The 2022 American College of Gastroenterology (ACG) guideline conditionally suggests 5-hydroxytryptamine 4 (5-HT4) receptor agonists over no treatment to improve gastric emptying in patients with gastroparesis, based on low-quality evidence, while noting inconsistent findings regarding symptom improvement. The guideline cites a 2021 randomized, double-blind, placebo-controlled crossover trial evaluating prucalopride 4 mg/day in 15 patients with diabetic or connective tissue disease–related gastroparesis, which demonstrated faster gastric emptying but no significant differences in gastroparesis or meal-related symptoms compared with placebo (see Table 1). Additionally, a 2019 randomized, double-blind, placebo-controlled crossover trial evaluating 2 mg/day in 34 patients with idiopathic or diabetic gastroparesis reported significant improvements in gastric emptying, gastroparesis symptoms, and quality of life, with benefits observed only in the idiopathic subgroup (see Table 2). Both trials included two 4-week treatment periods separated by a 2-week washout. Overall, the evidence remains limited, and the guideline does not establish an optimal prucalopride dose for gastroparesis. [1]
The 2025 American Gastroenterological Association (AGA) guidelines on the management of gastroparesis assess evidence and develop recommendations. The AGA advises against using prucalopride as a first-line treatment (conditional recommendation; very low certainty of evidence) due to limited clinical significance of study results and risk of serious adverse events and adverse events resulting in treatment discontinuation. However, in shared decision-making, patients who prioritize potential symptom improvement over the risk of adverse effects might choose prucalopride, particularly if dealing with idiopathic gastroparesis. For patients with gastroparesis and chronic idiopathic constipation (CIC), prucalopride may be considered due to its established efficacy in CIC. The response to prucalopride might be lower in gastroparesis linked to diabetes or connective tissue diseases compared to idiopathic cases. Prucalopride functions as a prokinetic agent through 5HT4 receptor agonism without antiemetic effects. The evidence behind the recommendation for prucalopride use in gastroparesis stems from two crossover randomized controlled trials (RCTs) comparing prucalopride to placebo in 49 patients diagnosed with gastroparesis. These studies focused on different subgroups: idiopathic gastroparesis and gastroparesis due to diabetes mellitus or mixed connective tissue disease. The studies exhibited a low risk of bias, yet the prucalopride-related improvements in nausea, vomiting, early satiety, postprandial fullness, and overall symptom scores did not achieve clinical significance. Prucalopride has had reports of new-onset or worsening depression, as well as suicidal thoughts and behavior, particularly in the initial phase of treatment. Despite some reduction in abdominal pain and improvement in quality of life, these improvements were not clinically significant. Conversely, the AGA suggests using metoclopramide (conditional recommendation, low certainty of evidence), based on data from 7 clinical trials comparing metoclopramide versus placebo. The guideline does not establish an optimal prucalopride dose for gastroparesis. [2]
A 2023 network meta-analysis (N= 29 RCTs; 3,772 patients) evaluated the efficacy and safety of treatments for gastroparesis. Across the synthesized data, clebopride (RR 0.30; 95% CI 0.16 to 0.57; P-score = 0.99) ranked first for efficacy regarding global symptom improvement, followed by domperidone (RR 0.68; 95% CI 0.48 to 0.98; P-score = 0.76). Drug class-level analysis identified oral dopamine antagonists (RR 0.58; 95% CI 0.44 to 0.77) and tachykinin-1 receptor antagonists (RR 0.69; 95% CI 0.52 to 0.93) as significantly superior to placebo. Neither motilin agonists, ghrelin receptor agonists, 5-HT4 agonists, nor tricyclic antidepressants demonstrated treatment superiority versus placebo. Among individual symptoms, metoclopramide showed directional benefit for nausea (RR 0.46; 95% CI 0.21 to 1.00), fullness (RR 0.67; 95% CI, 0.35–1.28), and bloating (RR 0.53; 95% CI, 0.30–0.93), though these findings were largely derived from a single small trial. Adverse event analysis revealed prucalopride (RR 2.96; 95% CI 1.24 to 7.07) was the only agent significantly more likely than placebo to result in adverse effects, while camicinal had the lowest associated risk (RR 0.77; 95% CI 0.55 to 1.08). Still, for individual symptoms, oral metoclopramide ranked as highest risk for nausea (RR 0.46; 95% CI, 0.21 to 1.00; P-score = 095), fullness (RR 0.67; 95% CI, 0.35 to 1.28; P-score = 0.86), and bloating (RR 0.53; 95% CI, 0.30 to 0.93; P-score = 0.97), but based on only 1 small trial. Overall, most comparisons were rated as low to moderate confidence, and findings underscore a pressing need for new, efficacious pharmacologic therapies in the management of gastroparesis. [3]
A 2024 systematic review and meta-analysis evaluated the safety and efficacy of highly selective 5-HT4 agonists (velusetrag [discontinued], felcisetrag, and prucalopride) for the treatment of diabetic and idiopathic gastroparesis. The included trials evaluated oral velusetrag 5-30 mg daily for 1-4 weeks, oral prucalopride 2 mg or 4 mg daily for 4 weeks, and intravenous felcisetrag 0.1 mg, 0.3 mg, or 1 mg daily for 3 days. The analysis comprised 6 RCTs (N= 570 patients), with intervention and placebo mean ages of 46 and 45.9 years, respectively. Pooled results indicated that highly selective 5-HT4 agonists significantly improved Gastroparesis Cardinal Symptom Index (GCSI) scores and gastric emptying time (GET) in comparison to placebo, with a mean difference of 4.283 and 2.534, respectively, both achieving statistical significance (p<0.05). Notably, while the overall incidence of adverse events was higher in the 5-HT4 agonist group, specific side effects such as diarrhea, abdominal pain, and headaches were similar between the groups. Efficacy and safety outcomes were not differentiated by individual drugs; thus, results specific to prucalopride could not be presented. Despite a generally acceptable safety profile, the authors noted the necessity of larger-scale studies with extended follow-ups to thoroughly assess the risk of rare or serious adverse events and reaffirm efficacy against established prokinetic agents. [4]
Lastly, a 2023 review analyzed the pharmacological rationale for selecting drugs intended to inhibit vomiting or promote gastric emptying in the treatment of gastroparesis. Various drugs and their targets were discussed, ranging from those targeting 5-HT, D2, H1, and muscarinic receptors, to more complex agents like mirtazapine and amitriptyline. For delayed gastric emptying, 5-HT4 receptor agonists can increase gastric emptying. Both prucalopride and metoclopramide fall under this category, but while prucalopride is a highly selective 5-HT4 receptor agonist, metoclopramide also antagonizes the D2 and 5-HT3 receptors, which are involved in vomiting. To date, only metoclopramide is FDA-approved for gastroparesis, but for short-term use, with a black box warning of a risk of tardive dyskinesia. This is due to metoclopramide’s ability to penetrate the brain and antagonize D2 receptors within the basal ganglia. Limited trials with selective 5-HT4 agonists such as prucalopride have shown variable efficacy in gastroparesis. Specifically, prucalopride 2 mg daily for 4 weeks improved gastroparesis symptoms, quality of life, and gastric emptying in patients with mostly idiopathic gastroparesis, whereas 4 mg daily for 4 weeks accelerated gastric emptying without improving symptoms in patients with diabetic or connective tissue disease-related gastroparesis (Tables 1 and 2). Prucalopride, which is currently only approved for chronic idiopathic constipation and has also been identified as a brain penetrant, requires further study to determine its effectiveness and safety in the setting of gastroparesis. [5]