Elsevier

Journal of Hepatology

Volume 37, Issue 6, December 2002, Pages 717-722
Journal of Hepatology

Efficacy and safety of oral naltrexone treatment for pruritus of cholestasis, a crossover, double blind, placebo-controlled study

https://doi.org/10.1016/S0168-8278(02)00318-5Get rights and content

Abstract

Background/Aims: To assess the efficacy and safety of naltrexone for the short and long term treatment of pruritus of cholestasis.

Methods: Twenty patients with pruritus and cholestasis were included. A baseline pruritus score was obtained over 1 week. Patients were then randomized to receive 50 mg/day of naltrexone or placebo for 2 weeks. Subsequently, a 1-week washout period ensued and patients were crossed over to the other therapy for 2 additional weeks. Pruritus was assessed daily with a visual analogue scale (VAS) from 0 to 10. Patients whose pruritus decreased >50% of basal with naltrexone received naltrexone 50 mg/day for 2 additional months.

Results: Mean basal VAS was similar in both groups. VAS showed greater and more significant changes with naltrexone than with placebo (P<0.0003). In nine out of 20 patients (45%) receiving naltrexone, pruritus decreased >50% compared to basal value, including five whose pruritus disappeared completely. No significant changes were observed in serum biochemistry. Most of the adverse events that occurred during the first 48 h of naltrexone therapy were consistent with opioid withdrawal-like phenomena and spontaneously disappeared 2 days after starting treatment.

Conclusions: Naltrexone can be considered as an alternative option to treat pruritus of cholestasis. In the current study, side effects were transient and did not require specific medication.

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)

  • F.H.J Wolfhagen et al.

    Oral naltrexone treatment for cholestatic pruritus: a double blind placebo-controlled study

    Gastroenterology

    (1997)
  • J.E Mitchell

    Naltrexone and hepatotoxicity

    Lancet

    (1986)
  • N.V Bergasa et al.

    The pruritus of cholestasis

    Semin Liver Dis

    (1993)
  • J Heathcote

    Management of primary biliary cirrhosis

    Hepatology

    (2000)
  • M Khandelwal et al.

    Pruritus associated with cholestasis: a review of pathogenesis and management

    Dig Dis Sci

    (1994)
  • D.M Heuman

    Hepatoprotective properties of ursodeoxycholic acid

    Gastroenterology

    (1993)
  • R.E Poupon et al.

    UDCA-PBC Study Group. Ursodiol for the long-term treatment of primary biliary cirrhosis

    N Engl J Med

    (1994)
  • A Podestá et al.

    Treatment of pruritus of primary biliary cirrhosis with rifampin

    Dig Dis Sci

    (1991)
  • L.B Cohen et al.

    Role of plasmapheresis in primary biliary cirrhosis

    Gut

    (1985)
  • B.H Markus et al.

    Efficacy of liver transplantation in patients with primary biliary cirrhosis

    N Engl J Med

    (1989)
  • Cited by (156)

    • Itch: Pathogenesis and treatment

      2022, Journal of the American Academy of Dermatology
    • Recent advances in understanding the molecular mechanisms of cholestatic pruritus: A review

      2020, Biochimica et Biophysica Acta - Molecular Basis of Disease
    View all citing articles on Scopus

    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.

    View full text