Is Rebamipide Good for GERD? A Review of Its Efficacy

October 9, 2025 •

4 min read

Globally, the prevalence of gastroesophageal reflux disease (GERD) is estimated at about 14% [1.6.3]. This has led to extensive research into various treatments, raising the question: Is rebamipide good for GERD as a therapeutic option?

Quick Summary

Rebamipide, a mucosal protective agent, shows promise in managing GERD, primarily as an add-on therapy to proton pump inhibitors (PPIs). It helps by strengthening the esophageal lining and reducing inflammation, potentially improving symptoms where PPIs alone are insufficient.

Key Points

Adjunctive Role: Rebamipide is most effective for GERD when used as an add-on therapy with Proton Pump Inhibitors (PPIs), not as a standalone treatment [1.2.4].
Mucosal Protection: Unlike PPIs that suppress acid, rebamipide works by protecting the esophageal lining, reducing inflammation, and scavenging free radicals [1.3.2, 1.3.6].
Symptom Improvement: Combination therapy of a PPI and rebamipide has been shown to be more effective at reducing GERD symptoms than PPI monotherapy [1.2.4].
Histological Benefits: In patients with non-erosive reflux disease (NERD), rebamipide can improve the microscopic structure of the esophageal lining [1.2.1].
Safety Profile: Rebamipide is generally well-tolerated, with most side effects being mild and gastrointestinal in nature, such as constipation or bloating [1.5.1, 1.5.2].
Mixed Evidence: While many studies show benefits, some analyses and studies on specific patient groups (like PPI-refractory NERD) have not found significant symptom improvement [1.2.2, 1.2.7].
Mechanism Synergy: The combination of rebamipide and a PPI addresses two key aspects of GERD: acid exposure (PPI) and mucosal defense (rebamipide) [1.4.3].

Understanding GERD and Standard Treatments

Gastroesophageal reflux disease (GERD) is a chronic condition where stomach acid frequently flows back into the esophagus, the tube connecting the mouth and stomach [1.4.3]. This backwash (acid reflux) can irritate the lining of the esophagus. The global burden of GERD has significantly increased, with population growth and aging being major contributors to a rise in cases [1.6.2].

The standard treatment for GERD typically involves proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs) [1.3.1, 1.3.2]. These drugs work by suppressing the production of gastric acid. However, a significant portion of patients, particularly those with non-erosive reflux disease (NERD), may not respond adequately to PPIs alone [1.2.2]. This has prompted investigation into alternative and adjunctive therapies.

What is Rebamipide?

Rebamipide is a gastroprotective drug primarily used for treating gastritis and peptic ulcers [1.3.6]. Unlike PPIs, it does not primarily work by suppressing acid. Instead, its mechanism is multi-faceted, focusing on protecting and healing the mucosal lining of the gastrointestinal tract [1.3.2, 1.3.5].

Mechanism of Action

Rebamipide's protective effects are attributed to several actions:

Increased Mucus and Prostaglandin Production It stimulates the synthesis of prostaglandins and mucous glycoproteins, which form a protective barrier on the mucosal surface [1.3.5, 1.3.7].
Anti-inflammatory Effects The drug inhibits inflammatory reactions by suppressing the activation of neutrophils and the production of inflammatory cytokines [1.3.6, 1.3.7]. Studies show it can decrease the expression of inflammatory markers like IL-8 in the esophageal mucosa [1.2.4].
Free Radical Scavenging Rebamipide acts as an antioxidant, scavenging harmful free radicals that contribute to mucosal damage [1.3.6].
Strengthening Mucosal Barriers In a rat model of GERD, combining rebamipide with a PPI was shown to increase the expression of tight junction proteins (claudin-3 and -4) in the esophageal mucosa. This helps restore the integrity of the esophageal barrier, which is often compromised in GERD [1.4.3].

Is Rebamipide Effective for GERD?

Clinical evidence on rebamipide for GERD presents a mixed but generally positive picture, especially when used in combination with standard therapies.

As an Add-on Therapy to PPIs

Multiple studies suggest that adding rebamipide to a PPI regimen offers superior symptom relief compared to PPI monotherapy.

One large, multinational study on patients with reflux esophagitis found that a combination of esomeprazole (a PPI) and rebamipide resulted in a significantly greater decrease in total symptom scores over four weeks compared to esomeprazole alone [1.2.4]. Another study noted that a higher proportion of GERD patients treated with a PPI plus rebamipide experienced at least a 50% decrease in their total symptom score compared to those on a PPI plus placebo (74.1% vs. 51.7%) [1.2.1]. This synergistic effect is thought to stem from rebamipide's ability to reduce inflammation and improve the mucosal defense of the esophagus, complementing the acid suppression from the PPI [1.2.4, 1.4.3].

For Specific GERD Subtypes

For patients with non-erosive reflux disease (NERD), rebamipide has been shown to improve histologic abnormalities in the esophageal mucosa, such as dilated intercellular spaces and lymphocyte infiltration, even if overall symptom scores do not always show a statistically significant difference compared to a placebo [1.2.1]. However, another study concluded that rebamipide was not effective in controlling reflux symptoms in NERD patients who were already refractory to PPI therapy [1.2.2].

A 2020 meta-analysis concluded that while there was a non-significant trend towards improvement, rebamipide did not significantly improve acid reflux symptoms compared to a placebo across the studies analyzed [1.2.7]. The authors suggested that the investigation into rebamipide's role in GERD is still in its early stages and more research is needed [1.2.7].

Comparison Table: Rebamipide vs. PPI Monotherapy


Feature	Proton Pump Inhibitors (PPIs)	Rebamipide	Combination (PPI + Rebamipide)
Primary Mechanism	Suppresses gastric acid secretion	Protects and heals mucosal lining, anti-inflammatory [1.3.2, 1.3.6]	Suppresses acid and protects mucosa
Primary Use in GERD	First-line treatment for acid suppression [1.3.1]	Adjunctive therapy to enhance mucosal defense [1.2.4]	For patients with insufficient response to PPIs or significant inflammation [1.2.4]
Effect on Symptoms	Reduces heartburn and regurgitation	May help reduce a range of GI symptoms [1.5.8]	Often provides superior symptom relief compared to PPI alone [1.2.4]
Effect on Esophageal Tissue	Allows healing by reducing acid exposure	Reduces inflammation and improves histologic abnormalities [1.2.1]	Provides both acid reduction and mucosal healing, potentially improving tissue integrity [1.4.3]

Safety and Side Effects

Rebamipide is generally considered a safe drug with a low incidence of adverse reactions [1.3.1, 1.5.2]. When side effects do occur, they are often mild and primarily gastrointestinal.

Commonly reported side effects include [1.5.1, 1.5.5]:

Constipation
Bloating or abdominal distention
Diarrhea
Nausea
Taste abnormality

Rarely, more serious side effects like leukopenia (low white blood cell count), thrombocytopenia (low platelet count), and liver dysfunction can occur [1.5.3, 1.5.4]. It is contraindicated for patients with a known hypersensitivity to the drug [1.5.1].

Conclusion

So, is rebamipide good for GERD? The evidence suggests its most effective role is not as a standalone, first-line treatment but as a valuable adjunctive therapy to proton pump inhibitors. Its unique mechanism of protecting the esophageal mucosa, reducing inflammation, and strengthening cellular barriers complements the acid-suppressing action of PPIs [1.2.4, 1.4.3]. For patients who continue to experience symptoms despite PPI treatment, or for those with underlying mucosal inflammation, adding rebamipide may lead to better symptom control and histological improvement [1.2.1, 1.2.4]. However, its efficacy as a monotherapy or in PPI-refractory NERD is less clear, and further high-quality research is needed to solidify its place in GERD treatment guidelines [1.2.2, 1.2.7].

For further reading, you can explore research on mucosal protective agents via the National Center for Biotechnology Information (NCBI).

Frequently Asked Questions

Rebamipide is not typically a replacement for PPIs in GERD treatment. Its primary benefit is seen when used as an adjunctive (add-on) therapy to enhance the effects of PPIs, as it works by protecting the esophageal lining rather than suppressing acid production [1.2.4, 1.3.2].

The main benefit is improved symptom control and mucosal healing. Rebamipide helps protect the esophageal lining from damage, reduces inflammation, and strengthens the tissue barrier, which complements the acid-suppressing effect of PPIs [1.2.4, 1.4.3].

Its effectiveness can vary. Studies show it is beneficial for reflux esophagitis when combined with PPIs [1.2.4]. For non-erosive reflux disease (NERD), results are mixed; it may improve tissue histology but does not always lead to significant symptom relief, especially in patients who don't respond to PPIs [1.2.1, 1.2.2].

Omeprazole is a PPI that works by reducing the amount of acid your stomach produces. Rebamipide is a mucosal protective agent that works by increasing protective mucus, boosting blood flow, and reducing inflammation in the gastrointestinal lining [1.3.1, 1.3.2].

Rebamipide is generally well-tolerated. The most common side effects are mild and gastrointestinal, including constipation, abdominal bloating, diarrhea, nausea, and taste abnormalities [1.5.1, 1.5.5].

In clinical studies where rebamipide was combined with a PPI, significant improvements in symptom scores were observed within a 4-week treatment period [1.2.4].

There is not yet a firm consensus or universal guideline for its use in GERD. While several studies and meta-analyses show a benefit for combination therapy, some reviews conclude that its role is not yet firmly established and requires more research [1.2.7, 1.4.6].