How to treat acid reflux that doesn't respond to Proton Pump Inhibitors (PPIs), prokinetics, and Histamine-2 (H2) blockers?

From the Guidelines

For acid reflux that doesn't respond to standard medications like PPIs, prokinetics, and H2 blockers, consider a precision approach to escalation of management, driven by factors such as integrity of the anti-reflux barrier, presence of visceral hypersensitivity and hypervigilance, confirmation of PPI refractory-GERD, symptom profile, body mass index, and esophageal motor function, as recommended by the AGA clinical practice update on the personalized approach to the evaluation and management of GERD 1.

Key Considerations

• Before pursuing advanced treatments, ensure that the patient has received education on GERD pathophysiology and lifestyle modifications, and has been involved in a shared decision-making model 1.
• A 4- to 8-week trial of single-dose PPI is considered safe and appropriate for patients with typical reflux symptoms and no alarm symptoms, with escalation to twice-a-day dosing or switching to a more potent acid suppressive agent if symptoms persist 1.
• Objective reflux testing, such as upper GI endoscopy, is warranted in PPI non-response, presence of alarm signs/symptoms, isolated extra-esophageal symptoms, or in patients who meet criteria to undergo screening for Barrett’s esophagus 1.
• In patients without erosive disease on endoscopy and with physiologic acid exposure, neuromodulation or behavioral interventions can be utilized, and PPI therapy can be titrated off as tolerated 1.

Additional Recommendations

• Combination therapy with a PPI twice daily plus an H2 blocker at night, and alginate-based formulations after meals and before bedtime, can create a physical barrier against reflux and may be beneficial in some patients.
• Lifestyle modifications, such as elevating the head of the bed, avoiding eating within 3 hours of bedtime, eliminating trigger foods, losing weight if needed, and wearing loose clothing, remain crucial in managing acid reflux.
• Refractory reflux may indicate misdiagnosis, so consider evaluation for other conditions like eosinophilic esophagitis, achalasia, or functional heartburn, and specialized testing including impedance-pH monitoring while on medication can determine if symptoms are truly acid-related or due to non-acid reflux.

From the Research

Treatment Options for Acid Reflux Unresponsive to PPI, Prokinetics, and H2 Blockers

• For patients with gastroesophageal reflux disease (GERD) that does not respond to proton pump inhibitors (PPIs), prokinetics, and histamine-2 (H2) blockers, several alternative treatment options are available 2, 3, 4, 5.
• These options include:
  • Pharmacologic treatments:
    • Antacids
    • Alginates
    • Bile acid binders
    • Reflux inhibitors
    • Antidepressants
    • Potassium competitive acid blockers (PCABs)
    • Gamma aminobutyric acid-B (GABA-B) receptor agonists
    • Metabotropic glutamate receptor-5 (mGluR5) antagonists
    • Pain modulators
  • Procedural options:
    • Laparoscopic fundoplication
    • LINX
    • Endoscopic procedures, such as transoral incisionless fundoplication (TIF) and Stretta
• The choice of treatment should be based on the underlying mechanism of PPI failure and the patient's specific symptoms and needs 3, 4.
• Diagnostic workup, including endoscopy and pH-impedance investigations, may be necessary to determine the cause of PPI-refractory GERD and to guide treatment decisions 2, 3.

Evaluation and Diagnosis

• Evaluation of patients with PPI-refractory GERD should start with a symptom assessment and may progress to imaging, endoscopy, and monitoring of esophageal pH, impedance, and bilirubin 2.
• Upper endoscopy may have limited diagnostic value, but esophageal impedance with pH testing on therapy can provide insightful information about the subsequent management of these patients 4.

Management Strategies

• Management strategies for refractory GERD include:
  • Checking patient compliance with PPIs and adjusting the timing of administration or switching to a different PPI 3.
  • Using alternative pharmacologic treatments, such as those listed above.
  • Considering invasive antireflux options, such as laparoscopic antireflux surgery (LARS), TIF, LINX, or radiofrequency therapy (Stretta), if medical therapy is ineffective and there is objective evidence of GERD 3.