For a patient with NSAID‑induced gastropathy requiring lifelong proton‑pump inhibitor therapy, is it appropriate to alternate the proton‑pump inhibitor with rebamipide every three months to minimize PPI‑related adverse effects?

Alternating PPI with Rebamipide Every 3 Months Is Not Recommended for NSAID-Induced Gastropathy Requiring Lifelong Protection

For patients with NSAID-induced gastropathy requiring lifelong gastroprotection, continuous PPI therapy should be maintained without alternating to rebamipide, as PPIs remain the evidence-based standard with proven efficacy in preventing serious gastrointestinal complications, and no guideline supports intermittent switching strategies. 1, 2

Why Continuous PPI Therapy Is the Standard

• PPIs reduce NSAID-related ulcer incidence by approximately 90% and are the only gastroprotective agents with robust evidence for preventing serious upper GI bleeding in high-risk patients. 2, 3

• The American College of Gastroenterology, American Heart Association, and European Society of Cardiology all recommend continuous PPI therapy for the entire duration of NSAID use in patients at high risk for GI complications. 1, 2, 3

• High-risk criteria that mandate lifelong PPI co-therapy include: prior peptic ulcer or ulcer bleeding, age >60-65 years, concomitant anticoagulants or antiplatelet agents, systemic corticosteroids, or high-dose/multiple NSAID regimens. 1, 2

• No guideline recommends alternating or cycling gastroprotective agents to minimize PPI side effects. 1, 2, 4

The Evidence on Rebamipide

• Rebamipide has shown comparable efficacy to misoprostol (not PPIs) in preventing gastric ulcers in NSAID users, with better tolerability. 5

• However, rebamipide is inferior to PPIs in high-risk patients. A 2022 study demonstrated that elderly chronic NSAID users with ≥2 GI risk factors had significantly higher rates of serious GI complications with rebamipide compared to PPIs (aHR 2.42-2.63). 6

• Rebamipide may be considered only in elderly patients without any GI risk factors as an alternative to PPIs, but this does not apply to patients with established NSAID-induced gastropathy requiring lifelong protection. 6

• The evidence for rebamipide preventing small bowel injury is limited to small pilot studies with no statistically significant differences from PPIs. 7

Why Alternating Strategies Are Problematic

• Intermittent PPI discontinuation exposes patients to rebound acid hypersecretion (RAHS), which can cause transient upper GI symptoms and potentially increase ulcer risk during the "off" periods. 1

• Patients with prior ulcer bleeding or multiple risk factors require uninterrupted gastroprotection—any gap in coverage could precipitate life-threatening bleeding. 1

• The proposed 3-month alternating schedule has no evidence base and would create repeated cycles of withdrawal and reinitiation, each potentially triggering RAHS. 1

Addressing PPI Safety Concerns

• The American Gastroenterological Association emphasizes that clinicians should emphasize the safety of PPIs for GERD and gastroprotection. 1

• Long-term PPI users should not routinely screen or monitor bone mineral density, serum creatinine, magnesium, or vitamin B12, as the absolute risks of these associations are very low. 4

• Long-term PPI users should not routinely increase intake of calcium, vitamin B12, or magnesium beyond the Recommended Dietary Allowance. 4

• The dose of long-term PPIs should be periodically reevaluated to ensure the lowest effective dose is used, but therapy should not be discontinued in high-risk patients. 1, 4

• Specific PPI formulations should not be selected based on potential risks; standard-dose omeprazole 20 mg, pantoprazole 40 mg, lansoprazole 30 mg, or esomeprazole 20-40 mg daily are all appropriate. 2, 4

The Correct Approach

Continue uninterrupted PPI therapy at the lowest effective dose for as long as NSAID therapy continues. 1, 2, 4

• Use standard-dose PPI: omeprazole 20 mg daily or pantoprazole 40 mg daily. 2, 3

• If the patient is also on clopidogrel, prefer pantoprazole due to minimal CYP2C19 interaction. 2

• Periodically reassess whether NSAID therapy can be discontinued or reduced, as this is the only way to truly eliminate GI risk. 1

• If NSAIDs cannot be stopped, consider whether a COX-2 inhibitor plus PPI might offer additional protection in very high-risk patients, though this does not eliminate risk. 1

Common Pitfalls to Avoid

• Do not withhold or interrupt PPIs based on theoretical long-term risks—the proven benefit in preventing life-threatening GI bleeding far outweighs unproven or minimal risks. 1, 4

• Do not substitute H2-receptor antagonists for PPIs, as they provide inadequate gastroprotection (effective only for duodenal ulcers, not gastric ulcers). 1, 2

• Do not use rebamipide in patients with established gastropathy or multiple risk factors, as it is demonstrably inferior to PPIs in this population. 6

• Do not assume COX-2 inhibitors eliminate the need for gastroprotection when combined with aspirin or in patients with prior ulcer bleeding. 1, 2