Treatment of Hepatic Encephalopathy: Lactulose vs Rifaximin
Lactulose is the first-line treatment for hepatic encephalopathy, and rifaximin should be added to lactulose (not used as monotherapy) after a second breakthrough episode to prevent recurrence. 1, 2, 3
Initial Treatment Algorithm
First Episode of Overt Hepatic Encephalopathy
- Start lactulose immediately as the first-choice treatment, dosed at 20-30g (30-45 mL) orally 3-4 times daily, titrated to achieve 2-3 soft bowel movements per day. 1, 2, 3
- Lactulose demonstrates significantly more frequent resolution of acute overt HE and reduction in mortality compared to placebo, with a risk ratio of 0.44 (95% CI: 0.31-0.64). 1
- Always identify and treat precipitating factors first—this is the highest priority in management, as nearly 90% of patients can be managed by correcting precipitating factors alone. 2
Prevention After First Episode
- Continue lactulose monotherapy for prevention of recurrent episodes after the initial episode. 2
- Lactulose significantly reduces 14-month recurrence risk to only 20% versus 47% without lactulose. 3
After Second Breakthrough Episode
- Add rifaximin 550 mg twice daily to ongoing lactulose therapy as secondary prophylaxis following more than one episode of overt HE within 6 months of the first episode. 2, 3, 4
- The combination reduces HE recurrence from 45.9% to 22.1% (hazard ratio 0.42; 95% CI 0.28-0.64; p<0.001), with a number needed to treat of 4. 3
- In the pivotal trials, 91% of patients were using lactulose concomitantly with rifaximin. 2, 4
Evidence Supporting Combination Therapy
Rifaximin plus lactulose is superior to lactulose alone for acute treatment, with one high-quality RCT showing:
- Better recovery from HE within 10 days: 76% vs 44% (p=0.004). 3
- Shorter hospital stays: 5.8 vs 8.2 days (p=0.001). 3
- Lower mortality: 23.8% vs 49.1% (p<0.05). 5
- Reduced HE-related hospitalizations (hazard ratio 0.50; 95% CI 0.29-0.87). 3
However, another study found no statistically significant superiority of combination therapy over lactulose alone for treatment effectiveness (96.87% vs 85.71%, p=0.3251), though both were effective. 6
Critical Pitfalls to Avoid
- Never use rifaximin as monotherapy for initial treatment of overt HE—evidence supports lactulose as first-line therapy. 2
- Do not add rifaximin after the first episode—wait until a second breakthrough episode occurs while on lactulose. 2, 3
- Failing to titrate lactulose properly to achieve 2-3 bowel movements daily is a common cause of treatment failure. 3
- Do not discontinue therapy after initial improvement—maintenance therapy is essential to prevent recurrence. 3
- Rifaximin monotherapy may only be considered when lactulose is poorly tolerated, though this is based on expert opinion rather than robust evidence. 2, 3
Special Considerations
Covert Hepatic Encephalopathy
- Either lactulose or rifaximin can be used to improve quality of life and reduce progression to overt HE. 2
- Rifaximin has fewer gastrointestinal side effects than lactulose, making it a reasonable choice based on tolerability in this population. 2
Severe Liver Disease
- Rifaximin has not been studied in patients with MELD scores >25, and only 8.6% of patients in controlled trials had MELD scores over 19. 4
- There is increased systemic exposure to rifaximin in patients with more severe hepatic dysfunction. 4
Cost Considerations
- Rifaximin costs approximately $1,500-2,000 per month, which may be a significant barrier to routine use. 3
- Benefits in reducing hospitalizations may offset costs through reduced hospital admissions. 3
Long-term Safety
- Rifaximin can be used safely for long-term continuous therapy (>24 months) with no increased risk of adverse events. 3
- Common adverse events (10-15%) include peripheral edema, nausea, dizziness, fatigue, and ascites, with rates similar to placebo. 3