In an adult patient requiring chronic non‑steroidal anti‑inflammatory drug therapy and at risk for NSAID‑induced gastropathy (e.g., older age, prior ulcer disease, high‑dose or multiple NSAIDs), what is the role of rebamipide for prevention or treatment, including recommended dosing and comparison to proton‑pump inhibitors?

Role of Rebamipide in NSAID-Induced Gastropathy

Primary Recommendation

Rebamipide is NOT recommended as first-line gastroprotection in high-risk patients requiring chronic NSAID therapy; proton pump inhibitors remain the evidence-based standard of care. However, rebamipide may serve as an alternative gastroprotective agent specifically in elderly chronic NSAID users without additional GI risk factors, or when PPI therapy is contraindicated or poorly tolerated. 1

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Evidence-Based Treatment Algorithm

Step 1: Risk Stratification (Mandatory Before Selecting Gastroprotection)

High-risk features requiring PPI therapy include:

• Prior peptic ulcer disease or GI bleeding (2-4 fold increased risk) 1
• Age ≥65 years (2-3.5 fold increased risk) 1
• Concurrent low-dose aspirin or antiplatelet therapy (>10-fold risk when combined with NSAID) 1
• Concurrent anticoagulant therapy (≈3-fold increased risk) 1, 2
• Concurrent corticosteroid use (≈2-fold increased risk) 1, 2
• High-dose or multiple NSAIDs 1

Step 2: Gastroprotection Strategy Based on Risk Profile

For patients with ≥1 high-risk feature:

• Use PPI as standard therapy (omeprazole 20-40 mg daily or pantoprazole 40 mg daily), which reduces upper GI complications by 75-85% 1, 3
• Alternative: COX-2 selective inhibitor (celecoxib) plus PPI for very high-risk patients 1
• Rebamipide is inferior to PPI in this population and showed 2.42-2.63 fold higher risk of serious GI complications in elderly patients with ≥2 risk factors 4

For elderly patients (≥65 years) WITHOUT additional risk factors:

• Rebamipide 100 mg three times daily is a reasonable alternative to PPI, showing comparable efficacy in preventing serious GI complications (aHR 0.69,95% CI 0.27-1.76, not statistically different from PPI) 4
• This represents the only population where rebamipide may substitute for PPI based on current evidence 4

For patients with contraindications to long-term PPI use:

• Rebamipide 100 mg three times daily may be considered as an alternative gastroprotective strategy 5
• Meta-analysis demonstrates rebamipide significantly reduces NSAID-induced GI mucosal breaks compared to placebo (RR 0.55,95% CI 0.31-0.99) and shows comparable efficacy to PPIs (RR 1.00,95% CI 0.51-1.95) 5

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Rebamipide Dosing and Administration

Standard dosing: 100 mg orally three times daily, taken continuously throughout NSAID therapy 6, 7, 8

Duration: Continue for the entire duration of NSAID exposure, similar to PPI therapy 7, 8

Mechanism: Rebamipide stimulates prostaglandin and mucus glycoprotein synthesis, inhibits reactive oxygen species and inflammatory cytokines, and enhances gastric mucosal protective function 6, 8

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Comparative Efficacy: Rebamipide vs. PPI vs. Misoprostol

Rebamipide vs. Misoprostol

• Equivalent efficacy: Peptic ulcer occurrence rates were similar (4.5% rebamipide vs. 4.4% misoprostol over 12 weeks) 7
• Superior tolerability: Rebamipide had significantly lower withdrawal rates (10.3% vs. 18.6%, p=0.0103) and fewer GI symptoms (p=0.0002) compared to misoprostol 8
• Better compliance: Patients required less antacid rescue medication with rebamipide (p=0.0258) 8

Rebamipide vs. PPI

• Comparable prevention of mucosal breaks in unselected populations (RR 1.00,95% CI 0.51-1.95) 5
• Inferior in high-risk elderly patients with ≥2 risk factors (2.42-2.63 fold higher complication risk) 4
• Non-inferior in low-risk elderly patients without additional risk factors 4

Rebamipide + PPI Combination

• Insufficient evidence to support adding rebamipide to PPI therapy for additional benefit (RR 0.72,95% CI 0.43-1.21, p=0.11) 5
• This combination strategy cannot be recommended based on current data 5

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Clinical Scenarios and Recommendations

Scenario 1: 70-year-old with chronic NSAID need, no prior ulcer, no aspirin/anticoagulants

• Option A (Preferred): Traditional NSAID + PPI 1
• Option B (Alternative): Traditional NSAID + rebamipide 100 mg three times daily 4
• Both strategies show comparable efficacy in this low-risk elderly population 4

Scenario 2: 55-year-old with prior peptic ulcer requiring chronic NSAID

• Mandatory: Traditional NSAID + PPI (or COX-2 inhibitor + PPI) 1
• Do NOT use rebamipide alone in this high-risk scenario 4
• PPI therapy must continue indefinitely for the entire duration of NSAID exposure 3

Scenario 3: Patient on chronic aspirin + NSAID

• Mandatory: NSAID + PPI (or COX-2 inhibitor + PPI) 1
• Combined aspirin + NSAID increases risk >10-fold compared to no NSAID use 1
• Rebamipide is inadequate for this high-risk combination 4

Scenario 4: Patient with PPI intolerance or contraindication

• Consider: Rebamipide 100 mg three times daily as alternative gastroprotection 5
• Also consider: COX-2 selective inhibitor (celecoxib) without PPI in low-risk patients 1

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Critical Pitfalls and Caveats

Common Errors to Avoid

1. Using rebamipide in high-risk patients:

• Rebamipide showed 2.42-2.63 fold higher serious GI complication rates in elderly patients with ≥2 risk factors compared to PPI 4
• Always use PPI (not rebamipide) in patients with prior ulcer/bleeding, concurrent aspirin, anticoagulants, or corticosteroids 1, 4

2. Assuming rebamipide + PPI provides additive benefit:

• Current evidence does not support combination therapy over PPI alone 5
• This adds cost without proven incremental benefit 5

3. Forgetting H. pylori testing:

• Test and eradicate H. pylori in all patients with peptic ulcer disease, as infection increases NSAID-related complication risk 2-4 fold even with gastroprotection 1, 3
• Eradication reduces peptic ulceration incidence in NSAID users 1

4. Discontinuing gastroprotection prematurely:

• Both PPI and rebamipide must continue for the entire duration of NSAID exposure 3, 7
• Patients with prior ulcer bleeding require indefinite PPI therapy while on NSAIDs 3

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Strength of Evidence and Guideline Gaps

What Guidelines Say

• No major North American or European guidelines currently recommend rebamipide as first-line gastroprotection 1
• All major guidelines (American College of Gastroenterology, American Geriatrics Society, Alimentary Pharmacology & Therapeutics consensus) recommend PPI or COX-2 inhibitor strategies for high-risk patients 1

What Recent Research Shows

• 2025 meta-analysis demonstrates rebamipide is effective vs. placebo and comparable to PPI in preventing NSAID-induced mucosal breaks 5
• 2022 real-world study from national claims database shows rebamipide is non-inferior to PPI specifically in elderly patients without risk factors, but inferior in those with ≥2 risk factors 4
• Multiple RCTs confirm rebamipide 100 mg three times daily prevents gastric ulcers as effectively as misoprostol with superior tolerability 7, 8

Clinical Interpretation

The evidence supports rebamipide as a niche alternative rather than a replacement for PPI therapy. Its role is limited to:

1. Elderly chronic NSAID users without additional GI risk factors 4
2. Patients with contraindications to long-term PPI use 5
3. Patients who cannot tolerate misoprostol 7, 8

For all other patients—particularly those with prior ulcer, concurrent aspirin/anticoagulants, or multiple risk factors—PPI remains the evidence-based standard of care. 1, 3, 4