What is the comparison between lactulose and rifaximin (Rifaximin) in the treatment of hepatic encephalopathy?

Lactulose vs. Rifaximin in Hepatic Encephalopathy

Lactulose is the first-line treatment for hepatic encephalopathy, while rifaximin should be added to lactulose therapy after a second episode of overt hepatic encephalopathy recurrence. 1, 2, 3

First-Line Treatment: Lactulose

• Lactulose is recommended as the initial therapeutic option for overt hepatic encephalopathy (OHE) based on extensive clinical evidence and cost-effectiveness 1, 2
• Lactulose works by converting ammonia to ammonium (making it less absorbable) and producing an osmotic laxative effect that flushes ammonia out of the intestines 1
• The recommended dosage is 30-45 mL (20-30g) of lactulose every 1-2 hours initially until the patient has at least 2 bowel movements daily, then titrate to maintain 2-3 soft stools per day 1, 2
• For patients unable to take oral medications, lactulose can be administered via nasogastric tube or as an enema (300 mL lactulose with 700 mL water, 3-4 times daily) 1
• FDA-approved indication: "For the prevention and treatment of portal-systemic encephalopathy, including the stages of hepatic pre-coma and coma" 4

Second-Line/Add-on Treatment: Rifaximin

• Rifaximin should be added to lactulose therapy after a second episode of OHE recurrence 1, 2, 3
• Rifaximin is a non-absorbable antibiotic that inhibits bacterial RNA synthesis, reducing ammonia production in the intestine 1
• The recommended dosage is 550 mg twice daily or 400 mg three times daily 1, 5
• FDA-approved indication: "For reduction in risk of overt hepatic encephalopathy recurrence in adults" 5
• In the clinical trials for rifaximin, 91% of patients were using lactulose concomitantly, indicating its role as an add-on therapy rather than monotherapy 5

Comparative Efficacy

• As monotherapy, rifaximin has shown similar therapeutic effects to lactulose or lactitol in several small RCTs 1
• A landmark study demonstrated that rifaximin added to lactulose decreased the risk of HE recurrence to 22.1% versus 45.9% with placebo plus lactulose (hazard ratio 0.42; 95% CI 0.28 to 0.64; p<0.001) 3
• Combination therapy with rifaximin and lactulose showed better recovery from HE within 10 days (76% vs. 44%, p=0.004) and shorter hospital stays (5.8 vs. 8.2 days, p=0.001) compared to lactulose alone 1, 6
• However, some studies have shown conflicting results, with one study finding no statistical difference between rifaximin plus lactulose versus lactulose alone in treatment of refractory hepatic encephalopathy 7

Common Pitfalls and Considerations

• Failing to identify and treat precipitating factors for HE can lead to poor outcomes, regardless of medication choice 1, 2
• Overuse of lactulose can lead to complications including aspiration, dehydration, hypernatremia, and severe perianal skin irritation 2
• Using rifaximin alone without lactulose is not supported by solid evidence, as most clinical trials used rifaximin as an add-on to lactulose 2, 5
• Long-term use of other antibiotics like neomycin and metronidazole is not recommended due to risks of ototoxicity, nephrotoxicity, and neurotoxicity 1
• Rifaximin has not been well-studied in patients with MELD scores >25, and only 8.6% of patients in controlled trials had MELD scores over 19 5

Treatment Algorithm

1. For first episode of OHE:

   • Start lactulose 30-45 mL every 1-2 hours until ≥2 bowel movements daily 1, 2
   • Titrate to maintenance dose achieving 2-3 soft stools per day 1, 2
   • Continue lactulose for prevention of recurrence 1, 2

2. After second episode of OHE despite lactulose therapy:

   • Add rifaximin 550 mg twice daily or 400 mg three times daily 1, 3, 5
   • Continue both medications for long-term prevention 1, 2

3. For severe HE (West-Haven grade 3 or more) or patients unable to take oral medications:

   • Administer lactulose via nasogastric tube or as an enema (300 mL lactulose with 700 mL water, 3-4 times daily) 1
   • Consider adding rifaximin when oral administration becomes possible 1