Prokinetic Agents for Esophageal Dysmotility in Scleroderma
Prokinetic drugs should be used for symptomatic esophageal dysmotility in scleroderma, with domperidone, prucalopride, or buspirone as preferred agents, while avoiding metoclopramide for long-term use due to significant adverse effects. 1, 2
Guideline-Based Recommendations
The 2025 EULAR recommendations explicitly state that prokinetic drugs should be considered for treatment of symptomatic motility disturbances related to systemic sclerosis, including dysphagia and gastroesophageal reflux disease. 1 This recommendation has been consistently maintained since 2009, though the evidence base remains limited by lack of large randomized controlled trials specific to scleroderma. 1
Specific Agent Selection
First-Line Options
Domperidone is supported by the highest quality recent evidence in an RCT of 148 scleroderma patients with partial response to high-dose PPIs, showing 86.8% response rate for GERD symptoms when added to ongoing PPI therapy. 1 This represents the most robust trial data available for esophageal dysmotility in scleroderma specifically.
Prucalopride (a 5-HT4 receptor agonist) has demonstrated effectiveness for both upper and lower GI symptoms in scleroderma patients using validated questionnaires, with particular benefit for constipation and overall GI function. 1, 3, 4 Case reports and observational studies show success even when previous prokinetic treatments failed. 3
Buspirone (a 5-HT1A receptor agonist) showed positive effects in increasing lower esophageal sphincter pressure compared to baseline and outperformed domperidone in a small open-label study. 1
Agents to Avoid
Cisapride, while showing beneficial effects on gastric emptying and lower esophageal sphincter pressure in small RCTs, has been withdrawn or severely restricted in most countries due to long QT syndrome and risk of severe arrhythmias. 1 Do not use this agent despite historical evidence of efficacy.
Metoclopramide has received a black box warning limiting long-term use due to significant extrapyramidal symptoms and other adverse effects, making it unsuitable for chronic management despite its ability to improve reflux and gastric emptying. 2, 5, 6 The FDA label confirms metoclopramide produces sedation and extrapyramidal reactions as dopamine antagonist effects. 5
Clinical Algorithm for Implementation
Step 1: Optimize Acid Suppression First
Ensure patients are on adequate PPI therapy (e.g., omeprazole 20 mg twice daily) before adding prokinetics, as the strongest RCT evidence evaluated prokinetics added to ongoing high-dose PPI therapy. 1
Step 2: Select Prokinetic Based on Symptom Pattern
- For predominantly upper GI symptoms (dysphagia, reflux): Start with domperidone given the RCT evidence in scleroderma patients. 1
- For mixed upper and lower GI symptoms: Consider prucalopride, which has shown benefit across the entire GI tract. 1, 4
- For refractory lower esophageal sphincter dysfunction: Consider buspirone based on its specific mechanism. 1
Step 3: Monitor and Adjust
Prokinetics are most effective early in scleroderma when GI musculature remains relatively intact. 6 Long-term efficacy data from RCTs is limited, with most studies focusing on short-term outcomes (4 weeks in the domperidone trial). 1 Regular monitoring for continued therapeutic need is essential. 2
Important Caveats
Timing matters: Prokinetic agents are useful primarily in early stages of scleroderma when gastrointestinal musculature is still intact; they become less effective as smooth muscle atrophy progresses. 6, 7
Combination therapy: The evidence supports using prokinetics as adjuncts to PPI therapy rather than monotherapy, since esophageal dysmotility in scleroderma involves both impaired motility and severe reflux. 1
Rotating antibiotics: Consider adding rotating antibiotics if small intestinal bacterial overgrowth develops, as this commonly complicates chronic intestinal dysmotility in scleroderma patients requiring long-term prokinetic therapy. 1, 2
Avoid high-dose corticosteroids: Monitor blood pressure carefully if corticosteroids are necessary, as doses ≥15 mg/day prednisone significantly increase risk of scleroderma renal crisis. 1
Evidence Quality Considerations
The EULAR task force acknowledges substantial unmet need for better control of GI manifestations in scleroderma and has endorsed high priority for future research on GI disease. 1 The current recommendation carries a strength of C, reflecting expert consensus based on limited RCT data. 1 The most recent systematic review (2025) confirms that while prokinetics may improve GI motility and symptoms, there remains an unmet need for well-designed studies to optimize treatment outcomes. 4