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Management of Pruritus in Primary Biliary Cholangitis: A Narrative Review

Published:February 23, 2017DOI:https://doi.org/10.1016/j.amjmed.2017.01.037

      Abstract

      Primary biliary cholangitis is an autoimmune condition characterized by destruction of intrahepatic bile ducts. It causes debilitating symptoms that dramatically affect the patient's quality of life. Pruritus affects 60% to 70% of individuals with primary biliary cholangitis and leads to sleep disturbances, fatigue, depression, and suicidal ideation. A complete search was performed with studies from PubMed, EMBASE, Web of Science, Cochrane database, Countway Library, and CINAHL with specific search terms. This narrative review was prepared after a comprehensive literature review. Treating patients with cholestatic pruritus is challenging and may have a profound impact on quality of life. The standard of therapy for primary biliary cholangitis, ursodeoxycholic acid, does not have a beneficial effect in cholestatic pruritus. Patients often do not respond to conventional therapies such as cholestyramine, rifampicin, opioid antagonists, and sertraline. These therapies lack long-term efficacy and have side effects. Patients who have not responded to these initial treatments can be considered for experimental therapies or clinical trials. This review outlines the current and emerging treatment modalities for patients with primary biliary cholangitis who have pruritus.

      Keywords

      Clinical Significance
      • Pruritus affects 60% to 70% of patients with primary biliary cholangitis.
      • Pruritus is a potentially debilitating symptom that directly reduces the quality of life.
      • Conventional therapies are limited by adverse effects and lack of long-term efficacy, making pruritus a challenging symptom to treat.
      • Clinicians should be aware of the emerging experimental therapies to reduce pruritus and optimize the quality of life in patients with primary biliary cholangitis.
      Primary biliary cholangitis is an immune-mediated, cholestatic condition associated with debilitating symptoms. Approximately 60% to 70% of patients with primary biliary cholangitis experience pruritus, a potentially incapacitating symptom.
      • Hegade V.S.
      • Mells G.F.
      • Beuers U.
      • et al.
      Patient experience and characteristics of cholestatic pruritus in the UK-PBC research cohort.
      • Hegade V.S.
      • Mells G.F.
      • Lammert C.
      • et al.
      A comparative study of pruritus in PBC cohorts from UK, USA and Italy.
      It can occur at any stage and significantly affects quality of life.
      • Beuers U.
      • Boberg K.M.
      • Chapman R.W.
      • et al.
      EASL Clinical practice guidelines: management of cholestatic liver diseases.
      • Mells G.F.
      • Pells G.
      • Newton J.L.
      • et al.
      Impact of primary biliary cirrhosis on perceived quality of life: the UK-PBC national study.
      Pruritus leads to severe fatigue, sleep disturbance, depression, and suicidal tendencies.
      • Mells G.F.
      • Pells G.
      • Newton J.L.
      • et al.
      Impact of primary biliary cirrhosis on perceived quality of life: the UK-PBC national study.
      These often unbearable symptoms require close follow-up with a focused and multidisciplinary management approach in addition to pharmacologic intervention. A heightened awareness of the treatment modalities for pruritus in primary biliary cholangitis is imperative for the treating clinician to optimize the quality of life for their patients.
      Pharmacologic therapy is the main treatment modality for pruritus in primary biliary cholangitis. Ursodeoxycholic acid, the current standard of therapy for primary biliary cholangitis, is not effective in the treatment of pruritus.
      • Beuers U.
      • Boberg K.M.
      • Chapman R.W.
      • et al.
      EASL Clinical practice guidelines: management of cholestatic liver diseases.
      The treatments that are used in the management of pruritus in primary biliary cholangitis include bile acid sequestrants, rifampicin, opioid antagonists, and sertraline.
      • Beuers U.
      • Boberg K.M.
      • Chapman R.W.
      • et al.
      EASL Clinical practice guidelines: management of cholestatic liver diseases.
      Although recommended by the American Association for the Study of Liver Disease and European Association for the Study of the Liver, these medications often are limited by their adverse effects and lack of efficacy. Alternate therapies must be considered in patients who have pruritus refractory to these treatments. This article reviews the literature of the current and emerging treatments for pruritus in primary biliary cholangitis.

      Pathogenesis of Pruritus in Primary Biliary Cholangitis

      The pathogenesis of pruritus within primary biliary cholangitis is multifaceted. Bile acids are thought to play a prominent role in mediating cholestatic pruritus. The uptake of bile acids in the ileum is increased in cholestatic environments.
      • Lanzini A.
      • De Tavonatti M.G.
      • Panarotto B.
      • et al.
      Intestinal absorption of the bile acid analogue 75Se-homocholic acid-taurine is increased in primary biliary cirrhosis, and reverts to normal during ursodeoxycholic acid administration.
      These bile acids are brought back to the liver through the portal venous system and act as pruritogens, which may diffuse from the systemic circulation to the skin.
      • Lanzini A.
      • De Tavonatti M.G.
      • Panarotto B.
      • et al.
      Intestinal absorption of the bile acid analogue 75Se-homocholic acid-taurine is increased in primary biliary cirrhosis, and reverts to normal during ursodeoxycholic acid administration.
      Sensory neurons associated with itch contain a plasma membrane receptor called “TGR5,” which is activated by bile acids and may play a role in cholestatic pruritus.
      • Alemi F.
      • Kwon E.
      • Poole D.P.
      • et al.
      The TGR5 receptor mediates bile acid-induced itch and analgesia.
      • Lieu T.
      • Jayaweera G.
      • Zhao P.
      • et al.
      The bile acid receptor TGR5 activates the TRPA1 channel to induce itch in mice.
      Additional mechanisms of cholestatic pruritus have been proposed. One explanation involves the lysophosphatidic acid and autotaxin pathway. Lysophosphatidic acid is formed from lysophosphatidylcholine by the enzyme autotaxin.
      • Kremer A.E.
      • Martens J.J.
      • Kulik W.
      • et al.
      Autotaxin but not bile salts correlate with itch intensity in cholestasis.
      Autotaxin levels have been found to correlate with the intensity of pruritus in cholestasis compared with those without pruritus (P <.0001).
      • Kremer A.E.
      • Martens J.J.
      • Kulik W.
      • et al.
      Autotaxin but not bile salts correlate with itch intensity in cholestasis.
      As a result, lysophosphatidic acid, a pruritogen, is increased in patients with cholestatic liver diseases and pruritus.
      • Kremer A.E.
      • Martens J.J.
      • Kulik W.
      • et al.
      Autotaxin but not bile salts correlate with itch intensity in cholestasis.
      Serum autotaxin levels can be measured to determine the therapeutic effect of antipruritic agents in cholestasis.
      • Kremer A.E.
      • Kuiper E.M.
      • Leckie P.
      • et al.
      Autotaxin levels mirror efficacy of treatment of cholestatic pruritus.
      Other mechanisms exist, but are beyond the scope of this review.

      Initial Management of Pruritus

      The management of pruritus in primary biliary cholangitis is a sequential process with multiple steps. As an often presenting symptom of primary biliary cholangitis, pruritus is debilitating and leads to fatigue with sleep disturbance. It is estimated that 20% to 70% of patients with primary biliary cholangitis develop pruritus at some point in their illness,
      • Beuers U.
      • Boberg K.M.
      • Chapman R.W.
      • et al.
      EASL Clinical practice guidelines: management of cholestatic liver diseases.
      • Lindor K.D.
      • Gershwin M.E.
      • Poupon R.
      • Kaplan M.
      • Bergasa N.V.
      • Heathcote E.J.
      Primary biliary cirrhosis.
      and 75% of patients have pruritus preceding their diagnosis.
      • Rishe E.
      • Azarm A.
      • Bergasa N.V.
      Itch in primary biliary cirrhosis: a patients' perspective.
      Regardless of its onset, the management of pruritus requires a multidimensional approach before initiating pharmacologic interventions.

      Initial Evaluation

      Pruritus is a common manifestation of other systemic illnesses. Initially, an evaluation for other causes of pruritus must be considered. These conditions include renal failure, psoriasis, atopic dermatitis, and a number of other diseases. Once the pruritus is determined to be secondary to primary biliary cholangitis, a multidisciplinary approach should be instituted to facilitate its treatment.

      Quality of Life Assessment

      A large proportion of patients with primary biliary cholangitis experience debilitating symptoms, which causes a dramatic impact on quality of life.
      • Beuers U.
      • Boberg K.M.
      • Chapman R.W.
      • et al.
      EASL Clinical practice guidelines: management of cholestatic liver diseases.
      • Mells G.F.
      • Pells G.
      • Newton J.L.
      • et al.
      Impact of primary biliary cirrhosis on perceived quality of life: the UK-PBC national study.
      • Poupon R.E.
      • Chrétien Y.
      • Chazouillères O.
      • Poupon R.
      • Chwalow J.
      Quality of life in patients with primary biliary cirrhosis.
      The symptoms that impair quality of life in patients with primary biliary cholangitis include pruritus, fatigue, cognitive decline, social and emotional dysfunction, sleep disturbance, and depression.
      • Mells G.F.
      • Pells G.
      • Newton J.L.
      • et al.
      Impact of primary biliary cirrhosis on perceived quality of life: the UK-PBC national study.
      In a large UK primary biliary cholangitis national cohort study, impaired health status and the perception of a poor quality of life were noted in 46% and 35% of patients with primary biliary cholangitis, respectively, compared with their age-matched and sex-matched control groups (15% and 5%, respectively, P <.0001 for both).
      • Mells G.F.
      • Pells G.
      • Newton J.L.
      • et al.
      Impact of primary biliary cirrhosis on perceived quality of life: the UK-PBC national study.
      Fatigue and depression had a significant impact on quality of life.
      • Mells G.F.
      • Pells G.
      • Newton J.L.
      • et al.
      Impact of primary biliary cirrhosis on perceived quality of life: the UK-PBC national study.
      Close follow-up and a multidisciplinary treatment approach to address issues of social isolation, cognitive decline, depression, and other associated symptoms are imperative in the overall management of primary biliary cholangitis.

      Assessment of the Severity of Pruritus

      Pruritus is a subjective symptom with individual threshold variations. Nonetheless, the monitoring of pruritus is essential to improve individual patient symptoms. The techniques used to measure the pruritus of primary biliary cholangitis in a research setting are grading scales or simple questionnaires, which can potentially be applied to a clinical scenario. The numeric grading scale, visual analogue scale, and 5-D itch scale are easy measuring tools but are not specific to primary biliary cholangitis. The PBC-40 and PBC-27 questionnaires are health-related quality of life assessment tools validated specifically for primary biliary cholangitis used commonly in clinical trials.
      • 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.
      • Montali L.
      • Tanaka A.
      • Riva P.
      • et al.
      A short version of a HRQoL questionnaire for Italian and Japanese patients with primary biliary cirrhosis.
      Of all of these modalities, the visual analogue scale is the most commonly used and grades the severity of pruritus by identifying a point on a line, which correlates to a numeric value between 0 and 10 (Figure 1).
      • Reich A.
      • Heisig M.
      • Phan N.Q.
      • et al.
      Visual analogue scale: evaluation of the instrument for the assessment of pruritus.
      Regardless of the technique chosen to monitor pruritus, the clinician should individualize the approach for each patient and practice the selected modality in a consistent manner.
      Figure thumbnail gr1
      Figure 1Visual analogue scale. 0 = no pruritus; 1-3 = mild pruritus; 4-6 = moderate pruritus; 7-8 = severe pruritus; 9-10 = very severe pruritus.

      Medical Therapies for Pruritus

      Pharmacologic interventions can be considered once the initial management of pruritus is undergone. Determining the best medical therapy remains challenging. Commonly used therapies have limitations and side effects, and should be instituted in a stepwise manner. Figure 2 illustrates a sequential approach in the treatment of pruritus in primary biliary cholangitis, and Table provides the essential features of the individual medical therapies along with their recommended dosages. Oftentimes, a combination approach with these therapies is required to minimize pruritus, improve efficacy, and optimize patient comfort.
      Figure thumbnail gr2
      Figure 2Stepwise approach to managing pruritus in primary biliary cholangitis. *Opioid antagonists include naltrexone and naloxone. **Experimental therapies include phototherapy, plasmapheresis, albumin dialysis, nasobiliary drainage, or clinical trials (all should be performed at a specialized facility).
      TableManagement of Pruritus in Primary Biliary Cholangitis
      DrugMechanismRecommended DosagesLimitationsReferences
      Cholestyramine
      Randomized controlled trials provide higher level of evidence for these agents.
      Removes pruritogenic substances4-16 g/d, given 2-4 h before or after UDCADiarrhea, constipation, bloating, unpleasant taste
      • Lindor K.D.
      • Gershwin M.E.
      • Poupon R.
      • Kaplan M.
      • Bergasa N.V.
      • Heathcote E.J.
      Primary biliary cirrhosis.
      • Datta D.V.
      • Sherlock S.
      Cholestyramine for long term relief of the pruritus complicating intrahepatic cholestasis.
      • Van Itallie T.B.
      • Hashim S.A.
      • Crampton R.S.
      • Tennent D.M.
      The treatment of pruritus and hypercholesteremia of primary biliary cirrhosis with cholestyramine.
      Rifampicin
      Randomized controlled trials provide higher level of evidence for these agents.
      PXR agonist and enzyme inducer150-300 mg twice dailyHepatic failure, renal failure, hemolysis, and drug interactions
      • Lindor K.D.
      • Gershwin M.E.
      • Poupon R.
      • Kaplan M.
      • Bergasa N.V.
      • Heathcote E.J.
      Primary biliary cirrhosis.
      • Tandon P.
      • Rowe B.H.
      • Vandermeer B.
      • Bain V.G.
      The efficacy and safety of bile acid binding agents, opioid antagonists, or rifampin in the treatment of cholestasis-associated pruritus.
      • Khurana S.
      • Singh P.
      Rifampin is safe for treatment of pruritus due to chronic cholestasis: a meta-analysis of prospective randomized-controlled trials.
      • Talwalkar J.A.
      • Souto E.
      • Jorgensen R.A.
      • Lindor K.D.
      Natural history of pruritus in primary biliary cirrhosis.
      • Bachs L.
      • Pares A.
      • Elena M.
      • Piera C.
      • Rodes J.
      Comparison of rifampicin with phenobarbitone for treatment of pruritus in biliary cirrhosis.
      • Prince M.I.
      • Burt A.D.
      • Jones D.E.
      Hepatitis and liver dysfunction with rifampicin therapy for pruritus in primary biliary cirrhosis.
      • Podesta A.
      • Lopez P.
      • Terg R.
      • et al.
      Treatment of pruritus of primary biliary cirrhosis with rifampin.
      Opiate antagonists (naltrexone, naloxone)
      Randomized controlled trials provide higher level of evidence for these agents.
      Reduces opiodergic tone in cholestasisNaltrexone: 50 mg/dOpioid withdrawal-like reaction

      Rare: hepatotoxicity
      • Lindor K.D.
      • Gershwin M.E.
      • Poupon R.
      • Kaplan M.
      • Bergasa N.V.
      • Heathcote E.J.
      Primary biliary cirrhosis.
      • Tandon P.
      • Rowe B.H.
      • Vandermeer B.
      • Bain V.G.
      The efficacy and safety of bile acid binding agents, opioid antagonists, or rifampin in the treatment of cholestasis-associated pruritus.
      • Terg R.
      • Coronel E.
      • Sorda J.
      • Munoz A.E.
      • Findor J.
      Efficacy and safety of oral naltrexone treatment for pruritus of cholestasis, a crossover, double blind, placebo-controlled study.
      • Bergasa N.V.
      • Alling D.W.
      • Talbot T.L.
      • et al.
      Effects of naloxone infusions in patients with the pruritus of cholestasis. A double-blind, randomized, controlled trial.
      • Bergasa N.V.
      • Jones E.A.
      The pruritus of cholestasis: potential pathogenic and therapeutic implications of opioids.
      • Wolfhagen F.H.
      • Sternieri E.
      • Hop W.C.
      • Vitale G.
      • Bertolotti M.
      • Van Buuren H.R.
      Oral naltrexone treatment for cholestatic pruritus: a double-blind, placebo-controlled study.
      • Mansour-Ghanaei F.
      • Taheri A.
      • Froutan H.
      • et al.
      Effect of oral naltrexone on pruritus in cholestatic patients.
      • Krystal J.H.
      • Cramer J.A.
      • Krol W.F.
      • Kirk G.F.
      • Rosenheck R.A.
      Naltrexone in the treatment of alcohol dependence.
      • Mitchell J.E.
      Naltrexone and hepatotoxicity.
      SSRI
      Randomized controlled trials provide higher level of evidence for these agents.
      Affects serotonergic pathwaysSertraline: 75-100 mg/dMinimal: dizziness, insomnia, loose stools
      • Lindor K.D.
      • Gershwin M.E.
      • Poupon R.
      • Kaplan M.
      • Bergasa N.V.
      • Heathcote E.J.
      Primary biliary cirrhosis.
      • Mayo M.J.
      • Handem I.
      • Saldana S.
      • Jacobe H.
      • Getachew Y.
      • Rush A.J.
      Sertraline as a first-line treatment for cholestatic pruritus.
      • Zylicz Z.
      • Krajnik M.
      • Sorge A.A.
      • Costantini M.
      Paroxetine in the treatment of severe non-dermatological pruritus: a randomized, controlled trial.
      Experimental therapies
      TherapyMechanismPruritus ReliefStatistical SignificanceReferences
      VAS (or GS) BeforeVAS (or GS) After
      PhototherapyUnknown8.02.0P <.001
      • Decock S.
      • Roelandts R.
      • Steenbergen W.V.
      • et al.
      Cholestasis-induced pruritus treated with ultraviolet B phototherapy: an observational case series study.
      PlasmapheresisRemoves pruritogens8.3 ± 1.4 (GS)3.1 ± 2.2 (GS)P <.0001
      • Krawczyk M.
      • Liebe R.
      • Wasilewicz M.
      • Wunsch E.
      • Raszeja-Wyszomirska J.
      • Milkiewicz P.
      Effects of plasmapheresis on pruritus in patients with PBC: Prospective analysis of 121 procedures performed in a single center.
      Albumin dialysisRemoves pruritogens70.2 ± 4.820.1 ± 4.2P <.001
      • Pares A.
      • Herrera M.
      • Aviles J.
      • Sanz M.
      • Mas A.
      Treatment of resistant pruritus from cholestasis with albumin dialysis: combined analysis of patients from three centers.
      Nasobiliary drainageReduces circulating bile10.00.3P <.0001
      • Hegade V.S.
      • Krawczyk M.
      • Kremer A.E.
      • et al.
      The safety and efficacy of nasobiliary drainage in the treatment of refractory cholestatic pruritus: a multicentre European study.
      FibratesActs of PPAR family4.4 ± 0.50.8 ± 0.2P <.001
      • Reig A.
      • Sese P.
      • Pares A.
      Bezafibrate: a novel and effective alternative for relieving pruritus in patients with primary biliary cirrhosis.
      GS = grading scale; PPAR = peroxisome proliferator activated receptor; PXR = pregnane X receptor; SSRI = selective serotonin reuptake inhibitor; UDCA = ursodeoxycholic acid; VAS = visual analogue scale.
      Randomized controlled trials provide higher level of evidence for these agents.

      Bile Acid Binding Resins

      Bile acid binding resins are often used for pruritus in primary biliary cholangitis. Cholestyramine is recommended as first-line therapy.
      • Beuers U.
      • Boberg K.M.
      • Chapman R.W.
      • et al.
      EASL Clinical practice guidelines: management of cholestatic liver diseases.
      • Lindor K.D.
      • Gershwin M.E.
      • Poupon R.
      • Kaplan M.
      • Bergasa N.V.
      • Heathcote E.J.
      Primary biliary cirrhosis.
      • Datta D.V.
      • Sherlock S.
      Cholestyramine for long term relief of the pruritus complicating intrahepatic cholestasis.
      • Oster Z.H.
      • Rachmile E.A.
      • Moran E.
      • Stein Y.
      Relief of pruritus by cholestyramine in chronic liver disease.
      It has been proposed to exert its antipruritic effects by decreasing the reabsorption of bile acids and reducing their levels in the systemic circulation.
      An antipruritic agent for primary biliary cirrhosis and cholestatic jaundice. Cholestyramine resin (cuemid).
      In one study, microporous cholestyramine was associated with a significant reduction in itch intensity (P <.01) and serum bile acids (P <.01).
      • Di Padova C.
      • Tritapepe R.
      • Rovagnati P.
      • Rossetti S.
      Double-blind placebo-controlled clinical trial of microporous cholestyramine in the treatment of intra- and extra-hepatic cholestasis: relationship between itching and serum bile acids.
      A systematic review evaluated the 2 randomized controlled trials that studied cholestyramine and found the data to be insufficient to determine efficacy due to heterogeneity.
      • Tandon P.
      • Rowe B.H.
      • Vandermeer B.
      • Bain V.G.
      The efficacy and safety of bile acid binding agents, opioid antagonists, or rifampin in the treatment of cholestasis-associated pruritus.
      Its associated side effects include an unpleasant taste, diarrhea, constipation, and bloating.
      • Lindor K.D.
      • Gershwin M.E.
      • Poupon R.
      • Kaplan M.
      • Bergasa N.V.
      • Heathcote E.J.
      Primary biliary cirrhosis.
      • Datta D.V.
      • Sherlock S.
      Cholestyramine for long term relief of the pruritus complicating intrahepatic cholestasis.
      • Van Itallie T.B.
      • Hashim S.A.
      • Crampton R.S.
      • Tennent D.M.
      The treatment of pruritus and hypercholesteremia of primary biliary cirrhosis with cholestyramine.
      It also can interfere with absorption of other medications and therefore be given 2 to 4 hours before or after ursodeoxycholic acid.
      • Lindor K.D.
      • Gershwin M.E.
      • Poupon R.
      • Kaplan M.
      • Bergasa N.V.
      • Heathcote E.J.
      Primary biliary cirrhosis.

      Rifampicin

      Rifampicin also has shown benefit in treating cholestatic pruritus.
      • Tandon P.
      • Rowe B.H.
      • Vandermeer B.
      • Bain V.G.
      The efficacy and safety of bile acid binding agents, opioid antagonists, or rifampin in the treatment of cholestasis-associated pruritus.
      • Khurana S.
      • Singh P.
      Rifampin is safe for treatment of pruritus due to chronic cholestasis: a meta-analysis of prospective randomized-controlled trials.
      It can be considered in those who are intolerant or refractory to bile-acid binding resins.
      • Beuers U.
      • Boberg K.M.
      • Chapman R.W.
      • et al.
      EASL Clinical practice guidelines: management of cholestatic liver diseases.
      Its safety and efficacy have been proven in randomized controlled trials and 2 separate meta-analyses.
      • Tandon P.
      • Rowe B.H.
      • Vandermeer B.
      • Bain V.G.
      The efficacy and safety of bile acid binding agents, opioid antagonists, or rifampin in the treatment of cholestasis-associated pruritus.
      • Khurana S.
      • Singh P.
      Rifampin is safe for treatment of pruritus due to chronic cholestasis: a meta-analysis of prospective randomized-controlled trials.
      In a double-blind, randomized, crossover trial, rifampicin was associated with a significant reduction in the visual analogue scale score (P <.002).
      • Ghent C.N.
      • Carruthers S.G.
      Treatment of pruritus in primary biliary cirrhosis with rifampin. Results of a double-blind, crossover, randomized trial.
      In 1 meta-analysis consisting of 5 randomized control trials with 61 total patients, treatment with rifampicin led to complete resolution of pruritus in 77% of the patients and partial resolution in 20% of the patients (odds ratio, 5.2; confidence interval, 5.2-45.6; P = .001).
      • Khurana S.
      • Singh P.
      Rifampin is safe for treatment of pruritus due to chronic cholestasis: a meta-analysis of prospective randomized-controlled trials.
      The adverse effects of rifampicin, which occasionally limit its use, include hepatotoxicity, nephrotoxicity, hemolysis, and drug interactions.
      • Talwalkar J.A.
      • Souto E.
      • Jorgensen R.A.
      • Lindor K.D.
      Natural history of pruritus in primary biliary cirrhosis.
      • Bachs L.
      • Pares A.
      • Elena M.
      • Piera C.
      • Rodes J.
      Comparison of rifampicin with phenobarbitone for treatment of pruritus in biliary cirrhosis.
      • Prince M.I.
      • Burt A.D.
      • Jones D.E.
      Hepatitis and liver dysfunction with rifampicin therapy for pruritus in primary biliary cirrhosis.
      It is unclear which patient population is susceptible to these adverse reactions. However, short-term use of rifampicin is associated with a low risk of hepatotoxicity.
      • Khurana S.
      • Singh P.
      Rifampin is safe for treatment of pruritus due to chronic cholestasis: a meta-analysis of prospective randomized-controlled trials.
      The guidelines recommend routine monitoring of liver function tests and blood counts to screen for adverse reactions during rifampicin therapy.
      • Lindor K.D.
      • Gershwin M.E.
      • Poupon R.
      • Kaplan M.
      • Bergasa N.V.
      • Heathcote E.J.
      Primary biliary cirrhosis.

      Opioid Antagonists

      An increase in opioidergic tone has been observed in patients with pruritus.
      • Ballantyne J.C.
      • Loach A.B.
      • Carr D.B.
      The incidence of pruritus after epidural morphine.
      This has culminated in the use of opioid antagonists as a therapeutic approach to cholestatic pruritus. In one study using naltrexone, the mean daytime visual analogue scale reduced from 6.29 ± 2.28 to 3.55 ± 2.39 (P = .0003) and the night-time visual analogue scale reduced from 5.89 ± 2.49 to 3.55 ± 2.42 (P = .001).
      • Terg R.
      • Coronel E.
      • Sorda J.
      • Munoz A.E.
      • Findor J.
      Efficacy and safety of oral naltrexone treatment for pruritus of cholestasis, a crossover, double blind, placebo-controlled study.
      In a meta-analysis with a total of 84 patients, oral agents (naltrexone and nalmefene) and intravenous naloxone significantly decreased pruritus compared with the control intervention (standardized mean difference, −1.62; 95% confidence interval, −3.05 to −0.18).
      • Tandon P.
      • Rowe B.H.
      • Vandermeer B.
      • Bain V.G.
      The efficacy and safety of bile acid binding agents, opioid antagonists, or rifampin in the treatment of cholestasis-associated pruritus.
      A notable adverse effect associated with these medications is an opiate withdrawal-like reaction, which consists of hypertension, tachycardia, piloerection, abdominal pain, and neuropsychiatric symptoms.
      • Bergasa N.V.
      • Alling D.W.
      • Talbot T.L.
      • et al.
      Effects of naloxone infusions in patients with the pruritus of cholestasis. A double-blind, randomized, controlled trial.
      • Thornton J.R.
      • Losowsky M.S.
      Opioid peptides and primary biliary cirrhosis.
      • Bergasa N.V.
      • Alling D.W.
      • Talbot T.L.
      • Wells M.C.
      • Jones E.A.
      Oral nalmefene therapy reduces scratching activity due to the pruritus of cholestasis: a controlled study.
      • Bergasa N.V.
      • Schmitt J.M.
      • Talbot T.L.
      • et al.
      Open-label trial of oral nalmefene therapy for the pruritus of cholestasis.
      Patients with a more severe form of pruritus and higher opioidergic tone might be at higher risk for this reaction, although this has not been studied. If there is concern for this reaction, patients can be observed as an inpatient while starting intravenous naloxone and subsequently transitioning to an oral regimen before discharge if it is well tolerated.
      • Lindor K.D.
      • Gershwin M.E.
      • Poupon R.
      • Kaplan M.
      • Bergasa N.V.
      • Heathcote E.J.
      Primary biliary cirrhosis.

      Sertraline

      The serotonergic pathway also may play a role in the process of cholestasis pruritus.
      • Mayo M.J.
      • Handem I.
      • Saldana S.
      • Jacobe H.
      • Getachew Y.
      • Rush A.J.
      Sertraline as a first-line treatment for cholestatic pruritus.
      • Browning J.
      • Combes B.
      • Mayo M.J.
      Long-term efficacy of sertraline as a treatment for cholestatic pruritus in patients with primary biliary cirrhosis.
      Sertraline, a selective serotonin reuptake inhibitor used mainly as an antidepressant, had a noteworthy effect in cholestatic pruritus in 2 trials.
      • Mayo M.J.
      • Handem I.
      • Saldana S.
      • Jacobe H.
      • Getachew Y.
      • Rush A.J.
      Sertraline as a first-line treatment for cholestatic pruritus.
      • Browning J.
      • Combes B.
      • Mayo M.J.
      Long-term efficacy of sertraline as a treatment for cholestatic pruritus in patients with primary biliary cirrhosis.
      In one study, patients in the sertraline group improved by a mean of 1.86 points on the visual analogue scale, whereas those taking placebo worsened by 0.38 points (P = .009).
      • Mayo M.J.
      • Handem I.
      • Saldana S.
      • Jacobe H.
      • Getachew Y.
      • Rush A.J.
      Sertraline as a first-line treatment for cholestatic pruritus.
      The effect of sertraline on pruritus relief was independent from an improvement of depression.
      • Mayo M.J.
      • Handem I.
      • Saldana S.
      • Jacobe H.
      • Getachew Y.
      • Rush A.J.
      Sertraline as a first-line treatment for cholestatic pruritus.
      Overall, sertraline was well tolerated with only a few patients experiencing mild side effects, such as dizziness, loose stools, and insomnia.
      • Mayo M.J.
      • Handem I.
      • Saldana S.
      • Jacobe H.
      • Getachew Y.
      • Rush A.J.
      Sertraline as a first-line treatment for cholestatic pruritus.
      This therapy requires further investigation.
      • Lindor K.D.
      • Gershwin M.E.
      • Poupon R.
      • Kaplan M.
      • Bergasa N.V.
      • Heathcote E.J.
      Primary biliary cirrhosis.

      Experimental Therapies for Pruritus

      Patients who have pruritus refractory to the conventional therapies should be managed by a specialist and considered for experimental treatments. These interventions are regarded as salvage therapies and are available in only a limited number of centers. Enrollment of patients into clinical trials also should be contemplated when these interventions are being considered.

      Phototherapy

      Ultraviolet B phototherapy exerts antipruritic effects through an unknown mechanism. In an observational case series, the median visual analogue scale score before and after treatment with phototherapy decreased from 8.0 to 2.0 (P <.001).
      • Decock S.
      • Roelandts R.
      • Steenbergen W.V.
      • et al.
      Cholestasis-induced pruritus treated with ultraviolet B phototherapy: an observational case series study.
      The mean number of treatments that were required to achieve a significant reduction in pruritus was 26 ± 17, with the average duration of phototherapy being 8 weeks.
      • Decock S.
      • Roelandts R.
      • Steenbergen W.V.
      • et al.
      Cholestasis-induced pruritus treated with ultraviolet B phototherapy: an observational case series study.
      This therapy was well tolerated with only 1 patient developing erythema and another developing paresthesias.
      • Decock S.
      • Roelandts R.
      • Steenbergen W.V.
      • et al.
      Cholestasis-induced pruritus treated with ultraviolet B phototherapy: an observational case series study.

      Plasmapheresis

      Plasmapheresis also may have a role in patients with primary biliary cholangitis and debilitating pruritus.
      • Cohen L.B.
      • Ambinder E.P.
      • Wolke A.M.
      Role of plasmapheresis in primary biliary cirrhosis.
      It removes pruritogens from the systemic circulation and reduces pruritus.
      • Kremer A.E.
      • Namer B.
      • Bolier R.
      • Fischer M.J.
      • Oude Elferink R.P.
      • Beuers U.
      Pathogenesis and management of pruritus in PBC and PSC.
      A recent study with 17 patients with primary biliary cholangitis (9 with cirrhosis) showed a mean decrease in pruritus score on a 10-point numeric scale from 8.3 ± 1.4 to 3.1 ± 2.2 (P <.0001).
      • Krawczyk M.
      • Liebe R.
      • Wasilewicz M.
      • Wunsch E.
      • Raszeja-Wyszomirska J.
      • Milkiewicz P.
      Plasmapheresis exerts a long-lasting antipruritic effect in severe cholestatic itch.
      The antipruritic effect lasted throughout the 90-day follow-up period (P <.0001) and was not affected by the presence of cirrhosis.
      • Krawczyk M.
      • Liebe R.
      • Wasilewicz M.
      • Wunsch E.
      • Raszeja-Wyszomirska J.
      • Milkiewicz P.
      Plasmapheresis exerts a long-lasting antipruritic effect in severe cholestatic itch.

      Albumin Dialysis

      Albumin dialysis using molecular adsorbent recirculating system can be considered in uncontrollable cholestatic pruritus, although long-term data are lacking. Similar to plasmapheresis, molecular adsorbent recirculating system exerts its antipruritic effects by removing pruritogens from the systemic circulation.
      • Kremer A.E.
      • Namer B.
      • Bolier R.
      • Fischer M.J.
      • Oude Elferink R.P.
      • Beuers U.
      Pathogenesis and management of pruritus in PBC and PSC.
      In a study of 21 patients with cholestatic liver disease, the visual analogue scale score decreased from 70.2 ± 4.8 to 20.1 ± 4.2 (P <.001).
      • Pares A.
      • Herrera M.
      • Aviles J.
      • Sanz M.
      • Mas A.
      Treatment of resistant pruritus from cholestasis with albumin dialysis: combined analysis of patients from three centers.
      Overall, the visual analogue scale score decreased by 72% immediately after treatment and by 51% 1 month after treatment.
      • Pares A.
      • Herrera M.
      • Aviles J.
      • Sanz M.
      • Mas A.
      Treatment of resistant pruritus from cholestasis with albumin dialysis: combined analysis of patients from three centers.
      No major adverse effects were noted in any of the patients.
      • Pares A.
      • Herrera M.
      • Aviles J.
      • Sanz M.
      • Mas A.
      Treatment of resistant pruritus from cholestasis with albumin dialysis: combined analysis of patients from three centers.
      In another study with 15 patients, the visual analogue scale and itch severity scale improved significantly (P <.001).
      • Leckie P.
      • Tritto G.
      • Mookerjee R.
      • Davies N.
      • Jones D.
      • Jalan R.
      ‘Out-patient’ albumin dialysis for cholestatic patients with intractable pruritus.
      It was safe and associated with an immediate and complete response in 11 of the patients.
      • Leckie P.
      • Tritto G.
      • Mookerjee R.
      • Davies N.
      • Jones D.
      • Jalan R.
      ‘Out-patient’ albumin dialysis for cholestatic patients with intractable pruritus.
      In the remaining 4 patients, 2 had a partial response and 2 had no response.
      • Leckie P.
      • Tritto G.
      • Mookerjee R.
      • Davies N.
      • Jones D.
      • Jalan R.
      ‘Out-patient’ albumin dialysis for cholestatic patients with intractable pruritus.

      Nasobiliary Drainage

      Nasobiliary drainage of bile salts reduces pruritus and serum autotaxin levels, but effects are only transient.
      • Kremer A.E.
      • Martens J.J.
      • Kulik W.
      • et al.
      Autotaxin but not bile salts correlate with itch intensity in cholestasis.
      • Kremer A.E.
      • Kuiper E.M.
      • Leckie P.
      • et al.
      Autotaxin levels mirror efficacy of treatment of cholestatic pruritus.
      • Kremer A.E.
      • Martens J.J.
      • Kulik W.
      • et al.
      Autotaxin is a potential mediator of cholestatic pruritus.
      In one study, it decreased pruritus by 80% (P <.01).
      • Kremer A.E.
      • Kuiper E.M.
      • Leckie P.
      • et al.
      Autotaxin levels mirror efficacy of treatment of cholestatic pruritus.
      In another multicenter retrospective study, nasobiliary drainage reduced pruritus in 89.6% of cases with the visual analogue scale score decreasing from 10.0 to 0.3 (P <.0001).
      • Hegade V.S.
      • Krawczyk M.
      • Kremer A.E.
      • et al.
      The safety and efficacy of nasobiliary drainage in the treatment of refractory cholestatic pruritus: a multicentre European study.
      Significant reductions in alkaline phosphatase levels (P = .001) and serum bilirubin (P = .03) were noted, but not in total serum bile salts.
      • Hegade V.S.
      • Krawczyk M.
      • Kremer A.E.
      • et al.
      The safety and efficacy of nasobiliary drainage in the treatment of refractory cholestatic pruritus: a multicentre European study.
      The most commonly observed complication of nasobiliary drainage was mild after endoscopic retrograde cholangiopancreatography pancreatitis.
      • Hegade V.S.
      • Krawczyk M.
      • Kremer A.E.
      • et al.
      The safety and efficacy of nasobiliary drainage in the treatment of refractory cholestatic pruritus: a multicentre European study.

      Liver Transplantation

      Although the number of patients requiring liver transplantation for primary biliary cholangitis has declined, it remains the sixth leading indication in the United States.
      • Lindor K.D.
      • Gershwin M.E.
      • Poupon R.
      • Kaplan M.
      • Bergasa N.V.
      • Heathcote E.J.
      Primary biliary cirrhosis.
      Transplantation improves symptoms of pruritus and fatigue.
      • Lindor K.D.
      • Gershwin M.E.
      • Poupon R.
      • Kaplan M.
      • Bergasa N.V.
      • Heathcote E.J.
      Primary biliary cirrhosis.
      It should only be considered when all other measures have failed or if urgently required.
      • Lindor K.D.
      • Gershwin M.E.
      • Poupon R.
      • Kaplan M.
      • Bergasa N.V.
      • Heathcote E.J.
      Primary biliary cirrhosis.

      Ileal Bile Acid Transporter Inhibitors

      The ileal bile acid transporter inhibitors are a novel drug class currently undergoing investigation for pruritus in primary biliary cholangitis. Ileal bile acid transporter, also known as “apical sodium-dependent bile acid transporter,” is a protein in the terminal ileum that is responsible for the intestinal reabsorption of bile acids to the liver. Ileal bile acid transporter inhibitors reduce the reabsorption of bile acids, facilitating their excretion into the stool and disrupting the enterohepatic circulation.
      • Hegade V.S.
      • Kendrick S.F.W.
      • Dobbins R.L.
      • et al.
      BAT117213: ileal bile acid transporter (IBAT) inhibition as a treatment for pruritus in primary biliary cirrhosis: study protocol for a randomised controlled trial.
      Experimental studies have shown beneficial effects of ileal bile acid transporter inhibitors in cholestasis.
      • Baghdasaryan A.
      • Fuchs C.D.
      • Osterreicher C.H.
      • et al.
      Inhibition of intestinal bile acid absorption improves cholestatic liver and bile duct injury in a mouse model of sclerosing cholangitis.
      • Graffner H.
      • Gillberg P.G.
      • Rikner L.
      • Marschall H.U.
      The ileal bile acid transporter inhibitor A4250 decreases serum bile acids by interrupting the enterohepatic circulation.
      In a phase 2, multicenter, double-blinded, placebo-controlled, crossover trial presented at the American Association for the Study of Liver Disease in November of 2016, ileal bile acid transporter inhibitor was associated with a significant reduction in pruritus when compared with placebo.
      • Hegade V.S.
      • Kendrick S.F.W.
      • Dobbins R.L.
      • et al.
      BAT117213: ileal bile acid transporter (IBAT) inhibition as a treatment for pruritus in primary biliary cirrhosis: study protocol for a randomised controlled trial.
      The reduction in pruritus was noted using the following scales: numeric rating scale (−23% [−1% to −45%]), PBC-40 itch domain (−14% [−1% to −26%]), and 5-D itch (−20% [−7% to −34%]).
      • Hegade V.S.
      • Kendrick S.F.W.
      • Dobbins R.L.
      • et al.
      BAT117213: ileal bile acid transporter (IBAT) inhibition as a treatment for pruritus in primary biliary cirrhosis: study protocol for a randomised controlled trial.
      The use of the ileal bile acid transporter inhibitor also was associated with a decrease in total bile acid levels and autotaxin activity.
      • Hegade V.S.
      • Kendrick S.F.W.
      • Dobbins R.L.
      • et al.
      BAT117213: ileal bile acid transporter (IBAT) inhibition as a treatment for pruritus in primary biliary cirrhosis: study protocol for a randomised controlled trial.
      The adverse effects were mild and included diarrhea and headache.
      • Hegade V.S.
      • Kendrick S.F.W.
      • Dobbins R.L.
      • et al.
      BAT117213: ileal bile acid transporter (IBAT) inhibition as a treatment for pruritus in primary biliary cirrhosis: study protocol for a randomised controlled trial.
      Further investigation is required.

      Fibrates

      Recent evidence on fibrate therapy suggests that it improves biochemical parameters, such as alkaline phosphatase, in those who are unresponsive to ursodeoxycholic acid therapy
      • Lens S.
      • Leoz M.
      • Nazal L.
      • Bruguera M.
      • Pares A.
      Bezafibrate normalizes alkaline phosphatase in primary biliary cirrhosis patients with incomplete response to ursodeoxycholic acid.
      • Levy C.
      • Peter J.A.
      • Nelson D.R.
      • et al.
      Pilot study: fenofibrate for patients with primary biliary cirrhosis and an incomplete response to ursodeoxycholic acid.
      • Hazzan R.
      • Tur-Kaspa R.
      Bezafibrate treatment of primary biliary cirrhosis following incomplete response to ursodeoxycholic acid.
      and may have a possible antipruritic effect.
      • Reig A.
      • Sese P.
      • Pares A.
      Bezafibrate: a novel and effective alternative for relieving pruritus in patients with primary biliary cirrhosis.
      In a recent study of 46 patients with pruritus from ursodeoxycholic acid-refractory primary biliary cholangitis, there was a significant reduction in the visual analogue scale with the use of bezafibrate (from 4.4 ± 0.5 to 0.8 ± 0.2, P <.001).
      • Reig A.
      • Sese P.
      • Pares A.
      Bezafibrate: a novel and effective alternative for relieving pruritus in patients with primary biliary cirrhosis.
      This effect was only transient and dissipated once it was discontinued.
      • Reig A.
      • Sese P.
      • Pares A.
      Bezafibrate: a novel and effective alternative for relieving pruritus in patients with primary biliary cirrhosis.

      Methotrexate and Colchicine

      Methotrexate has shown benefit in treating pruritus.
      • Kaplan M.M.
      • Bonder A.
      • Ruthazer R.
      • Bonis P.A.
      Methotrexate in patients with primary biliary cirrhosis who respond incompletely to treatment with ursodeoxycholic acid.
      • Babatin M.A.
      • Sanai F.M.
      • Swain M.G.
      Methotrexate therapy for the symptomatic treatment of primary biliary cirrhosis patients, who are biochemical incomplete responders to ursodeoxycholic acid therapy.
      In 1 trial, pruritus had decreased significantly (P = .0001) in patients receiving combination therapy with ursodeoxycholic acid, colchicine, and methotrexate.
      • Kaplan M.M.
      • Bonder A.
      • Ruthazer R.
      • Bonis P.A.
      Methotrexate in patients with primary biliary cirrhosis who respond incompletely to treatment with ursodeoxycholic acid.
      However, colchicine for pruritus treatment remains controversial. One trial showed significant benefit (P = .001) compared with the placebo group,
      • Vuoristo M.
      • Färkkilä M.
      • Karvonen A.L.
      • et al.
      A placebo-controlled trial of primary biliary cirrhosis treatment with colchicine and ursodeoxycholic acid.
      whereas another study showed no difference.
      • Almasio P.L.
      • Floreani A.
      • Chiaramonte M.
      • et al.
      Multicentre randomized placebo-controlled trial of ursodeoxycholic acid with or without colchicine in symptomatic primary biliary cirrhosis.
      Further investigation of these therapies is required before clinical application.

      Obeticholic Acid–Induced Pruritus

      Obeticholic acid, a farnesoid X receptor agonist, is a recently approved medication that improves biochemical parameters in patients with primary biliary cholangitis and a suboptimal response to ursodeoxycholic acid.
      • Nevens F.
      • Andreone P.
      • Mazzella G.
      • et al.
      A placebo-controlled trial of obeticholic acid in primary biliary cholangitis.
      Pruritus is the most common side effect of obeticholic acid and requires dose adjustments. Certain pretreatment baseline characteristics have been found to be associated with higher risk of obeticholic acid–induced pruritus.
      • Malecha E.S.
      • Beuers U.
      • Liberman A.
      • Hooshmand-Rad R.
      • Peters Y.
      • Pencek R.
      Baseline factors predicting obeticholic acid induced pruritus in patients with PBC.
      These include higher baseline levels of gamma-glutamyl transferase, direct bilirubin, or alkaline phosphatase, as well as age at primary biliary cholangitis diagnosis and free triiodothyronine levels.
      • Malecha E.S.
      • Beuers U.
      • Liberman A.
      • Hooshmand-Rad R.
      • Peters Y.
      • Pencek R.
      Baseline factors predicting obeticholic acid induced pruritus in patients with PBC.
      In a phase III clinical trial called the POISE trial, the group that started off at a lower (5 mg) dose of obeticholic acid had the lowest risk of developing pruritus.
      • Nevens F.
      • Andreone P.
      • Mazzella G.
      • et al.
      A placebo-controlled trial of obeticholic acid in primary biliary cholangitis.
      Obeticholic acid can be reduced to 5 mg every other day for patients who were taking 5 mg daily and to 5 mg once per day to those who were taking 10 mg daily.
      Intercept Pharmaceuticals, I, Ocaliva (Obeticholic Acid) [Prescribing Information].
      Another option is to stop therapy completely and restart 2 weeks later at a lower dose.
      Intercept Pharmaceuticals, I, Ocaliva (Obeticholic Acid) [Prescribing Information].

      Conclusions

      Pruritus is a debilitating symptom of primary biliary cholangitis and dramatically affects the patient's quality of life.
      • Hegade V.S.
      • Mells G.F.
      • Beuers U.
      • et al.
      Patient experience and characteristics of cholestatic pruritus in the UK-PBC research cohort.
      • Hegade V.S.
      • Mells G.
      • Lammert C.
      • et al.
      A comparative study of cholestatic pruritus in primary biliary cirrhosis cohorts from USA, UK and Italy.
      It can lead to sleep disturbances, fatigue, depression, and suicidality.
      • Mells G.F.
      • Pells G.
      • Newton J.L.
      • et al.
      Impact of primary biliary cirrhosis on perceived quality of life: the UK-PBC national study.
      Ursodeoxycholic acid, the mainstay of therapy in primary biliary cholangitis, does not have an effect on pruritus.
      • Beuers U.
      • Boberg K.M.
      • Chapman R.W.
      • et al.
      EASL Clinical practice guidelines: management of cholestatic liver diseases.
      Although multiple therapies currently exist, their long-term antipruritic effects have yet to be established. These therapies often are ineffective and have adverse effects. In cases of refractory pruritus, patients should be referred to a specialized facility where they can be considered for experimental therapies or clinical trials. Liver transplantation should be considered only when all therapies have failed in patients with severe intractable pruritus.
      • Beuers U.
      • Boberg K.M.
      • Chapman R.W.
      • et al.
      EASL Clinical practice guidelines: management of cholestatic liver diseases.
      • Neuberger J.
      • Jones E.A.
      Liver transplantation for intractable pruritus is contraindicated before an adequate trial of opiate antagonist therapy.
      Treating pruritus in primary biliary cholangitis remains difficult. Despite the different therapeutic options, a significant proportion of patients are still experiencing this unbearable symptom.
      • Hegade V.S.
      • Mells G.F.
      • Beuers U.
      • et al.
      Patient experience and characteristics of cholestatic pruritus in the UK-PBC research cohort.
      • Hegade V.S.
      • Mells G.F.
      • Lammert C.
      • et al.
      A comparative study of pruritus in PBC cohorts from UK, USA and Italy.
      The absence of effective long-term therapeutic modalities is a result of the incomplete understanding behind the mechanism of cholestatic pruritus. Our ongoing learning of this multifaceted symptom will hopefully lead to the development of more effective therapies and improve the quality of life for patients with primary biliary cholangitis.

      References

        • Hegade V.S.
        • Mells G.F.
        • Beuers U.
        • et al.
        Patient experience and characteristics of cholestatic pruritus in the UK-PBC research cohort.
        Hepatology. 2014; 60: 362A-363A
        • Hegade V.S.
        • Mells G.F.
        • Lammert C.
        • et al.
        A comparative study of pruritus in PBC cohorts from UK, USA and Italy.
        J Hepatol. 2015; 62: S785
        • Beuers U.
        • Boberg K.M.
        • Chapman R.W.
        • et al.
        EASL Clinical practice guidelines: management of cholestatic liver diseases.
        J Hepatol. 2009; 51: 237-267
        • Mells G.F.
        • Pells G.
        • Newton J.L.
        • et al.
        Impact of primary biliary cirrhosis on perceived quality of life: the UK-PBC national study.
        Hepatology. 2013; 58: 273-283
        • Lanzini A.
        • De Tavonatti M.G.
        • Panarotto B.
        • et al.
        Intestinal absorption of the bile acid analogue 75Se-homocholic acid-taurine is increased in primary biliary cirrhosis, and reverts to normal during ursodeoxycholic acid administration.
        Gut. 2003; 52: 1371-1375
        • Alemi F.
        • Kwon E.
        • Poole D.P.
        • et al.
        The TGR5 receptor mediates bile acid-induced itch and analgesia.
        J Clin Invest. 2013; 123: 1513-1530
        • Lieu T.
        • Jayaweera G.
        • Zhao P.
        • et al.
        The bile acid receptor TGR5 activates the TRPA1 channel to induce itch in mice.
        Gastroenterology. 2014; 147: 1417-1428
        • Kremer A.E.
        • Martens J.J.
        • Kulik W.
        • et al.
        Autotaxin but not bile salts correlate with itch intensity in cholestasis.
        J Hepatol. 2010; 52: S1
        • Kremer A.E.
        • Kuiper E.M.
        • Leckie P.
        • et al.
        Autotaxin levels mirror efficacy of treatment of cholestatic pruritus.
        Hepatology. 2010; 52: 481A
        • Lindor K.D.
        • Gershwin M.E.
        • Poupon R.
        • Kaplan M.
        • Bergasa N.V.
        • Heathcote E.J.
        Primary biliary cirrhosis.
        Hepatology. 2009; 50: 291-308
        • Rishe E.
        • Azarm A.
        • Bergasa N.V.
        Itch in primary biliary cirrhosis: a patients' perspective.
        Acta Derm Venereol. 2008; 88: 34-37
        • Poupon R.E.
        • Chrétien Y.
        • Chazouillères O.
        • Poupon R.
        • Chwalow J.
        Quality of life in patients with primary biliary cirrhosis.
        Hepatology. 2004; 40: 489-494
        • 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: 1622-1629
        • Montali L.
        • Tanaka A.
        • Riva P.
        • et al.
        A short version of a HRQoL questionnaire for Italian and Japanese patients with primary biliary cirrhosis.
        Dig Liver Dis. 2010; 42: 718-723
        • Reich A.
        • Heisig M.
        • Phan N.Q.
        • et al.
        Visual analogue scale: evaluation of the instrument for the assessment of pruritus.
        Acta Derm Venereol. 2012; 92: 497-501
        • Datta D.V.
        • Sherlock S.
        Cholestyramine for long term relief of the pruritus complicating intrahepatic cholestasis.
        Gastroenterology. 1966; 50: 323-332
        • Van Itallie T.B.
        • Hashim S.A.
        • Crampton R.S.
        • Tennent D.M.
        The treatment of pruritus and hypercholesteremia of primary biliary cirrhosis with cholestyramine.
        N Engl J Med. 1961; 265: 469-474
        • Tandon P.
        • Rowe B.H.
        • Vandermeer B.
        • Bain V.G.
        The efficacy and safety of bile acid binding agents, opioid antagonists, or rifampin in the treatment of cholestasis-associated pruritus.
        Am J Gastroenterol. 2007; 102: 1528-1536
        • Khurana S.
        • Singh P.
        Rifampin is safe for treatment of pruritus due to chronic cholestasis: a meta-analysis of prospective randomized-controlled trials.
        Liver Int. 2006; 26: 943-948
        • Talwalkar J.A.
        • Souto E.
        • Jorgensen R.A.
        • Lindor K.D.
        Natural history of pruritus in primary biliary cirrhosis.
        Clin Gastroenterol Hepatol. 2003; 1: 297-302
        • Bachs L.
        • Pares A.
        • Elena M.
        • Piera C.
        • Rodes J.
        Comparison of rifampicin with phenobarbitone for treatment of pruritus in biliary cirrhosis.
        Lancet. 1989; 1: 574-576
        • Prince M.I.
        • Burt A.D.
        • Jones D.E.
        Hepatitis and liver dysfunction with rifampicin therapy for pruritus in primary biliary cirrhosis.
        Gut. 2002; 50: 436-439
        • Podesta A.
        • Lopez P.
        • Terg R.
        • et al.
        Treatment of pruritus of primary biliary cirrhosis with rifampin.
        Dig Dis Sci. 1991; 36: 216-220
        • Terg R.
        • Coronel E.
        • Sorda J.
        • Munoz A.E.
        • Findor J.
        Efficacy and safety of oral naltrexone treatment for pruritus of cholestasis, a crossover, double blind, placebo-controlled study.
        J Hepatol. 2002; 37: 717-722
        • Bergasa N.V.
        • Alling D.W.
        • Talbot T.L.
        • et al.
        Effects of naloxone infusions in patients with the pruritus of cholestasis. A double-blind, randomized, controlled trial.
        Ann Intern Med. 1995; 123: 161-167
        • Bergasa N.V.
        • Jones E.A.
        The pruritus of cholestasis: potential pathogenic and therapeutic implications of opioids.
        Gastroenterology. 1995; 108: 1582-1588
        • Wolfhagen F.H.
        • Sternieri E.
        • Hop W.C.
        • Vitale G.
        • Bertolotti M.
        • Van Buuren H.R.
        Oral naltrexone treatment for cholestatic pruritus: a double-blind, placebo-controlled study.
        Gastroenterology. 1997; 113: 1264-1269
        • Mansour-Ghanaei F.
        • Taheri A.
        • Froutan H.
        • et al.
        Effect of oral naltrexone on pruritus in cholestatic patients.
        World J Gastroenterol. 2006; 12: 1125-1128
        • Krystal J.H.
        • Cramer J.A.
        • Krol W.F.
        • Kirk G.F.
        • Rosenheck R.A.
        Naltrexone in the treatment of alcohol dependence.
        N Engl J Med. 2001; 345: 1734-1739
        • Mitchell J.E.
        Naltrexone and hepatotoxicity.
        Lancet. 1986; 1: 1215
        • Mayo M.J.
        • Handem I.
        • Saldana S.
        • Jacobe H.
        • Getachew Y.
        • Rush A.J.
        Sertraline as a first-line treatment for cholestatic pruritus.
        Hepatology. 2007; 45: 666-674
        • Zylicz Z.
        • Krajnik M.
        • Sorge A.A.
        • Costantini M.
        Paroxetine in the treatment of severe non-dermatological pruritus: a randomized, controlled trial.
        J Pain Symptom Manage. 2003; 26: 1105-1112
        • Oster Z.H.
        • Rachmile E.A.
        • Moran E.
        • Stein Y.
        Relief of pruritus by cholestyramine in chronic liver disease.
        Isr J Med Sci. 1965; 1: 599-606
      1. An antipruritic agent for primary biliary cirrhosis and cholestatic jaundice. Cholestyramine resin (cuemid).
        JAMA. 1966; 197: 261-262
        • Di Padova C.
        • Tritapepe R.
        • Rovagnati P.
        • Rossetti S.
        Double-blind placebo-controlled clinical trial of microporous cholestyramine in the treatment of intra- and extra-hepatic cholestasis: relationship between itching and serum bile acids.
        Methods Find Exp Clin Pharmacol. 1984; 6: 773-776
        • Ghent C.N.
        • Carruthers S.G.
        Treatment of pruritus in primary biliary cirrhosis with rifampin. Results of a double-blind, crossover, randomized trial.
        Gastroenterology. 1988; 94: 488-493
        • Ballantyne J.C.
        • Loach A.B.
        • Carr D.B.
        The incidence of pruritus after epidural morphine.
        Anaesthesia. 1989; 44: 863
        • Thornton J.R.
        • Losowsky M.S.
        Opioid peptides and primary biliary cirrhosis.
        BMJ. 1988; 297: 1501-1504
        • Bergasa N.V.
        • Alling D.W.
        • Talbot T.L.
        • Wells M.C.
        • Jones E.A.
        Oral nalmefene therapy reduces scratching activity due to the pruritus of cholestasis: a controlled study.
        J Am Acad Dermatol. 1999; 41: 431-434
        • Bergasa N.V.
        • Schmitt J.M.
        • Talbot T.L.
        • et al.
        Open-label trial of oral nalmefene therapy for the pruritus of cholestasis.
        Hepatology. 1998; 27: 679-684
        • Browning J.
        • Combes B.
        • Mayo M.J.
        Long-term efficacy of sertraline as a treatment for cholestatic pruritus in patients with primary biliary cirrhosis.
        Am J Gastroenterol. 2003; 98: 2736-2741
        • Decock S.
        • Roelandts R.
        • Steenbergen W.V.
        • et al.
        Cholestasis-induced pruritus treated with ultraviolet B phototherapy: an observational case series study.
        J Hepatol. 2012; 57: 637-641
        • Cohen L.B.
        • Ambinder E.P.
        • Wolke A.M.
        Role of plasmapheresis in primary biliary cirrhosis.
        Gut. 1985; 26: 291-294
        • Kremer A.E.
        • Namer B.
        • Bolier R.
        • Fischer M.J.
        • Oude Elferink R.P.
        • Beuers U.
        Pathogenesis and management of pruritus in PBC and PSC.
        Dig Dis. 2015; 33: 164-175
        • Krawczyk M.
        • Liebe R.
        • Wasilewicz M.
        • Wunsch E.
        • Raszeja-Wyszomirska J.
        • Milkiewicz P.
        Plasmapheresis exerts a long-lasting antipruritic effect in severe cholestatic itch.
        Liver Int. 2016; (http://dx.doi.org/10.1111/liv.13281. [Epub ahead of print])
        • Pares A.
        • Herrera M.
        • Aviles J.
        • Sanz M.
        • Mas A.
        Treatment of resistant pruritus from cholestasis with albumin dialysis: combined analysis of patients from three centers.
        J Hepatol. 2010; 53: 307-312
        • Leckie P.
        • Tritto G.
        • Mookerjee R.
        • Davies N.
        • Jones D.
        • Jalan R.
        ‘Out-patient’ albumin dialysis for cholestatic patients with intractable pruritus.
        Aliment Pharmacol Ther. 2012; 35: 696-704
        • Kremer A.E.
        • Martens J.J.
        • Kulik W.
        • et al.
        Autotaxin is a potential mediator of cholestatic pruritus.
        Acta Dermato Venereologica. 2009; 89: 702
        • Hegade V.S.
        • Krawczyk M.
        • Kremer A.E.
        • et al.
        The safety and efficacy of nasobiliary drainage in the treatment of refractory cholestatic pruritus: a multicentre European study.
        Aliment Pharmacol Ther. 2016; 43: 294-302
        • Hegade V.S.
        • Kendrick S.F.W.
        • Dobbins R.L.
        • et al.
        BAT117213: ileal bile acid transporter (IBAT) inhibition as a treatment for pruritus in primary biliary cirrhosis: study protocol for a randomised controlled trial.
        BMC Gastroenterol. 2016; 16: 71
        • Baghdasaryan A.
        • Fuchs C.D.
        • Osterreicher C.H.
        • et al.
        Inhibition of intestinal bile acid absorption improves cholestatic liver and bile duct injury in a mouse model of sclerosing cholangitis.
        J Hepatol. 2016; 64: 674-681
        • Graffner H.
        • Gillberg P.G.
        • Rikner L.
        • Marschall H.U.
        The ileal bile acid transporter inhibitor A4250 decreases serum bile acids by interrupting the enterohepatic circulation.
        Aliment Pharmacol Ther. 2016; 43: 303-310
        • Lens S.
        • Leoz M.
        • Nazal L.
        • Bruguera M.
        • Pares A.
        Bezafibrate normalizes alkaline phosphatase in primary biliary cirrhosis patients with incomplete response to ursodeoxycholic acid.
        Liver Int. 2014; 34: 197-203
        • Levy C.
        • Peter J.A.
        • Nelson D.R.
        • et al.
        Pilot study: fenofibrate for patients with primary biliary cirrhosis and an incomplete response to ursodeoxycholic acid.
        Aliment Pharmacol Ther. 2011; 33: 235-242
        • Hazzan R.
        • Tur-Kaspa R.
        Bezafibrate treatment of primary biliary cirrhosis following incomplete response to ursodeoxycholic acid.
        J Clin Gastroenterol. 2010; 44: 371-373
        • Reig A.
        • Sese P.
        • Pares A.
        Bezafibrate: a novel and effective alternative for relieving pruritus in patients with primary biliary cirrhosis.
        Hepatology. 2015; 62: 508A
        • Kaplan M.M.
        • Bonder A.
        • Ruthazer R.
        • Bonis P.A.
        Methotrexate in patients with primary biliary cirrhosis who respond incompletely to treatment with ursodeoxycholic acid.
        Dig Dis Sci. 2010; 55: 3207-3217
        • Babatin M.A.
        • Sanai F.M.
        • Swain M.G.
        Methotrexate therapy for the symptomatic treatment of primary biliary cirrhosis patients, who are biochemical incomplete responders to ursodeoxycholic acid therapy.
        Aliment Pharmacol Ther. 2006; 24: 813-820
        • Vuoristo M.
        • Färkkilä M.
        • Karvonen A.L.
        • et al.
        A placebo-controlled trial of primary biliary cirrhosis treatment with colchicine and ursodeoxycholic acid.
        Gastroenterology. 1995; 108: 1470-1478
        • Almasio P.L.
        • Floreani A.
        • Chiaramonte M.
        • et al.
        Multicentre randomized placebo-controlled trial of ursodeoxycholic acid with or without colchicine in symptomatic primary biliary cirrhosis.
        Aliment Pharmacol Ther. 2000; 14: 1645-1652
        • Nevens F.
        • Andreone P.
        • Mazzella G.
        • et al.
        A placebo-controlled trial of obeticholic acid in primary biliary cholangitis.
        N Engl J Med. 2016; 375: 631-643
        • Malecha E.S.
        • Beuers U.
        • Liberman A.
        • Hooshmand-Rad R.
        • Peters Y.
        • Pencek R.
        Baseline factors predicting obeticholic acid induced pruritus in patients with PBC.
        Gastroenterology. 2016; 150: S1058
      2. Intercept Pharmaceuticals, I, Ocaliva (Obeticholic Acid) [Prescribing Information].
        Intercept Pharmaceuticals, New York, NYMay 2016
        • Hegade V.S.
        • Mells G.
        • Lammert C.
        • et al.
        A comparative study of cholestatic pruritus in primary biliary cirrhosis cohorts from USA, UK and Italy.
        Gastroenterology. 2015; 148: S1059-S1060
        • Neuberger J.
        • Jones E.A.
        Liver transplantation for intractable pruritus is contraindicated before an adequate trial of opiate antagonist therapy.
        Eur J Gastroenterol Hepatol. 2001; 13: 1393-1394
        • Krawczyk M.
        • Liebe R.
        • Wasilewicz M.
        • Wunsch E.
        • Raszeja-Wyszomirska J.
        • Milkiewicz P.
        Effects of plasmapheresis on pruritus in patients with PBC: Prospective analysis of 121 procedures performed in a single center.
        J Hepatol. 2016; 64: S201