What prokinetic agents are used in functional dyspepsia?

Prokinetic Agents Used in Functional Dyspepsia

Prokinetics are recommended for functional dyspepsia, particularly for postprandial distress syndrome (PDS) with symptoms of bloating, early satiation, and fullness, with cinitapride, acotiamide, and metoclopramide being the most evidence-supported agents. 1, 2, 3

First-Line Prokinetic Options

For dysmotility-like symptoms (fullness, bloating, early satiety), prokinetics should be used as first-line therapy rather than acid suppression. 2, 3 The British Society of Gastroenterology guidelines specifically recommend prokinetics as the preferred option for patients with PDS subtype. 1

Specific Prokinetic Agents

Cinitapride is recommended as a first-line prokinetic with a favorable safety profile and minimal QT prolongation risk, though caution is advised when combining with other QT-prolonging medications. 2 The American College of Chest Physicians recognizes cinitapride as effective, particularly when combined with acid suppression for overlapping GERD symptoms. 2

Acotiamide demonstrates efficacy specifically for PDS, with a number needed to treat (NNTB) of 20, making it a reasonable choice for postprandial symptoms. 4 This agent has shown consistent benefit in reducing global dyspepsia symptoms. 4

Metoclopramide (10 mg three times daily) is widely available and has demonstrated 30% excess probability of symptom response compared to placebo across multiple studies. 5, 4 However, metoclopramide carries significant risks that require careful consideration: 6

• Black box warning for tardive dyskinesia (TD): Risk increases with duration beyond 12 weeks and total cumulative dose 6
• Acute dystonic reactions occur in approximately 1 in 500 patients, more frequently in those under 30 years of age 6
• Parkinsonian-like symptoms can develop, particularly within the first 6 months 6
• Depression and suicidal ideation have been reported 6
• Treatment duration should not exceed 12 weeks except in rare circumstances 6

Domperidone (10 mg three times daily) is commonly used internationally, though meta-analyses show other prokinetics may have slightly better symptom scores compared to domperidone. 4 Domperidone has low risk of QT prolongation at usual oral therapeutic doses, though caution is warranted. 1

Prucalopride (a 5-HT4 agonist) shows promise for constipation-predominant symptoms and may reduce GERD severity, though evidence in FD specifically is emerging. 1

Tegaserod demonstrated efficacy with NNTB of 14 in clinical trials. 4

Treatment Algorithm

1. Identify predominant symptom pattern: 1

   • If epigastric pain predominates → Start with PPI therapy 3
   • If postprandial fullness, bloating, early satiety predominate → Start with prokinetic 1, 3

2. Select appropriate prokinetic based on availability and risk profile: 2, 4

   • Cinitapride or acotiamide preferred if available (better safety profile) 2, 4
   • Metoclopramide if others unavailable, but limit to <12 weeks 6
   • Avoid metoclopramide in patients <30 years (higher dystonia risk), with depression history, or pre-existing Parkinson's disease 6

3. If no response after 4-8 weeks: 3

   • Consider symptom misclassification and switch from prokinetic to PPI or vice versa 3
   • Reassess for H. pylori if not previously tested/treated 3

4. For refractory symptoms despite prokinetic trial: 1, 3

   • Add tricyclic antidepressant (amitriptyline 10 mg daily, titrate to 30-50 mg) 1, 3
   • Consider combination therapy with PPI if overlapping symptoms 2

Critical Safety Considerations

Metoclopramide requires specific monitoring and patient counseling: 6

• Inform patients about tardive dyskinesia risk before initiating therapy 6
• Discontinue immediately if involuntary movements develop 6
• Have diphenhydramine 50 mg available for acute dystonic reactions 6
• Dose reduction required in renal impairment 6

Avoid prokinetics in patients with: 6

• Gastrointestinal obstruction or perforation
• Pheochromocytoma (metoclopramide specifically)
• History of tardive dyskinesia or significant extrapyramidal symptoms

Evidence Quality and Limitations

The overall quality of evidence for prokinetics in FD is very low due to heterogeneity, risk of bias, and possible publication bias. 4 A 2018 Cochrane review found significant heterogeneity (I² = 91%) across prokinetic studies, and funnel plot asymmetry suggested reporting bias. 4 Despite these limitations, the consistent direction of effect across multiple agents supports their use, particularly for PDS. 5, 4

The therapeutic effect appears most robust for cisapride (NNTB = 4), but this agent was withdrawn from most markets due to cardiac arrhythmia risk. 4 Among currently available agents, acotiamide and cinitapride have the most favorable evidence-to-safety profiles. 2, 4

Treatment Duration and Withdrawal

After initial symptom control, consider a treatment withdrawal trial, with re-treatment justified if symptoms recur. 3 This approach is particularly important with metoclopramide given the time-dependent risk of tardive dyskinesia. 6 For other prokinetics with better safety profiles, longer-term use may be appropriate for chronic symptoms. 2