What are the Rome IV criteria for functional chest pain, its diagnostic work‑up, and recommended management?

Rome IV Functional Chest Pain: Diagnostic Criteria, Work-Up, and Management

Rome IV Diagnostic Criteria

Functional chest pain is diagnosed when recurrent retrosternal chest pain or discomfort occurs in the absence of gastroesophageal reflux disease (GERD), eosinophilic esophagitis, major esophageal motor disorders, or structural abnormalities, and is not better explained by another functional esophageal disorder. 1

The Rome IV criteria require:

• Midline chest pain or discomfort that is not of burning quality 1
• Absence of symptom relief with acid suppression 1
• Absence of GERD (by endoscopy and pH/impedance testing) 1, 2
• Absence of major esophageal motor disorders (by high-resolution manometry) 1, 2
• Symptoms present for at least 3 months with onset at least 6 months before diagnosis 1

Mandatory Diagnostic Work-Up Sequence

Step 1: Exclude Cardiac Causes (Always First)

• Obtain a 12-lead ECG within 10 minutes and measure high-sensitivity cardiac troponin immediately to rule out acute coronary syndrome 3, 4
• Cardiac evaluation must be completed before any gastrointestinal work-up begins 1, 2

Step 2: Proton Pump Inhibitor (PPI) Trial

• Administer high-dose PPI therapy (e.g., omeprazole 40 mg twice daily or equivalent) for 8 weeks 1, 2, 5
• If symptoms resolve, the diagnosis is GERD-related chest pain, not functional chest pain 2

Step 3: Upper Endoscopy with Esophageal Biopsies

• Perform endoscopy to exclude eosinophilic esophagitis, esophageal strictures, rings, or mucosal abnormalities 1, 2
• Obtain esophageal mucosal biopsies even if mucosa appears normal 1

Step 4: Ambulatory Reflux Monitoring

• Perform wireless pH capsule or pH-impedance monitoring off PPI therapy for 48–96 hours 2
• This definitively excludes GERD as the cause 1, 2

Step 5: High-Resolution Esophageal Manometry

• Perform high-resolution manometry to exclude major motor disorders (achalasia, distal esophageal spasm, jackhammer esophagus, absent contractility) 1, 2
• Minor motor abnormalities (ineffective esophageal motility, fragmented peristalsis) do not exclude functional chest pain 2

Step 6: Esophageal Sensory Testing (Optional)

• Esophageal balloon distension testing can identify visceral hypersensitivity, which serves as a biomarker for functional chest pain 6, 5
• This test is not required for diagnosis but supports the mechanism 6

Pathophysiology

Esophageal hypersensitivity (visceral hyperalgesia) is the primary mechanism underlying functional chest pain and can be considered a biomarker for this disorder. 6, 5

• Central sensitization and peripheral afferent neuronal dysfunction of the esophagus drive symptom generation 5
• Psychological comorbidities—anxiety, depression, neuroticism, and somatization—are present in the majority of patients 6, 2
• These psychological factors are often secondary outcomes rather than primary causes 3

Evidence-Based Treatment Algorithm

First-Line: Neuromodulators (Pain Modulators)

Tricyclic antidepressants (TCAs) are the first-line pharmacologic treatment for functional chest pain. 1, 2, 7

• Imipramine 50 mg at bedtime (titrate up to 150 mg as tolerated) 2, 7
• Trazodone 100–150 mg at bedtime is an alternative with fewer anticholinergic side effects 7
• TCAs work by modulating visceral pain perception, not by treating depression 2, 7

Second-Line: Alternative Neuromodulators

If TCAs are not tolerated or ineffective:

• Selective serotonin reuptake inhibitors (SSRIs): sertraline, citalopram, or paroxetine 7
• Serotonin-norepinephrine reuptake inhibitors (SNRIs): venlafaxine or duloxetine 7
• Pregabalin 75–150 mg twice daily for neuropathic-type pain 7
• Ramelteon (melatonin receptor agonist) for patients with sleep disturbance 7

Adjunctive Non-Pharmacologic Interventions

Cognitive-behavioral therapy (CBT) is recommended as a Class IIa intervention for functional chest pain and should be offered alone or in combination with neuromodulators. 4, 1

• Biofeedback and hypnotherapy have demonstrated efficacy in reducing symptom frequency and severity 6, 1
• These interventions address the psychological comorbidities that perpetuate visceral hypersensitivity 6, 2

Therapies to Avoid

• Do not continue high-dose PPI therapy once GERD has been excluded; it provides no benefit and increases cost and side-effect risk 1, 2
• Do not prescribe smooth muscle relaxants (calcium channel blockers, nitrates, phosphodiesterase-5 inhibitors) for functional chest pain; these are indicated only for esophageal spastic motor disorders 7

Common Diagnostic Pitfalls

• Do not diagnose functional chest pain without completing the full diagnostic work-up; premature diagnosis leads to inappropriate treatment and persistent symptoms 1, 2
• Do not attribute symptoms to anxiety or psychological factors until objective testing excludes GERD and motor disorders; this perpetuates underdiagnosis 3, 2
• Do not confuse functional chest pain with globus pharyngeus; globus is a sensation of a lump in the throat that improves with eating, whereas functional chest pain is retrosternal and unrelated to swallowing 3
• Recognize that functional chest pain and functional dysphagia can coexist in 20% of patients, but they are distinct diagnoses 3

Quality-of-Life Impact

Functional chest pain produces quality-of-life impairment comparable to that seen in head and neck cancer patients, with significant social withdrawal, anxiety, panic, and depression 3. Addressing psychological comorbidities through CBT and neuromodulators is essential for improving morbidity and quality of life 4, 6, 2.