What is prokinetic therapy for Gastroesophageal Reflux Disease (GERD)?

Prokinetic Therapy for GERD

Prokinetic therapy for GERD involves medications that enhance gastrointestinal motility by increasing lower esophageal sphincter pressure, accelerating gastric emptying, and improving esophageal peristalsis—but should only be used in highly selected patients with coexistent gastroparesis, not as routine adjunctive therapy for typical GERD. 1

Mechanism of Action

Prokinetic agents work by stimulating motility of the upper gastrointestinal tract through different mechanisms 2:

• Metoclopramide increases the tone and amplitude of gastric contractions, relaxes the pyloric sphincter, increases peristalsis of the duodenum and jejunum, and increases resting tone of the lower esophageal sphincter 2
• These effects result in accelerated gastric emptying and intestinal transit 2
• The mechanism appears to involve sensitizing tissues to acetylcholine and antagonizing dopamine receptors 2

Current Guideline Recommendations

The most recent 2022 AGA guidelines explicitly state that prokinetics should be personalized to the GERD phenotype rather than used empirically, and are specifically indicated only for coexistent gastroparesis—not for routine GERD management. 1

Appropriate Use:

• Prokinetics are reserved for patients with proven gastroparesis in addition to GERD 1
• They may be considered for regurgitation-predominant symptoms, though baclofen (a GABA-B agonist) is preferred over traditional prokinetics for this indication 1

Critical Limitation:

• Metoclopramide is NOT recommended as monotherapy or adjunctive therapy for esophageal GERD syndromes 3, 4
• Prokinetics have not been shown to be useful in GERD except when gastroparesis coexists 3, 4

Historical Context vs. Current Practice

There is a notable divergence between older and newer evidence:

Older Guidelines (2006):

• The 2006 ACCP guidelines suggested adding prokinetic therapy (specifically metoclopramide) if there was no or little response to PPI and lifestyle modifications 1
• These guidelines recommended trying prokinetic agents before labeling patients as having medically refractory GERD 1

Current Evidence (2022):

• The 2022 AGA guidelines represent a paradigm shift away from empiric prokinetic use 1
• This change reflects accumulating evidence that prokinetics lack consistent efficacy for typical GERD and carry significant side effects 3, 4

Specific Agents and Their Limitations

Metoclopramide:

• Produces dose-related increases in lower esophageal sphincter pressure (5-20 mg doses) 2
• Effects last 45 minutes to 3 hours depending on dose 2
• Major concern: produces sedation and may cause extrapyramidal reactions 2
• Also causes release of prolactin and transient fluid retention 2

Historical Agents (No Longer Available):

• Cisapride was previously the most effective prokinetic for GERD, relieving symptoms and healing grade I-II esophagitis 5, 6
• It has been withdrawn from most markets due to cardiac safety concerns 7, 5, 6

Domperidone:

• A 2019 randomized controlled trial showed that adding domperidone to PPI provided no improvement in quality of life or symptoms compared to PPI alone in refractory GERD 8

Recommended Treatment Algorithm

For patients with GERD symptoms not responding to PPI therapy: 1

1. First: Optimize PPI dosing (timing, twice-daily dosing, or switch to different PPI)
2. Second: Add phenotype-specific adjunctive therapy:
   • Alginate antacids for breakthrough symptoms 1
   • H2-receptor antagonists for nocturnal symptoms 1
   • Baclofen for regurgitation or belch-predominant symptoms 1
3. Third: Consider neuromodulation with low-dose antidepressants 3, 4
4. Only if gastroparesis is documented: Consider prokinetic therapy 1, 3, 4

Common Pitfalls to Avoid

• Do not use prokinetics as first-line or routine adjunctive therapy for GERD 3, 4
• Do not assume prokinetics will help with typical reflux symptoms or esophagitis healing—evidence shows they are ineffective for these indications 8, 9
• Do not overlook the significant side effect profile of metoclopramide, including extrapyramidal symptoms and sedation 2
• Do not use prokinetics without first documenting delayed gastric emptying through appropriate testing 1