What is the role of cholestyramine in treating itching, particularly in conditions like primary biliary cirrhosis?

Cholestyramine for Cholestatic Itching

Cholestyramine remains the recommended first-line therapy for cholestatic pruritus due to its favorable safety profile, despite newer evidence suggesting bezafibrate or rifampicin may be more effective in certain populations. 1, 2

Treatment Algorithm

First-Line: Cholestyramine

• Start with cholestyramine 4g daily and titrate up to 8-12g/day in divided doses (up to four times daily) 1, 2
• Critical timing consideration: Administer cholestyramine at least 4 hours apart from ursodeoxycholic acid (UDCA) to prevent binding and loss of UDCA efficacy 1, 3
• Mix with orange juice and refrigerate overnight to improve palatability 2
• Monitor for fat-soluble vitamin deficiencies during long-term use 1
• Common side effects include constipation and gastrointestinal symptoms, which are the primary limitations 2

Important caveat: Cholestyramine may be less effective in patients with very high baseline serum bile acid levels, as biliary excretion and enterohepatic circulation may already be severely impaired 4

Second-Line: Rifampicin

• If cholestyramine fails or is not tolerated after adequate trial, initiate rifampicin at 150mg once to twice daily 1, 2
• Titrate upward to 300-600mg/day based on symptoms and liver function monitoring 1, 2
• Check liver function tests 2-4 weeks after initiation, as rifampicin carries up to 12% risk of drug-induced hepatitis after 4-12 weeks in cholestatic patients 1, 2
• Use with particular caution in advanced liver disease 2

Emerging Evidence: Bezafibrate as Alternative First-Line

• The 2025 European guidelines now recommend bezafibrate or rifampicin as first-line options for moderate to severe pruritus in primary sclerosing cholangitis and fibrosing cholangiopathies, based on the FITCH trial 2
• Bezafibrate has a favorable safety profile but requires monitoring for mild serum creatinine increases, myalgia, and rarely elevated transaminases 2
• This represents a shift from traditional cholestyramine-first approach, though cholestyramine remains guideline-recommended for primary biliary cirrhosis 1

Third-Line: Naltrexone

• Oral opioid antagonist naltrexone 25-50mg daily should be considered if first and second-line agents fail 1, 2
• Start at very low doses (25mg) to avoid opioid withdrawal-like reactions 1, 2

Fourth-Line: Sertraline

• Sertraline (up to 100mg daily) can be used as third or fourth-line treatment, though data for cholestatic itch are insufficient 1, 2

Special Population: Pregnancy

• For intrahepatic cholestasis of pregnancy, ursodeoxycholic acid (UDCA) 10-15mg/kg/day divided into 2-3 doses is first-line, not cholestyramine 2
• UDCA typically decreases pruritus within 1-2 weeks, with maximum dose up to 21mg/kg/day 2

Refractory Cases

• Consider experimental physical approaches in specialized centers: extracorporeal albumin dialysis, plasmapheresis, bile duct drainage, or UV light therapy 1, 2, 5
• Liver transplantation is highly effective for intractable pruritus, with rapid reduction often within 24 hours, and should be considered when all available interventions have failed 1, 2
• Pruritus that is "persistent and intractable" after therapeutic trials is a recognized indication for transplantation 1, 2

Treatments to Avoid

• Antihistamines have limited specific efficacy for cholestatic pruritus, though sedative properties may provide non-specific relief 1, 5
• Gabapentin is not recommended due to lack of efficacy in clinical trials 5
• Ondansetron has shown inconsistent results and is not routinely recommended 5
• Phenobarbital is not recommended due to excessive side-effect profile 1

Monitoring

• Use visual analogue scales to assess response to interventions 1, 5
• In primary sclerosing cholangitis, exclude mechanical bile duct obstruction with dominant strictures before escalating medical therapy, as endoscopic intervention may be needed 2