What's the next best treatment step for a 31-year-old male with chronic epigastric pain (abdominal pain above the stomach), worsened by eating, with occasional nausea and diarrhea, whose symptoms have not improved with proton pump inhibitors (PPIs) and has a normal endoscopy and biopsy result, and is currently taking loperamide (anti-diarrheal medication)?

Treatment of Functional Dyspepsia with Nortriptyline

Nortriptyline is the most appropriate next step in treatment for this 31-year-old male with functional dyspepsia who has failed PPI therapy and has normal endoscopic findings.

Clinical Assessment and Diagnosis

This patient presents with classic features of functional dyspepsia (FD):

• Chronic epigastric pain (6 months duration)
• Pain worsens with eating
• Occasional nausea and diarrhea
• Normal endoscopy and biopsy
• Negative H. pylori test
• Failed PPI therapy
• Currently taking loperamide for diarrhea

The normal endoscopy and biopsy rule out structural disease, confirming a diagnosis of functional dyspepsia according to Rome criteria. The patient's symptoms most closely align with the epigastric pain syndrome (EPS) subtype of functional dyspepsia, characterized by pain that worsens with eating 1.

Treatment Algorithm

1. First-line therapy (already tried):

   • H. pylori eradication (patient is negative)
   • PPI therapy (ineffective in this case)

2. Second-line therapy (recommended next step):

   • Tricyclic antidepressants (TCAs) such as nortriptyline

3. Alternative options (less appropriate):

   • Prokinetics (metoclopramide)
   • H2 receptor antagonists (famotidine)
   • SSRIs (citalopram)

Evidence for Nortriptyline

The British Society of Gastroenterology (BSG) guidelines recommend tricyclic antidepressants for patients with functional dyspepsia who fail to respond to first-line therapies such as PPIs 1. TCAs have shown efficacy in managing functional dyspepsia with response rates of 64-70% 2.

Tricyclic antidepressants are particularly effective for the pain component of functional dyspepsia through their neuromodulatory effects 3. The AGA Clinical Practice Update specifically recommends low-dose tricyclic antidepressants for chronic gastrointestinal pain in disorders of gut-brain interaction when first-line therapies fail 1.

Why Not the Other Options?

1. Metoclopramide (Option A):

   • While prokinetics can be useful for dysmotility-like dyspepsia (fullness, bloating), they are less effective for epigastric pain syndrome 1.
   • Metoclopramide has significant side effect concerns including extrapyramidal symptoms and tardive dyskinesia.
   • Guidelines suggest prokinetics only after TCAs have failed 1.

2. Famotidine (Option C):

   • H2 receptor antagonists have lower efficacy than PPIs for acid suppression.
   • Since the patient has already failed PPI therapy, which provides more potent acid suppression, famotidine is unlikely to be effective 1, 4.

3. Citalopram (Option D):

   • SSRIs like citalopram have not shown benefit in patients with functional dyspepsia according to recent evidence 3.
   • Multiple studies indicate that SSRIs are "no better than placebo" for functional dyspepsia 2.

Implementation and Monitoring

• Start nortriptyline at a low dose (10-25mg at bedtime) and titrate slowly.
• Warn the patient about potential side effects including dry mouth, constipation, and drowsiness.
• Monitor for improvement in pain symptoms over 4-6 weeks.
• If partial response, consider dose adjustment.
• If no response after 8 weeks, consider alternative neuromodulators or combination therapy.

Important Considerations

• Avoid opioids for chronic functional dyspepsia as they can worsen symptoms and lead to dependency 1.
• Consider dietary modifications to avoid trigger foods.
• The patient's family history of stomach cancer has been addressed through endoscopy, which was normal.
• The patient's current use of loperamide for diarrhea can be continued but should be reassessed as the diarrhea may improve with nortriptyline due to its anticholinergic effects.

Tricyclic antidepressants represent the most evidence-based approach for this patient with functional dyspepsia who has failed first-line therapy with PPIs and has normal endoscopic findings.