What neuromodulators can be used to treat patients with Non-Erosive Reflux Disease (NERD) who have not responded to first-line treatments?

Neuromodulators for NERD

For patients with NERD who have failed PPI therapy and have physiologic acid exposure on testing, neuromodulators should be initiated as they target the underlying visceral hypersensitivity and esophageal dysfunction that drives symptoms in these patients. 1

When to Consider Neuromodulators

The 2022 AGA guidelines provide clear direction on when neuromodulators are appropriate for NERD patients:

• Patients without erosive disease on endoscopy AND with physiologic (normal) acid exposure on prolonged wireless pH monitoring off PPI therapy should be considered for neuromodulation or behavioral interventions 1
• These patients often have a functional esophageal disorder rather than true acid-mediated disease 1
• PPI therapy can be titrated off as tolerated in this population once neuromodulators are initiated 1

Which Neuromodulators to Use

While the guidelines mention neuromodulators as a treatment option for NERD and extraesophageal reflux symptoms, specific agents are not detailed in the current AGA recommendations 1. The evidence notes that "more robust data are needed" regarding specific neuromodulator protocols 1.

Based on the pathophysiology described in the research literature:

• Tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) are the primary neuromodulator classes used, as NERD involves visceral hypersensitivity, esophageal motor abnormalities, and psychic effects 2, 3
• The choice targets esophageal hypersensitivity, which is the key mechanism in NERD patients with normal acid exposure 3

Clinical Algorithm for NERD Management

Step 1: Initial PPI Trial

• Start with standard-dose PPI once daily for 4-8 weeks 1
• If inadequate response, increase to twice daily 1

Step 2: Diagnostic Workup for PPI Non-Responders

• Perform endoscopy to rule out erosive disease (Los Angeles B or greater) or Barrett's esophagus 1
• If endoscopy is negative, obtain prolonged wireless pH monitoring OFF PPI therapy (96-hour preferred) 1

Step 3: Treatment Based on pH Monitoring Results

• If physiologic acid exposure: Initiate neuromodulators and/or behavioral interventions; taper PPI as tolerated 1
• If pathologic acid exposure: Optimize anti-reflux therapy with continued PPI or consider surgical options 1

Complementary Approaches

Neuromodulators work best when combined with:

• Cognitive-behavioral therapy 1
• Lifestyle modifications including weight management, dietary changes, and relaxation strategies 1
• Hypnotherapy may have a role in reducing symptoms 1

Critical Pitfall to Avoid

Do not continue empiric PPI therapy long-term without objective testing in NERD patients. Up to 50-60% of patients with reflux-like symptoms do not have true GERD and will not respond to acid suppression 1. Continuing PPIs in these patients exposes them to unnecessary medication risks without benefit 1. The guidelines explicitly state that appropriateness of PPI therapy should be evaluated within 12 months if GERD is unproven, with endoscopy and pH monitoring offered to establish appropriate long-term use 1.