Treatment of Pruritus in Cholestasis
For moderate to severe cholestatic pruritus, bezafibrate is the recommended first-line pharmacological treatment, with rifampicin as an alternative first-line option, based on the largest randomized controlled trial evidence from the FITCH trial. 1
Initial Assessment and Non-Pharmacological Management
Before initiating pharmacological therapy, exclude mechanical bile duct obstruction as the underlying cause of progressive pruritus, particularly in large duct cholestatic diseases like primary sclerosing cholangitis. 1 If relevant strictures are present and reachable, they should be treated with endoscopic balloon dilation (or stenting if balloon dilation is insufficient). 1
General Supportive Measures
All patients should implement these non-pharmacological strategies: 1
- Use emollients to prevent skin dryness
- Avoid hot baths or showers
- Apply cooling gels (e.g., menthol gels) to affected skin areas
- Keep nails shortened to minimize excoriation from scratching
Pharmacological Treatment Algorithm
First-Line: Bezafibrate or Rifampicin
Bezafibrate is now positioned as the preferred first-line agent based on the FITCH trial, which demonstrated clear superiority over placebo in treating moderate to severe cholestasis-associated pruritus in both PSC and PBC patients. 1 This broad PPAR agonist showed sustained antipruritic effects and has the added benefit of exerting anticholestatic effects when combined with UDCA. 1
- Safety profile: No major side effects observed during short-term (3 weeks) or long-term (2 years) treatment 1
- Monitoring: Watch for mild serum creatinine increases, myalgia, myopathies, and rarely elevated transaminases 1
Rifampicin (150-300 mg daily) remains an effective alternative first-line option, previously considered the most effective evidence-based treatment. 1 However, it carries a significant caveat: it may induce drug-induced hepatitis after 4-12 weeks in up to 12% of cholestatic patients, though the first 2 weeks are considered safe. 1
Second-Line: Naltrexone
If first-line agents fail or are not tolerated, the oral opioid antagonist naltrexone (12.5-50 mg daily) should be considered. 1
Critical prescribing point: Start at very low doses (12.5 mg) to avoid early side effects resembling opioid withdrawal syndrome. 1
Third-Line: Sertraline
Sertraline (25-75 mg daily), a selective serotonin reuptake inhibitor, can be used as fourth-line treatment, though data for sclerosing cholangitis-associated itch are insufficient. 1
Role of Cholestyramine: Limited Evidence
Important caveat: Cholestyramine (4-16 g/day) is FDA-approved for pruritus associated with partial biliary obstruction 2, but recent EASL guidelines have excluded anion exchange resins as evidence-based treatments for cholestatic pruritus in sclerosing cholangitis due to limited efficacy data compared to PBC. 1
Drug interaction warning: If cholestyramine is used, it must be administered separately from other medications (particularly UDCA) as it impairs absorption. 1 Research demonstrates that simultaneous administration of UDCA and cholestyramine decreases UDCA serum levels by 60%, and administration should be separated by at least 5 hours. 3
UDCA Considerations
While UDCA is not generally considered a first-line treatment for pruritus due to lack of evidence, it is often tried early because of its low risk profile. 1 In intrahepatic cholestasis of pregnancy specifically, UDCA is recommended as first-line treatment for maternal symptoms. 4
Emerging and Experimental Therapies
Novel antipruritic strategies under investigation include: 1
- Non-absorbable inhibitors of the ileal apical sodium bile salt transporter (ASBT/IBAT)
- Selective PPARα or PPARδ agonists
For medically refractory cases, invasive options such as charcoal hemoperfusion, biliary diversion, or liver transplantation may be considered, though these carry significant risks and provide only temporary benefit. 5, 6
Pathophysiology Context
The molecular mechanisms remain incompletely understood, but recent evidence suggests lysophosphatidic acid (LPA) and autotaxin (ATX) may form key elements of the pruritogenic signaling cascade in cholestatic patients. 7, 8 Serum ATX correlates with pruritus intensity and responds to therapeutic interventions. 8
Quality of Life Impact
Pruritus in cholestasis is not merely a nuisance symptom—it can dramatically impair quality of life, leading to sleep deprivation, loss of daytime concentration, auto-mutilation, and in severe cases, suicidal ideations. 1, 7, 8 This underscores the importance of aggressive symptom management.