How to manage pruritus in a patient with chronic liver disease (CLD) and hepatocellular carcinoma (HCC) who is experiencing pruritus while on opioids?

Management of Pruritus in Chronic Liver Disease with HCC in Patients on Opioids

Primary Recommendation

Start with rifampicin 150 mg twice daily as first-line treatment for the underlying hepatic pruritus, while simultaneously addressing the opioid-induced component with antihistamines (diphenhydramine 25-50 mg every 6 hours or promethazine 12.5-25 mg every 6 hours). 1, 2

Understanding the Dual Etiology

This clinical scenario involves two overlapping causes of pruritus that require simultaneous management:

• Hepatic pruritus from chronic liver disease/HCC is the primary driver 1, 3
• Opioid-induced pruritus compounds the problem, occurring in 10-50% of patients receiving opioids 2, 4

The key insight is that these mechanisms are distinct and require different therapeutic approaches that can be used concurrently.

Stepwise Treatment Algorithm

Step 1: First-Line Therapy for Hepatic Pruritus

Rifampicin is the drug of first choice for hepatic pruritus (Strength of recommendation A; Level of evidence 1+) 1:

• Start at 150 mg twice daily, can increase to 600 mg twice daily 1
• Monitor for hepatotoxicity with liver function tests 1
• Inform patients about discoloration of secretions (urine, tears, sweat) 1
• Two meta-analyses demonstrate effectiveness in reducing hepatic pruritus 1
• Importantly, rifampicin does not have increased side effects compared to placebo, unlike opioid antagonists 1

Step 2: Concurrent Management of Opioid-Induced Pruritus

Add antihistamines as initial therapy for the opioid component 2:

• Diphenhydramine 25-50 mg IV or PO every 6 hours (sedating) 2
• Promethazine 12.5-25 mg PO every 6 hours (sedating) 2
• Cetirizine as a non-sedating alternative 2

Critical caveat: Sedating antihistamines may compound opioid-induced sedation, requiring close monitoring 2

Step 3: If Rifampicin Fails for Hepatic Pruritus

Cholestyramine 9 g daily orally as second-line (Strength of recommendation D) 1:

• Binds bile salts in the gut lumen 1
• Limited evidence but traditionally used 1, 3
• Generally well tolerated 3

Sertraline 75-100 mg daily as third-line (Strength of recommendation D) 1:

• Well tolerated in small RCT 1
• Should be used before opioid antagonists 1

Step 4: If Antihistamines Fail for Opioid-Induced Pruritus

Consider opioid rotation (changing to a different opioid) 2:

• This is preferred before escalating to opioid antagonists 2

If rotation not feasible, add low-dose opioid antagonists 2:

• Nalbuphine (mixed agonist-antagonist) 0.5-1 mg IV every 6 hours 2
• Naloxone continuous infusion starting at 0.25 mcg/kg/h, titrate carefully 2
• Critical warning: Careful dose titration is essential to avoid reversing analgesic effects 2, 4

Step 5: Advanced Options for Refractory Hepatic Pruritus

Naltrexone or nalmefene as fourth-line (Strength of recommendation D) 1:

• Naltrexone 50 mg daily orally 1
• Important consideration: Opioid antagonists have significantly more side effects than cholestyramine and rifampicin, which limits their use 1
• In this specific scenario with concurrent opioid use for pain, naltrexone would precipitate withdrawal and reverse analgesia - this option is contraindicated 2, 4

Fifth-line options 1:

• Dronabinol, phenobarbitone, propofol (systemic) 1
• Topical tacrolimus ointment 1
• Novel agents targeting bile acid transport, autotaxin, and lysophosphatidic acid metabolism 1

What NOT to Use

Avoid gabapentin in hepatic pruritus (Strength of recommendation D) 1, 5

Do not routinely use ondansetron 1, 4:

• Despite efficacy for opioid-induced nausea, ondansetron does not reduce opioid-induced pruritus incidence or severity in recent studies 4
• Two early RCTs showed benefit, but two more recent RCTs did not 1

Critical Clinical Pitfalls

The major challenge in this scenario is the contraindication of using opioid antagonists (naltrexone, naloxone) for hepatic pruritus when the patient requires opioids for pain control 2, 4:

• These agents would reverse analgesia and potentially precipitate withdrawal 2, 4
• This eliminates a major therapeutic option for refractory hepatic pruritus 1

Monitor for hepatotoxicity with rifampicin, especially given underlying liver disease and HCC 1

Assess for other causes of pruritus before attributing all symptoms to liver disease and opioids (other medications, skin conditions) 2, 4

Sedation risk: Combining sedating antihistamines with opioids increases sedation burden 2

Practical Implementation

The optimal approach is to:

1. Initiate rifampicin for the hepatic component while monitoring liver function 1
2. Add non-sedating antihistamine (cetirizine) for the opioid component to minimize additive sedation 2
3. If inadequate response, escalate hepatic pruritus treatment to cholestyramine, then sertraline (avoiding opioid antagonists) 1
4. For persistent opioid-induced pruritus, consider opioid rotation before using low-dose mixed agonist-antagonists 2
5. In severe refractory cases, consider experimental therapies such as albumin dialysis, photopheresis, or plasmapheresis 3