What are the effective drugs for Non-Erosive Reflux Disease (NERD)?

Effective Drugs for Non-Erosive Reflux Disease (NERD)

Proton pump inhibitors (PPIs) are the most effective first-line pharmacotherapy for NERD, with standard-dose once-daily therapy for 4-8 weeks recommended as initial treatment, though they provide more modest therapeutic benefit compared to erosive esophagitis. 1

First-Line Therapy: Standard-Dose PPIs

Initial treatment consists of FDA-approved single-dose PPI therapy for 4-8 weeks, taken 30-60 minutes before a meal. 1

• Any commercially available PPI can be used initially, with choice guided by insurance coverage and cost 1
• Standard doses include: omeprazole 20 mg, lansoprazole 30 mg, esomeprazole 40 mg, or rabeprazole 20 mg once daily 2, 3, 4
• Therapeutic gain of PPIs over placebo ranges from 25-35% for heartburn control in NERD patients 5
• Complete heartburn resolution occurs in approximately 37% of NERD patients at 4 weeks, compared to 56% in erosive esophagitis 5

Important caveat: NERD patients show overall poorer response to PPI treatment than erosive esophagitis patients because NERD encompasses a heterogeneous group—only 50% have pathologic acid exposure, while others have esophageal hypersensitivity or functional heartburn 6, 7

Response Assessment and Dose Optimization

Assess response at 4-8 weeks; if partial or no response occurs, increase to twice-daily PPI (though not FDA-approved) or switch to a more potent acid suppressive agent. 1

• For inadequate response, options include: increasing to twice-daily dosing, switching to PPIs less metabolized through CYP2C19 (rabeprazole, esomeprazole), or using extended-release formulations (dexlansoprazole) 1
• Omeprazole 20 mg demonstrates superior symptomatic relief compared to omeprazole 10 mg or rabeprazole 5 mg 4
• Dexlansoprazole 30 mg shows significantly improved symptomatic relief versus rabeprazole 5 mg 4

Potassium-Competitive Acid Blockers (P-CABs)

P-CABs should generally NOT be used as first-line therapy for NERD; they may be considered in selected patients with documented acid-related reflux who fail twice-daily PPI therapy. 1

• Evidence for P-CABs in NERD is less robust than for erosive esophagitis 1
• One Japanese trial showed vonoprazan had similar low heartburn-free days as placebo (10-12% vs 7%), likely due to enrichment with functional heartburn patients 1
• A second trial showed trend toward higher heartburn-free days with vonoprazan (72% vs 62%, p=0.06) 1
• Cost considerations and less long-term safety data limit P-CAB use as first-line agents 1

Long-Term Management

For patients with sustained symptom resolution, wean to the lowest effective dose and consider converting to on-demand therapy. 1

• On-demand PPI treatment is the best long-term management option for NERD patients who respond to initial therapy 7
• Patients requiring chronic PPI should undergo reflux testing at 1 year to determine appropriateness of lifelong therapy 1
• For on-demand therapy, vonoprazan showed 56-70% complete relief within 3 hours sustained for 24 hours versus 27% with placebo 1

Adjunctive Pharmacotherapy

Adjunctive agents should be personalized to the GERD phenotype rather than used empirically. 1

• Alginate antacids for breakthrough symptoms 1
• H2-receptor antagonists (ranitidine 150 mg twice daily, though availability limited) for nocturnal symptoms or as step-down from PPI 1, 3
• Baclofen for regurgitation or belch-predominant symptoms 1, 8
• Prokinetics for coexistent gastroparesis 1

Management of PPI Non-Responders

If symptoms persist despite optimized PPI therapy, perform endoscopy and prolonged wireless pH monitoring off PPI to confirm GERD diagnosis versus functional disorder. 1

• Patients with physiologic acid exposure (AET <4.0% on all days) and normal endoscopy likely have functional esophageal disorder—stop PPI 1
• For borderline GERD (AET ≥4.0% but not meeting full GERD criteria), optimize PPI with aggressive lifestyle modifications 1
• Consider neuromodulators (tricyclic antidepressants, SSRIs) and behavioral therapy (cognitive behavioral therapy, gut-directed hypnotherapy) for functional heartburn or reflux hypersensitivity 1, 8

Common Pitfalls

• Avoid empiric long-term PPI use without objective confirmation of GERD, as many NERD patients have functional disorders that won't respond to acid suppression 1
• Don't assume treatment failure means more severe disease—consider functional overlay or non-acid reflux 1, 6
• Ensure proper PPI timing (30-60 minutes before meals) as incorrect administration reduces efficacy 1
• Most NERD patients do NOT require chronic PPI therapy and should be considered for de-prescribing after initial symptom control 1