What are the recommended next steps in managing a patient with persistent reflux‑type symptoms, a normal recent endoscopy, esophageal hypersensitivity on Bravo pH‑impedance testing, ineffective esophageal motility with a hiatal hernia on high‑resolution manometry, and only intermittent relief from famotidine and simethicone after multiple failed trials of proton pump inhibitors, baclofen, and venlafaxine?

Management of Persistent Reflux Symptoms with Esophageal Hypersensitivity and Ineffective Motility

Restart twice-daily PPI therapy immediately and add a trial of low-dose tricyclic antidepressant (TCA) neuromodulation, as this patient has esophageal hypersensitivity confirmed on pH testing—a phenotype that requires both acid suppression and visceral pain modulation rather than continued empiric trials of reflux-reducing agents. 1, 2

Understanding the Clinical Phenotype

Your patient's diagnostic workup has clearly defined the problem:

• Esophageal hypersensitivity confirmed on Bravo pH testing means symptoms are triggered by normal or near-normal amounts of reflux, indicating heightened esophageal perception rather than excessive acid exposure 1
• Ineffective esophageal motility with peristaltic reserve on high-resolution manometry indicates impaired but not absent clearance, which contributes to prolonged mucosal contact time with refluxate 1
• Manometric hiatal hernia disrupts the anti-reflux barrier and increases transient lower esophageal sphincter relaxations (TLESRs), the primary mechanism of both acid and non-acid reflux 2
• Normal recent endoscopy rules out erosive disease, Barrett's esophagus, stricture, and eosinophilic esophagitis, confirming this is a functional disorder rather than structural pathology 1, 3

The British Society of Gastroenterology guidelines explicitly state that approximately 60% of non-erosive reflux disease patients refractory to PPIs have a positive reflux-symptom association primarily due to non-acid reflux, and classifying patients with symptomatic non-acid reflux as having a hypersensitive esophagus guides therapy away from escalating acid suppression alone 1

Immediate Management Steps

Step 1: Reinitiate Twice-Daily PPI Therapy

• Resume pantoprazole 40 mg twice daily (or equivalent PPI: omeprazole 20 mg, esomeprazole 40 mg, lansoprazole 30 mg) taken 30–60 minutes before breakfast and dinner 1, 2
• The American Gastroenterological Association recommends twice-daily PPI as first-line for chest pain and throat symptoms suspected to be reflux-related, even when pH testing shows hypersensitivity rather than excessive acid exposure 1, 2
• Continue for a minimum of 8–12 weeks before assessing response, as extraesophageal symptoms (globus, throat burning) require longer treatment duration than typical heartburn 1, 2

Rationale: Although your patient's Bravo study met criteria for esophageal hypersensitivity rather than pathological acid exposure, the British Society of Gastroenterology guidelines emphasize that patients with hypersensitivity to non-acid reflux still benefit from acid suppression because reducing the acidity of refluxate decreases mucosal irritation and symptom generation 1

Step 2: Add Neuromodulator Therapy for Esophageal Hypersensitivity

• Initiate low-dose tricyclic antidepressant (TCA): start with amitriptyline 10 mg or nortriptyline 10 mg at bedtime, increasing by 10 mg every 1–2 weeks as tolerated to a target dose of 25–50 mg 2, 4
• Alternative if TCA is not tolerated: selective serotonin reuptake inhibitor (SSRI) such as citalopram 10–20 mg daily or sertraline 25–50 mg daily 2, 4

Rationale: The patient already failed venlafaxine (an SNRI), but TCAs have the strongest evidence for visceral hypersensitivity and esophageal pain modulation in refractory GERD 2, 4. TCAs work by modulating central and peripheral pain pathways, reducing esophageal hypersensitivity to both acid and non-acid reflux events 4, 5. The British Society of Gastroenterology guidelines specifically recommend neuromodulation for patients with esophageal hypersensitivity identified on pH-impedance testing 1

Step 3: Optimize Lifestyle and Dietary Modifications

• Elevate head of bed by 6–8 inches using blocks under bed legs (not just pillows) to reduce nocturnal reflux and regurgitation 2, 6
• Avoid lying down for 3 hours after meals to allow gastric emptying and reduce postprandial reflux 2, 6
• Limit dietary fat to ≤45 grams per day and eliminate coffee, tea, carbonated beverages, chocolate, mints, citrus, tomatoes, and alcohol 2, 6
• Weight loss if BMI ≥25 kg/m², as this is the single most effective lifestyle intervention with Grade B evidence 2, 6

Step 4: Consider Alginate-Antacid Combination for Breakthrough Symptoms

• Add alginate-antacid combination (e.g., Gaviscon Advance) 10 mL after meals and at bedtime for breakthrough regurgitation and globus symptoms 2, 4
• This provides a physical barrier that floats on gastric contents and reduces proximal reflux extent, which is particularly relevant given the barium swallow finding of spontaneous reflux to the proximal esophagus 2, 4

Timeline and Reassessment

• Allow 8–12 weeks of combined PPI + neuromodulator therapy before concluding treatment failure 1, 2
• Schedule follow-up at 4 weeks to assess medication tolerance and titrate TCA dose, then at 12 weeks to assess symptom response 2
• If symptoms improve by ≥50%, continue therapy for 6–12 months before attempting gradual taper 2, 4

If Symptoms Persist After 12 Weeks of Optimized Medical Therapy

Option A: Repeat pH-Impedance Testing On PPI

• Perform 24-hour pH-impedance monitoring while on twice-daily PPI to determine if there is persistent pathological reflux (acid or non-acid) or if symptoms are occurring without reflux events (functional heartburn) 1
• This distinguishes true PPI-refractory GERD from esophageal hypersensitivity versus functional heartburn, which have different management strategies 1

Option B: Trial of Reflux Inhibitor (Baclofen)

• Although the patient previously discontinued baclofen due to sleepiness, consider retrying at a lower dose: start with 5 mg three times daily and increase gradually to 10 mg three times daily only if tolerated 4, 7, 5
• Baclofen is a GABA-B agonist that reduces transient lower esophageal sphincter relaxations (TLESRs), the primary mechanism of reflux in patients with hiatal hernia 7, 5, 6
• Take 30 minutes before meals to maximize effect on postprandial TLESRs 7, 5

Caveat: Baclofen's central nervous system side effects (drowsiness, dizziness, confusion) limit its use, but lower starting doses and slower titration may improve tolerability 7, 5, 6. The patient's previous trial at 10 mg three times daily may have been too aggressive an initial dose 7

Option C: Consider Anti-Reflux Surgery

• Laparoscopic fundoplication (partial fundoplication preferred given ineffective esophageal motility) is appropriate for carefully selected patients with confirmed reflux hypersensitivity who have failed medical therapy for at least 3 months 1, 4, 5
• The American Gastroenterological Association states that high-quality evidence for anti-reflux surgery efficacy exists for patients with excessive distal esophageal acid exposure or esophagitis when PPI therapy is withheld, and requires preserved peristaltic function 1
• Candidacy criteria: (1) objective documentation of pathological reflux on pH testing off PPI, (2) symptom-reflux correlation on impedance testing, (3) preserved esophageal peristalsis (which this patient has—ineffective motility with peristaltic reserve), (4) failed medical therapy for ≥3 months, (5) significant quality of life impairment 1, 2, 4

Important consideration: The patient's most recent Bravo study showed esophageal hypersensitivity rather than pathological acid exposure, which is a less robust indication for surgery than proven excessive acid reflux 1, 4. However, approximately two-thirds of patients with reflux hypersensitivity respond to anti-reflux surgery, though the response rate is lower than in patients with proven pathological acid reflux 4, 5

What NOT to Do: Common Pitfalls

• Do not continue famotidine as primary therapy—H2-receptor antagonists are significantly less effective than PPIs for GERD and are appropriate only as adjunctive therapy for breakthrough nocturnal symptoms 2, 6, 8
• Do not add nocturnal H2RA to twice-daily PPI—the American Gastroenterological Association recommends against this combination as standard practice due to lack of evidence for improved efficacy and risk of tachyphylaxis 2
• Do not perform repeat endoscopy—the patient had normal endoscopy in the most recent evaluation, and repeating endoscopy is not indicated unless new alarm symptoms develop (dysphagia, weight loss, bleeding) 1, 3
• Do not trial metoclopramide—prokinetic agents have not been proven effective for GERD symptom control and carry significant risk of tardive dyskinesia with prolonged use 2, 6, 8
• Do not continue empiric therapy indefinitely without objective testing—if symptoms persist after 12 weeks of optimized medical therapy, repeat pH-impedance testing on PPI is necessary to guide further management 1, 2

Why This Approach Is Evidence-Based

The British Society of Gastroenterology 2019 guidelines provide the strongest and most recent evidence for managing esophageal hypersensitivity, explicitly stating that pH-impedance monitoring allows recognition of patients with hypersensitivity to non-acid reflux and esophageal distension, and that these patients require management focused on modulating esophageal perception and reducing reflux burden 1. The combination of acid suppression plus neuromodulation addresses both components of the pathophysiology: reducing the chemical stimulus (refluxate acidity) and modulating the heightened perception of normal physiologic reflux events 1, 2, 4.