Efficacy and Safety of Drugs for Gastroparesis: Dopamine Receptor Antagonists Should Not Be Considered as a Single Pharmacologic Entity

The network meta-analysis and systematic review of Ingrosso et al1Ingrosso M.R. et al.Gastroenterology. 2023; Google Scholar added to the growing realization that drug treatment of gastroparesis remains inadequate for many patients. This is an area of research heavily populated by small studies into potential actions of drugs that were originally designed to inhibit nausea and vomiting and/or increase gastric emptying in a range of other clinical areas (eg, cancer chemotherapy, motion sickness, gastroesophageal reflux), hoping that the same mechanisms apply to gastroparesis. More recently, some of these drugs (eg, NK1 receptor antagonists) have also been evaluated in phase II and III trials but without consistent success. In addition, the analysis concluded that although the quality of evidence was low to moderate, the data favored the use of the dopamine receptor antagonists domperidone and clebopride and the NK1 receptor antagonist aprepitant. Ingrosso et al1Ingrosso M.R. et al.Gastroenterology. 2023; Google Scholar then concluded that dopamine receptor antagonism (ie, metoclopramide in addition to clebopride and domperidone) may be a useful mechanism by which symptoms of gastroparesis could be treated. It is well known that domperidone and other D2 receptor antagonists prevent vomiting by blocking the functions of the D2 receptors within the area postrema outside the blood–brain barrier.2Sanger G.J. et al.Front Pharmacol. 2018; 9: 913Crossref PubMed Scopus (49) Google Scholar However, an additional ability of domperidone to antagonize at the D3 receptor may offer advantages. Thus, experiments in animals indicate an ability of D3 receptor agonists to act at the area postrema and cause vomiting, with a functional interaction between D2 and D3 receptors. Together, these data suggest that an antagonist at both receptors might be superior to an antagonist at D2 alone.3Belkacemi L. et al.Pharmacol Res. 2020; 161105124Crossref Scopus (13) Google Scholar The ability of metoclopramide at higher doses to antagonize at the 5-HT3 receptor undoubtedly provides an additional benefit in the use of this drug to help control the nausea and vomiting caused by anticancer chemotherapy.2Sanger G.J. et al.Front Pharmacol. 2018; 9: 913Crossref PubMed Scopus (49) Google Scholar However, the evidence to date suggests little or no consistent benefit of 5-HT3 receptor antagonists in the treatment of patients with gastroparesis.1Ingrosso M.R. et al.Gastroenterology. 2023; Google Scholar Unlike domperidone, metoclopramide and also clebopride activate the 5-HT4 receptor.4Sanger G.J. et al.Drug Design Deliv. 1988; 3: 273-295PubMed Google Scholar,5Langlois M. et al.Bioorg Med Chem Lett. 1995; 5: 795-798Crossref Scopus (13) Google Scholar 5-HT4 receptor agonism provides a mechanism whereby delayed gastric emptying can be directly increased by facilitation of cholinergic transmission within the myenteric plexus of the stomach. Thus, classification of these drugs (solely) as dopamine antagonists may lead to erroneous interpretation of the mechanisms of their clinical action. By contrast, if domperidone is to increase gastric emptying, it must antagonize an inhibitory action of endogenous dopamine released during the disorder in which gastric emptying is delayed. However, in patients with gastroparesis, evidence for such an increase in lacking. A systematic review concluded that much of the early evidence suggesting that domperidone could increase gastric emptying in humans depended on small trials often without placebo control.6Sugumar A. et al.Clin Gastroenterol Hepatol. 2008; 6: 726-733Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar In 2 positive studies with placebo controls (diabetic gastroparesis), domperidone increased gastric emptying of a solid meal after acute dosing (n = 6) or after chronic (35–51 days) but not acute administration (n = 12). A systematic review on trials in patients with functional dyspepsia or gastroparesis found some ability of domperidone to increase gastric emptying (overall the change in gastric emptying T1/2 was not significant but was significant when using optimal gastric emptying test methods: breath test or scintigraphy measured for 3 hours with solid meals).7Vijayvargiya P. et al.Gastroenterology. 2019; 156: 1650-1660Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar Recently, the peripherally restricted D2/D3 receptor antagonist trazpiroben was found not to affect gastric emptying (breath test) in patients with gastroparesis.8Kuo B. et al.Aliment Pharmacol Ther. 2021; 54: 267-280Crossref PubMed Scopus (10) Google Scholar In conclusion, this brief analysis suggests that the term “dopamine receptor antagonists” should not be used to describe a collection of drugs with additional and varying pharmacology capable of exerting different actions on gastric functions. Thus, ignoring the nonselectivity of activity of these drugs to produce simplistic summary tables obscures their mechanisms of action and, of potentially greater importance, hampers the design of new drugs by directing focus to mechanisms that may offer little advance in the treatment of this difficult and poorly served disorder. Efficacy and Safety of Drugs for Gastroparesis: Systematic Review and Network Meta-analysisGastroenterologyVol. 164Issue 4PreviewAlthough there have been multiple drugs tested in gastroparesis, their relative efficacy and safety are unknown. We evaluated this in a network meta-analysis of randomized controlled trials (RCTs). Full-Text PDF Open Access