Gastroenterology
(1966) - et al.
A randomized double-blind placebo controlled trial of Ursodeoxycholic acid in primary biliary cirrhosis
Hepatology
(1995) - et al.
Treatment of pruritus in primary biliary cirrhosis with rifampin. Results of a double-blind crossover randomized trial
Gastroenterology
(1988) - et al.
Comparison of rifampicin with phenobarbitone for treatment of pruritus in biliary cirrhosis
Lancet
(1989) - et al.
Rifampin relieves pruritus in children with cholestasis liver disease
Gastroenterology
(1990) - et al.
Effects of long-term rifampicin administration in primary biliary cirrhosis
Gastroenterology
(1992) - et al.
A controlled trial of naloxone infusions for the pruritus of chronic cholestasis
Gastroenterology
(1992) - et al.
Florid opioid withdrawal-like reaction precipitated by naltrexone in a patient with chronic cholestasis
Gastroenterology
(2000) - et al.
Delayed opioid withdrawal-like reaction in primary biliary cirrhosis following naloxone therapy
Gastroenterology
(2001) - et al.
Effect of liver cirrhosis on the systemic availability of naltrexone in humans
J Hepatol
(1997)
Oral naltrexone treatment for cholestatic pruritus: a double blind placebo-controlled study
Gastroenterology
Naltrexone and hepatotoxicity
Lancet
The pruritus of cholestasis
Semin Liver Dis
Management of primary biliary cirrhosis
Hepatology
Pruritus associated with cholestasis: a review of pathogenesis and management
Dig Dis Sci
Hepatoprotective properties of ursodeoxycholic acid
Gastroenterology
UDCA-PBC Study Group. Ursodiol for the long-term treatment of primary biliary cirrhosis
N Engl J Med
Treatment of pruritus of primary biliary cirrhosis with rifampin
Dig Dis Sci
Role of plasmapheresis in primary biliary cirrhosis
Gut
Efficacy of liver transplantation in patients with primary biliary cirrhosis
N Engl J Med
Cited by (156)
Evaluation and Management of Pruritus and Scabies in the Elderly Population
2024, Clinics in Geriatric MedicineEvaluation and Management of Pruritus in Primary Biliary Cholangitis
2022, Clinics in Liver DiseaseItch: Pathogenesis and treatment
2022, Journal of the American Academy of DermatologyRecent advances in understanding the molecular mechanisms of cholestatic pruritus: A review
2020, Biochimica et Biophysica Acta - Molecular Basis of Disease
- ☆
Presented in part at the 51st Annual Meeting of the American Association for the Study of Liver Diseases, Dallas, TX, USA, October 28–31, 2000, and published in abstract form in Hepatology 2000;32:167A.