What are the recommended prokinetic agents (e.g. metoclopramide, domperidone) for managing Gastroesophageal Reflux Disease (GERD)?

Prokinetic Agents for GERD

Prokinetic agents are NOT recommended for routine treatment of GERD due to insufficient evidence of benefit and significant adverse effects. 1, 2

Current Guideline Recommendations

Strong Recommendation Against Metoclopramide

• The American Gastroenterological Association explicitly recommends against metoclopramide as monotherapy or adjunctive therapy in patients with GERD (Grade D recommendation) 1
• Metoclopramide carries a black box warning from the FDA for adverse effects including drowsiness, restlessness, and extrapyramidal reactions occurring in 11-34% of patients 1
• Pediatric guidelines unequivocally state there is insufficient evidence to support routine use of any prokinetic agent for GERD treatment in infants or older children 1

Limited Role for Specific Prokinetics

Baclofen may be considered only as adjunctive therapy in highly selected cases:

• Reserved for patients with regurgitation-predominant or belch-predominant symptoms refractory to PPI therapy 1
• Works as a GABA-B agonist to reduce transient lower esophageal sphincter relaxations 1
• Frequently limited by CNS and GI side effects including somnolence, dizziness, weakness, and trembling 1

Asian prokinetics (mosapride, itopride, domperidone):

• Available in Asia with overall modest effect 1
• A systematic review showed no benefit when adding mosapride to PPI compared with PPI monotherapy 1
• A 2019 randomized trial demonstrated that adding domperidone to PPI in refractory GERD patients showed no improvement in quality of life or symptoms compared to PPI alone 3

Prokinetics for gastroparesis overlap:

• May have a role only in patients with concomitant gastroparesis documented by gastric emptying studies 1
• Should not be used empirically without confirmed delayed gastric emptying 1

Treatment Algorithm for GERD (Without Prokinetics)

First-Line Approach

• PPI therapy is the cornerstone and most effective pharmacological treatment 1, 2
• PPIs are superior to H2-receptor antagonists, which are superior to placebo 1, 4
• Standard once-daily PPI for 4-8 weeks initially 2

If Inadequate Response to Standard PPI

1. Optimize PPI dosing: Increase to twice-daily dosing taken 30-60 minutes before meals 1, 2
2. Switch to different PPI if side effects or inadequate response 1
3. Add alginate antacids for breakthrough or post-prandial symptoms, particularly with hiatal hernia 1, 5
4. Add nighttime H2RA for nocturnal symptoms (limited by tachyphylaxis) 1, 5

For Refractory GERD After PPI Optimization

• Perform ambulatory 24-hour pH-impedance monitoring on PPI to confirm true refractory GERD versus other etiologies 1
• Consider high-resolution manometry to exclude achalasia and assess esophageal peristalsis 1
• Evaluate for delayed gastric emptying if suspected 1
• Consider neuromodulation with low-dose antidepressants for esophageal hypersensitivity 1
• Refer for behavioral interventions (CBT, hypnotherapy, diaphragmatic breathing) for hypervigilance or functional overlay 1
• Laparoscopic fundoplication in experienced centers for objectively documented reflux failing medical therapy 1, 2

Critical Pitfalls to Avoid

• Do not use prokinetics empirically without documented gastroparesis or specific indications 1, 2
• Do not rely on metoclopramide given unfavorable risk-benefit profile and FDA black box warning 1, 2
• Do not continue ineffective prokinetic therapy hoping for delayed benefit 2
• Cisapride, while historically the most effective prokinetic studied for GERD, is no longer commercially available in the United States due to cardiac side effects 1, 6, 7
• Do not use prokinetics as monotherapy for GERD—they are less effective than acid suppression 1, 4

Historical Context

While older research from the 1990s suggested cisapride had efficacy comparable to H2RAs for mild-moderate GERD 6, 7, 8, this agent was withdrawn from the market. Current guidelines based on more recent evidence and safety data have moved away from recommending prokinetics as standard GERD therapy 1, 2.