Editorial: finding the ideal prokinetic for gastroparesis—we are not there yet

Abstract

There is an urgent need for safe and effective pharmacotherapy in gastroparesis, a debilitating condition estimated to affect 13.8 per 100 000 persons in the United Kingdom.1 Adults with gastroparesis are recognised to suffer from repeated hospitalisation, physical and psychological disability, unemployment and increased mortality.1,2 Dietary modification is recommended as initial management in gastroparesis, but its efficacy appears modest in clinical practice.3 As delayed gastric emptying, together with typical symptoms (nausea, vomiting, early satiety, postprandial fullness and/or epigastric pain), are prerequisites for a diagnosis of gastroparesis, drugs with a prokinetic effect are the mainstay of pharmacotherapy.4 Prokinetic drugs studied in gastroparesis fall into one of the following classes: dopamine2 antagonists, 5HT3 antagonists, 5HT4 agonists, motilin receptor agonists and ghrelin receptor agonists.4 5HT3 antagonists such as ondansetron and granisetron, commonly used in chemotherapyinduced emesis, have shown symptom improvement in gastroparesis, but there is a lack of controlled studies. 5HT4 agonists such as cisapride and tegaserod, although effective, have been withdrawn from licensed use in gastroparesis due to welldocumented cardiac toxicity.5 Among the class of motilin receptor agonists, macrolide antibiotics such as erythromycin and azithromycin are clearly effective for acute exacerbations of gastroparesis, but the longterm risks of antibiotic resistance or tachyphylaxis have led to limited use.6 Relamorelin, a ghrelin receptor agonist, has recently been shown to have a modest effect in improving gastroparesis compared with placebo,7 but there are concerns about longterm systemic effects on obesity and worsening diabetes.8 To date, dopamine2 antagonists such as metoclopramide and domperidone appear to have the most robust efficacy for gastroparesis,9 with metoclopramide recommended as firstline pharmacotherapy in most management guidelines.3 However, both drugs have safety concerns regarding extrapyramidal side effects (metoclopramide) and cardiac arrhythmias (domperidone), and their longterm use is not advised. Hence, the development of a similar class of prokinetics without these side effects would be welcome. Kuo et al report the results of a pilot, multicentre, phase 2a study of trazpiroben, a dopamine2/3 antagonist among 51 (66.7% diabetic) adult patients with gastroparesis.10 The study was divided into two parts: an initial randomised trial of three different doses of the study drug compared with placebo, followed by an openlabel comparison with metoclopramide. Over a short duration of 9 days, the investigators confirmed the target efficacy of the drug (by increased serum prolactin levels), reported the best pharmacology for the 25 mg dose, and demonstrated no significant side effects with all doses. At the end of 9 days, there was no significant change in gastric emptying time, nor gastroparesis symptom scores between trazpiroben or placebo patients, nor with metoclopramide patients. However, subjects assigned to trazpiroben were observed to have a greater mean volume to fullness with a nutrient test drink compared with placebo (88.5 ml vs 26.3 ml, P = 0.019). The data from the current small sample study on the safety of this new dopamine2/3 antagonist are promising, but its efficacy remains uncertain. Nevertheless, we look forward to a larger sized study with a longer treatment duration of at least 8 weeks. In the meantime, the search for the ideal prokinetic in gastroparesis continues.