What is the appropriate first‑line proton‑pump inhibitor regimen for an adult with functional dyspepsia without alarm features?

PPI Use in Functional Dyspepsia

Proton pump inhibitors are the first-line pharmacologic treatment for functional dyspepsia after H. pylori testing and eradication (if positive), using standard-dose PPI (e.g., omeprazole 20 mg once daily) for 4–8 weeks. 1, 2, 3

Initial Management Algorithm

Step 1: H. pylori Testing

• All patients with functional dyspepsia must undergo non-invasive H. pylori testing (¹³C-urea breath test or stool antigen test preferred over serology) as the initial intervention, regardless of symptom subtype. 1, 2
• If H. pylori-positive, provide eradication therapy immediately; this eliminates peptic ulcer mortality risk and provides modest symptom improvement in a minority of functional dyspepsia patients. 1, 2

Step 2: Empirical PPI Therapy

• For H. pylori-negative patients or those with persistent symptoms after successful eradication, prescribe a standard-dose PPI (omeprazole 20 mg or equivalent) once daily, taken 30–60 minutes before a meal, for 4–8 weeks. 1, 2, 3
• PPIs demonstrate superiority over placebo (NNTB 11), H2-receptor antagonists, and antacid-alginate combinations for symptom relief in functional dyspepsia. 2, 3, 4
• PPIs are particularly effective for the epigastric pain syndrome (EPS) subtype of functional dyspepsia. 2, 3

Dose Escalation Protocol

• If symptoms persist after 4–8 weeks of once-daily PPI, escalate to twice-daily dosing (morning and evening before meals) for an additional 4–8 weeks. 2, 3
• Early response during the first week of PPI treatment is the strongest predictor of 4-week treatment success; fewer symptomatic days in week one correlate with higher response rates. 5

Second-Line Treatment Options

When PPI Monotherapy Fails

• Tricyclic antidepressants (TCAs) at low doses are the most effective second-line therapy, particularly for refractory epigastric pain syndrome. 2, 6
• Start amitriptyline 10 mg once nightly at bedtime and titrate slowly to a maximum of 30–50 mg daily based on symptom response and tolerability. 2
• Provide thorough counseling about the gut-brain neuromodulatory rationale and potential side effects when prescribing TCAs. 2

Alternative Second-Line Agents

• Prokinetic agents may be added for patients with predominant postprandial distress syndrome (PDS) symptoms (fullness, bloating, early satiety) who fail PPI therapy. 2, 3
• Avoid cisapride due to fatal cardiac arrhythmias and QT prolongation. 2
• Combination therapy of PPI plus prokinetic (e.g., acotiamide) may provide additional benefit in selected patients with residual symptoms despite PPI monotherapy, with 78% achieving overall symptom improvement in one study. 7

Important Clinical Considerations

Age-Based Approach

• Patients ≤55 years without alarm features should receive H. pylori test-and-treat followed by empirical PPI if symptoms persist. 1
• Patients >55 years with treatment-resistant dyspepsia warrant non-urgent endoscopy to exclude organic disease. 2

When to Consider Endoscopy

• Urgent endoscopy is indicated for alarm features: dysphagia, gastrointestinal bleeding, anemia, unintentional weight loss, or recurrent vomiting. 2, 3
• If symptoms persist despite optimized twice-daily PPI therapy for 8 weeks, perform upper endoscopy and consider off-medication prolonged wireless pH monitoring to confirm or exclude GERD. 3

Adjunctive Non-Pharmacologic Measures

• Regular aerobic exercise is recommended for all patients with functional dyspepsia as an evidence-based adjunctive measure. 2, 3
• Patients should avoid foods that trigger symptoms while being cautious not to adopt overly restrictive diets that could lead to malnutrition or eating disorders. 2
• Early involvement of a dietitian is recommended for patients with refractory symptoms. 2

Common Pitfalls to Avoid

• Do not use topical capsaicin, oral gabapentin, or oral sucralfate for functional dyspepsia—these agents lack evidence of efficacy. 3
• Avoid opioids and surgical interventions in severe or refractory functional dyspepsia to minimize iatrogenic harm. 2
• Do not perform routine gastric emptying studies or 24-hour pH monitoring in patients with typical functional dyspepsia symptoms. 2
• Empirical PPI therapy is the most cost-effective initial approach in populations with low H. pylori prevalence (≤10%), while test-and-treat is preferable when prevalence exceeds 10%. 1, 6

Refractory Cases

• A multidisciplinary team including primary care physicians, dietitians, gastroenterologists, and psychologists is mandatory for managing severe or refractory functional dyspepsia. 2
• Screen patients with severe symptoms, weight loss, or restrictive eating patterns for eating disorders such as avoidant restrictive food intake disorder (ARFID). 2
• Referral to gastroenterology is appropriate when there is diagnostic uncertainty, symptoms are severe or refractory to first-line treatments, or the patient requests specialist input. 2