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Limitations in PBC Pruritus Management
Current Limitations in PBC Pruritus Management

Released: August 20, 2024

Expiration: August 19, 2025

Stuart C Gordon
Stuart C Gordon, MD, FACP, FACG, AGAF, FAASLD
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Key Takeaways
  • Bile acid resins are recommended as first-line treatments for PBC-related pruritus, but they have complicated dosing schedules and interact with other medications.
  • Rifampin, sertraline, and naltrexone are next-line agents for bile-acid refractory pruritus, but each has important adverse effects.

Treatment of primary biliary cholangitis (PBC) is typically done with ursodeoxycholic acid (UDCA), which improves survival but does not improve cholestatic pruritus. In fact, there are some people with PBC whose itching worsens while receiving UDCA. This inability to effectively treat what is likely the most common—and bothersome—symptom of PBC has led to a frustrating situation for patients and their healthcare professional (HCP). More effective and better-tolerated pruritus treatments are needed.

First-line Pruritus Treatment
For many years, the bile acid–binding resin cholestyramine has been recommended as first-line treatment for the itching of liver disease in general. Yet the mechanism by which such a benefit may occur is largely unknown. It is thought that the drug may have some choleretic effect by decreasing enterohepatic circulation of bile acids. [CODER: https://clinicaloptions.com/CE-CME/gastroenterology/cholestatic-pruritus/21212-39346]

In general, use of bile acid resins for treatment is off label because most are approved to treat high cholesterol only. Cholestyramine is indicated for pruritus associated with partial biliary obstruction. HCPs often use this agent as first-line treatment for pruritus, and the American Association for the Study of Liver Diseases recommends such treatment.

But the dosing of cholestyramine causes problems for patients. Ideally, the medication should be taken approximately 30 minutes before a meal to coincide with postprandial gallbladder contraction and then again at bedtime. Patients are simultaneously advised to take their other medications, including UDCA for the underlying PBC, at least 1 hour before or 4 hours after receiving cholestyramine to avoid interference with the absorption of other medications. Such a dosing regimen is challenging at best and, in general, often impossible to adhere to for long durations.

Second-line Pruritus Treatments

Rifampin
Rifampin is also used to treat cholestatic pruritus. This drug belongs to the antibiotic class rifamycin and is a macrocyclic antibiotic that inhibits growth of tuberculosis. It was approved for the treatment of tuberculosis in 1971 and its use in the therapy of itching is off label. Rifampin inhibits the uptake of bile acids by hepatocytes.

HCPs may find that rifampin works effectively and promptly in people with refractory cholestatic itching, but its list of potential toxicities is concerning. Rifampin can be associated with an increase in both direct and total bilirubin, and this cholestatic drug injury may occur in people with significant underlying liver disease, including cirrhosis. Severe and even fatal liver toxicity has been described but usually when used in combination with isoniazid for treating tuberculosis. Liver injury risk increases with age and, perhaps, history of alcohol use.

These cases of liver injury, especially among people with cirrhosis, give rise to caution when using rifampin for any prolonged period in people with cholestatic pruritus. When rifampin works, it frequently works quickly and effectively, and people generally tolerate it quite well. But the benefit comes with significant risk.

Several other agents have been tried for this vexing condition of cholestatic pruritus, all of which are off label and largely ineffective.

Sertraline
The selective serotine reuptake inhibitor sertraline improved cholestatic pruritus in 2 trials, but it carries with it the adverse effect profile of its mechanism of action (eg, diarrhea, agitation). Anecdotally, it has limited effectiveness in a real-world setting.

Naltrexone
The opioid antagonist naltrexone, available both orally and intravenously, has proved effective at reducing cholestatic pruritus as measured by the visual analogue scale. However, opioid antagonists carry the risk of an opioid withdrawal syndrome and associated symptoms (eg, nausea, headache, abdominal pain), making this option risky.  

Newly Approved Agents for Pruritus

PPAR Agonists
In the FITCH trial, the peroxisome proliferator–activated receptor (PPAR) agonist bezafibrate markedly improved pruritus compared with placebo. However, this drug is not available for use in the United States. Two other PPAR agonists have recently been approved by the FDA: elafibranor is a dual PPARα/δ agonist and seladelpar is a PPARδ agonist. Each is approved for use in combination with UDCA in people who have had an inadequate response to UDCA or alone in people unable to tolerate UDCA.

Pruritus Treatments in Development

IBAT Inhibitors
Two IBAT inhibitors—volixibat and linerixibat—are being studied in phase II and III clinical trials for use in PBC pruritus in adults. For more information on these up-and-coming agents, I encourage you to read the commentary by Marlyn J. Mayo, MD: “Looking Toward the Future: Investigational PBC Pruritus Agents.”

Your Thoughts?
Which currently available PBC pruritus treatment has provided the most itching relief to your patients? Leave a comment to join the discussion!