In a male in his early 30s with a 4–5‑week history of recurrent, severe, position‑sensitive nausea that worsens with fatty or large meals, coffee, and post‑prandial movement and is accompanied by autonomic signs (tachycardia, hypersalivation, clamminess), with normal prior gastroscopy (mild gastritis) and colonoscopy, pending gastric biopsies and an upcoming abdominal CT, and currently taking domperidone, omeprazole, and ondansetron, what is the most likely diagnosis and what are the appropriate next diagnostic and therapeutic steps?

Most Likely Diagnosis and Management

The most likely diagnosis is functional dyspepsia with postprandial distress syndrome (PDS), possibly with delayed gastric emptying, given the 4–5 week duration of meal-triggered nausea with autonomic features, position sensitivity, and normal structural workup. 1

Diagnostic Reasoning

Why Functional Dyspepsia (PDS Subtype) is Most Likely

• The clinical presentation meets Rome IV criteria for PDS: bothersome postprandial fullness and nausea triggered by meals (especially fatty/large portions), occurring ≥3 times per week for >8 weeks using clinical criteria, with normal endoscopy findings. 1

• The British Society of Gastroenterology (2022) explicitly states that nausea can be present in functional dyspepsia, and vomiting is atypical—this patient has severe nausea without persistent vomiting, fitting the PDS pattern perfectly. 1

• Gastroparesis and functional dyspepsia are symptom-based constructs with significant overlapping features that cannot be fully distinguished by symptoms alone; the BSG recommends using the term "FD with or without delayed gastric emptying" rather than overemphasizing motor deficits. 1

Why Cyclic Vomiting Syndrome is Less Likely

• CVS requires discrete episodes lasting <7 days with complete symptom-free intervals of ≥1 week between episodes. 1 This patient has daily morning nausea with fluctuating severity but no true asymptomatic periods, which does not meet CVS criteria.

• The AGA (2024) notes that coalescent CVS can present with chronic nausea, but patients universally endorse years of prior episodic vomiting before the coalescent phase. 1 This patient has only 4–5 weeks of symptoms with no prior episodic history.

• The prominent autonomic features (tachycardia, hypersalivation, clamminess) can occur in both CVS and functional dyspepsia with autonomic dysfunction, so these do not distinguish between diagnoses. 1

Appropriate Next Diagnostic Steps

Complete Pending Workup (Within 1–2 Weeks)

• Await gastric biopsy results to exclude H. pylori, eosinophilic gastritis, or other microscopic pathology not visible on gross endoscopy. 1

• Proceed with scheduled abdominal CT to definitively exclude structural lesions, malignancy, or chronic pancreatitis. 1

Consider Gastric Emptying Study (If Symptoms Persist After CT)

• Gastric emptying scintigraphy of a radiolabeled solid meal performed for 4 hours is the gold standard for detecting delayed gastric emptying, which is present in 25–40% of functional dyspepsia patients. 1

• The AGA (2004) emphasizes that 4-hour testing increases diagnostic yield compared to 2-hour protocols in symptomatic patients. 1

• However, the BSG (2022) notes that gastric emptying results do not change management in most FD cases, as treatment is symptom-based regardless of emptying rate. 1 Order this test only if it will influence therapeutic decisions (e.g., considering gastric electrical stimulation for refractory cases).

Do NOT Pursue

• Repeated endoscopy is not indicated unless new alarm symptoms develop (hematemesis, progressive dysphagia, significant weight loss). 1, 2

• Antroduodenal manometry is reserved for suspected chronic intestinal pseudo-obstruction or when considering surgical intervention, not for routine functional dyspepsia evaluation. 1

Appropriate Therapeutic Steps

Immediate Optimization of Current Regimen (Days 1–14)

The current triple therapy (domperidone + omeprazole + ondansetron) is partially appropriate but requires adjustment:

Continue Prokinetic Therapy

• Domperidone 10 mg TID before meals should be continued as it is the preferred prokinetic in many countries and is already providing partial benefit. 1

• Metoclopramide 10–20 mg TID is an alternative if domperidone efficacy plateaus, though it carries higher risk of extrapyramidal side effects. 1, 2

Optimize Acid Suppression

• Omeprazole 40 mg BID is appropriate for the first 4–8 weeks to address the mild gastritis found on prior endoscopy and potential laryngopharyngeal reflux (morning throat rattling). 1

• After 8 weeks, attempt to de-escalate to omeprazole 20 mg daily or discontinue if symptoms are controlled, as prolonged high-dose PPI use can cause electrolyte disturbances. 3

Adjust Antiemetic Strategy

• Ondansetron 8 mg TID should be continued on a scheduled basis (not PRN) for the next 2–4 weeks, as prevention is more effective than treating established nausea. 2

• If nausea persists after 4 weeks of ondansetron, add prochlorperazine 10 mg QID rather than replacing ondansetron, to engage different dopaminergic pathways. 2, 3

• Monitor QTc interval if using ondansetron long-term, especially given the autonomic features (tachycardia) already present. 2

Dietary and Lifestyle Modifications (Ongoing)

• Small, frequent meals (5–6 per day) with low-fat, low-fiber content are essential for PDS management. 1

• Avoid trigger foods identified by the patient: chocolate, cheese, cured meats, sushi, coffee, and large portion sizes. 1

• Maintain upright posture or 30-degree head elevation for 2–3 hours after meals to minimize position-sensitive nausea. 1

• Ensure adequate hydration (≥1.5 L/day) to prevent dehydration-related nausea exacerbation. 2

Second-Line Therapy (If No Improvement After 4–6 Weeks)

If symptoms remain bothersome despite optimized prokinetic + antiemetic therapy:

Add Neuromodulator Therapy

• Amitriptyline 25 mg at bedtime, titrated by 10–25 mg every 2 weeks to a goal of 75–150 mg is the preferred neuromodulator for functional dyspepsia with prominent nausea. 1

• Tricyclic antidepressants reduce gastric hypersensitivity and have antiemetic properties independent of their psychiatric effects. 1

• Slow titration minimizes anticholinergic side effects (dry mouth, constipation, somnolence). 1

Consider Psychological Interventions

• Cognitive behavioral therapy or gut-directed hypnotherapy may be beneficial for functional dyspepsia, particularly when anxiety amplifies symptoms. 1

• The BSG (2022) notes that improving anxiety may decrease symptom frequency and improve overall functional status. 1

Third-Line Therapy (Refractory Cases After 8–12 Weeks)

If symptoms remain severe and disabling despite above measures:

• Olanzapine 5–10 mg daily provides broad-spectrum antiemetic activity (dopamine, serotonin, histamine receptors) and has Category 1 evidence for refractory nausea. 2

• Gastric electrical stimulation is an emerging therapy for refractory gastroparesis/functional dyspepsia but requires specialized center referral. 1

• Feeding jejunostomy is reserved for severe malnutrition when all pharmacologic options have failed. 1

Critical Pitfalls to Avoid

Do Not Misdiagnose as CVS

• Do not initiate CVS-specific prophylaxis (amitriptyline for CVS) without confirming episodic pattern with symptom-free intervals. 1 This patient's daily symptoms do not meet CVS criteria.

Do Not Overlook Autonomic Dysfunction

• The prominent autonomic features (tachycardia, clamminess, hypersalivation) suggest possible postural orthostatic tachycardia syndrome (POTS), which is observed in a substantial subgroup of CVS patients but can also occur in functional dyspepsia. 1

• Consider cardiology referral for tilt-table testing if orthostatic symptoms are prominent, as treating POTS may improve overall functional status. 1

Do Not Use Antiemetics in Undiagnosed Obstruction

• Never escalate antiemetic therapy before the scheduled CT scan excludes mechanical obstruction, as antiemetics can mask progressive ileus. 2, 3

Do Not Ignore Constipation

• The patient reports constipation likely secondary to ondansetron and domperidone; add polyethylene glycol 17 g daily to prevent fecal impaction, which can worsen nausea. 2

Do Not Prolong High-Dose PPI Unnecessarily

• Omeprazole 40 mg BID should not continue beyond 8 weeks without reassessment, as it may contribute to electrolyte disturbances (hypomagnesemia) that exacerbate autonomic symptoms. 3

Prognosis and Follow-Up

• 80% of functional dyspepsia patients will have symptom improvement with optimized medical therapy (prokinetic + acid suppression + neuromodulator). 1

• Reassess at 4-week intervals to titrate medications and identify treatment failures early. 1, 2

• If symptoms persist beyond 12 weeks despite maximal medical therapy, refer to a tertiary motility center for consideration of advanced diagnostics (antroduodenal manometry, wireless motility capsule) or experimental therapies. 1