Is patient-reported outcome improved by nalfurafine hydrochloride in patients with primary biliary cholangitis and refractory pruritus? A post-marketing, single-arm, prospective study

  • Minami Yagi
  • Atsushi Tanaka
  • Tadashi Namisaki
  • Atsushi Takahashi
  • Masanori Abe
  • Akira Honda
  • Yasushi Matsuzaki
  • Hiromasa Ohira
  • Hitoshi Yoshiji
  • Hajime Takikawa
  • Japan PBC Study Group (JPBCSG)
Original Article—Liver, Pancreas, and Biliary Tract



Patients with primary biliary cholangitis (PBC) frequently suffer from pruritus, which can severely impair their health-related quality of life (HRQOL). Nalfurafine hydrochloride, a selective κ-opioid receptor agonist, was recently approved in Japan for refractory pruritus in patients with chronic liver diseases, but it still remains unclear whether this treatment improves the patient-reported outcome (PRO) in PBC patients with refractory pruritus. Herein, we conducted a multicenter, post-marketing, single-arm prospective study to investigate the efficacy of nalfurafine in terms of PRO, and the associations of the efficacy with any clinical characteristics.


After screening for pruritus in 496 patients with PBC using PBC-40 and the visual analog scale (VAS), we identified 141 patients with moderate to severe pruritus; these were invited to participate in the study. The participants received 2.5 μg nalfurafine once daily for 12 weeks, and pruritus and HRQOL were assessed in week 12 of this treatment. Generic HRQOL, short form 36, blood chemistries, and serum autotaxin levels were also measured at baseline and at week 12.


Forty-four patients participated in this study. The mean PBC-40 itch domain scores and VAS declined during the study period, from 8.56 to 7.63 (P = 0.041) and from 42.9 to 29.3 (P = 0.001) at baseline and at week 12, respectively, indicating a significant effect of nalfurafine. The other domains of PBC-40 and all domains of SF-36 were not significantly altered by this treatment. We failed to find any association between the change in VAS and PBC-40 itch scores and any clinical variable. Serum autotaxin levels were significantly increased during the study period.


This study demonstrated that nalfurafine improved pruritus in patients with PBC, independent of their clinical characteristics, but had a limited effect on the PRO.


PBC-40 SF-36 Opioid Autotaxin Health-related quality of life 



Primary biliary cholangitis


Health-related quality of life


Ursodeoxycholic acid


Visual analog scale


Patient-reported outcomes


Short form 36



We are sincerely grateful to all of the patients who participated in this study. Also, we sincerely appreciate the secretarial assistance of Ms. Kayono Unno and Ms. Kanako Iwai.

Authors’ contributions

A.T. and M.Y. designed the study. T.N., A.T., M.A., A.H., Y.M., H.O., H.Y., and H.T. invited participants and collected clinical data. A.T., Y.N., and H.T. analyzed and interpreted the data. A.T. and M.Y. drafted the paper; all authors critically reviewed the manuscript.


This study was financially supported by the Japan Agency for Medical Research and Development (AMED; #17ek01091490003).

Compliance with ethical standards

Conflict of interest

AT received consultant fees from EA Pharma and GlaxoSmithKline. YM received lecture fees from Mitsubishi Tanabe Pharma, MSD K.K., AbbVie GK, Gilead Science, Janssen Pharmaceutical K.K. and commercial research findings from MSD K.K., AbbVie GK, Gilead Science, and Nobelpharma, Eisai Co.


  1. 1.
    Kaplan MM, Gershwin ME. Primary biliary cirrhosis. New Engl J Med. 2005;353(12):1261–73.CrossRefPubMedGoogle Scholar
  2. 2.
    Lindor KD, Gershwin ME, Poupon R, et al. Primary biliary cirrhosis. Hepatology. 2009;50(1):291–308.CrossRefPubMedGoogle Scholar
  3. 3.
    Talwalkar JA, Souto E, Jorgensen RA, et al. Natural history of pruritus in primary biliary cirrhosis. Clin Gastroenterol Hepatol. 2003;1(4):297–302.CrossRefPubMedGoogle Scholar
  4. 4.
    Dyson JK, Wilkinson N, Jopson L, et al. The inter-relationship of symptom severity and quality of life in 2055 patients with primary biliary cholangitis. Aliment Pharmacol Ther. 2016;44(10):1039–50.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Mells GF, Pells G, Newton JL, et al. Impact of primary biliary cirrhosis on perceived quality of life: the UK-PBC national study. Hepatology. 2013;58(1):273–83.CrossRefPubMedGoogle Scholar
  6. 6.
    Newton JL, Bhala N, Burt J, et al. Characterisation of the associations and impact of symptoms in primary biliary cirrhosis using a disease specific quality of life measure. J Hepatol. 2006;44(4):776–83.CrossRefPubMedGoogle Scholar
  7. 7.
    Beuers U, Kremer AE, Bolier R, et al. Pruritus in cholestasis: facts and fiction. Hepatology. 2014;60(1):399–407.CrossRefPubMedGoogle Scholar
  8. 8.
    Rudic JS, Poropat G, Krstic MN, et al. Ursodeoxycholic acid for primary biliary cirrhosis. Cochrane Database Syst Rev. 2012;12:CD000551.PubMedGoogle Scholar
  9. 9.
    EASL. EASL Clinical practice guidelines: management of cholestatic liver diseases. J Hepatol. 2009;51(2):237–67.CrossRefGoogle Scholar
  10. 10.
    Working Subgroup for Clinical Practice Guidelines for Primary Biliary Cirrhosis. Guidelines for the management of primary biliary cirrhosis: the intractable hepatobiliary disease Study Group supported by the Ministry of Health, Labour and Welfare of Japan. Hepatol Res. 2014;44(Suppl S1):71–90.CrossRefGoogle Scholar
  11. 11.
    Bergasa NV. Pruritus in primary biliary cirrhosis: pathogenesis and therapy. Clin Liver Dis. 2008;12(2):385–406.CrossRefPubMedGoogle Scholar
  12. 12.
    Bergasa NV, Jones A, Kleiner DE, et al. Pilot study of low dose oral methotrexate treatment for primary biliary cirrhosis. Am J Gastroenterol. 1996;91(2):295–9.PubMedGoogle Scholar
  13. 13.
    Kumagai H, Ebata T, Takamori K, et al. Effect of a novel kappa-receptor agonist, nalfurafine hydrochloride, on severe itch in 337 haemodialysis patients: a Phase III, randomized, double-blind, placebo-controlled study. Nephrol Dial Transplant. 2010;25(4):1251–7.CrossRefPubMedGoogle Scholar
  14. 14.
    Kumada H, Miyakawa H, Muramatsu T, et al. Efficacy of nalfurafine hydrochloride in patients with chronic liver disease with refractory pruritus: a randomized, double-blind trial. Hepatol Res. 2017;47(10):972–82.CrossRefPubMedGoogle Scholar
  15. 15.
    Akuta N, Kumada H, Fujiyama S, et al. Predictors of pruritus in patients with chronic liver disease and usefulness of nalfurafine hydrochloride. Hepatol Res. 2018;48(1):45–50.CrossRefPubMedGoogle Scholar
  16. 16.
    Kremer AE, van Dijk R, Leckie P, et al. Serum autotaxin is increased in pruritus of cholestasis, but not of other origin, and responds to therapeutic interventions. Hepatology. 2012;56(4):1391–400.CrossRefPubMedGoogle Scholar
  17. 17.
    Yagi M, Tanaka A, Abe M, et al. Symptoms and health-related quality of life in Japanese patients with primary biliary cholangitis. Submitted.Google Scholar
  18. 18.
    Tanaka A, Miura K, Yagi M, et al. The assessment of subjective symptoms and patient-reported outcomes in patients with primary biliary cholangitis using PBC-40. Kanzo [in Japanese]. 2016;57:457–67.CrossRefGoogle Scholar
  19. 19.
    Jacoby A, Rannard A, Buck D, et al. Development, validation, and evaluation of the PBC-40, a disease specific health related quality of life measure for primary biliary cirrhosis. Gut. 2005;54(11):1622–9.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Ware JEJ. The SF-36 health survey. In: Spilker B, editor. Quality of life and pharmacoeconomics in clinical trials. 2nd ed. Philadelphia: Lippincott-Raven; 1996.Google Scholar
  21. 21.
    Fukuhara S, Bito S, Green J, et al. Translation, adaptation, and validation of the SF-36 Health Survey for use in Japan. J Clin Epidemiol. 1998;51(11):1037–44.CrossRefPubMedGoogle Scholar
  22. 22.
    Fukuhara S, Ware JE Jr, Kosinski M, et al. Psychometric and clinical tests of validity of the Japanese SF-36 Health Survey. J Clin Epidemiol. 1998;51(11):1045–53.CrossRefPubMedGoogle Scholar
  23. 23.
    Sun Y, Zhang W, Evans JF, et al. Autotaxin, pruritus and primary biliary cholangitis (PBC). Autoimmun Rev. 2016;15(8):795–800.CrossRefPubMedGoogle Scholar
  24. 24.
    Kremer AE, Martens JJ, Kulik W, et al. Lysophosphatidic acid is a potential mediator of cholestatic pruritus. Gastroenterology. 2010;139(3):1008–18.CrossRefPubMedGoogle Scholar
  25. 25.
    Kremer AE, Martens JJ, Kulik W, et al. Autotaxin but not bile salts correlate with itch intensity in cholestasis. J Hepatol. 2010;52(Supplement 1):S1.CrossRefGoogle Scholar

Copyright information

© Japanese Society of Gastroenterology 2018

Authors and Affiliations

  • Minami Yagi
    • 1
  • Atsushi Tanaka
    • 1
  • Tadashi Namisaki
    • 2
  • Atsushi Takahashi
    • 3
  • Masanori Abe
    • 4
  • Akira Honda
    • 5
  • Yasushi Matsuzaki
    • 5
  • Hiromasa Ohira
    • 3
  • Hitoshi Yoshiji
    • 2
  • Hajime Takikawa
    • 1
  • Japan PBC Study Group (JPBCSG)
  1. 1.Department of MedicineTeikyo University School of MedicineTokyoJapan
  2. 2.Third Department of Internal MedicineNara Medical UniversityNaraJapan
  3. 3.Department of GastroenterologyFukushima Medical University School of MedicineFukushimaJapan
  4. 4.Department of Gastroenterology and MetabologyEhime University Graduate School of MedicineEhimeJapan
  5. 5.Division of Gastroenterology and Hepatology, Department of Internal MedicineTokyo Medical University Ibaraki Medical CenterIbarakiJapan

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