Investigational drug therapies for the treatment of gastroparesis

ABSTRACT

Introduction: Gastroparesis is defined by nausea, vomiting, pain, early satiety and bloating, and characterized by delayed gastric emptying without obvious structural abnormalities. Metoclopramide is widely used, increasing gastric emptying and inhibiting nausea and vomiting. Other drugs are available in certain countries and some are used ‘off-label’ because they increase gastric emptying or inhibit emesis. However, correlation between gastroparesis symptoms and rates of gastric emptying is poor. For anti-emetic drugs, dose-ranging and Phase III trials in gastroparesis are lacking.

Areas covered: Gastric motility may still be disordered, leading to nausea, even though gastric emptying is unchanged. One hypothesis is that interstitial cells of Cajal (ICC) are damaged by diabetes leading to gastric dysrhythmia and nausea. Novel approaches to treatment of nausea also include the use of ghrelin receptor agonists, highlighting a link between appetite and nausea.

Expert opinion: There is an urgent need to diversify away from historical drug targets. In particular, there is a need to control nausea by regulating ICC functions and/or by facilitating appetite via ghrelin receptor agonists. It is also important to note that different upper gastrointestinal disorders (gastroparesis, chronic unexplained nausea and vomiting, functional dyspepsia) are difficult to distinguish apart, suggesting wider therapeutic opportunity.

KEYWORDS:

• Gastric motility
• gastroparesis
• ghrelin
• interstitial cells of Cajal
• nausea

Article highlights

• Gastroparesis is poorly treated and only metoclopramide is registered world-wide as a drug treatment. Some drugs are available in certain countries and others are used ‘off-label’ to increase gastric emptying and/or as anti-emetics.

• Anti-emetic drugs have not been designed or optimised for treatment of gastroparesis. This is important because although the drugs are effective inhibitors of vomiting in other conditions, they may be less efficacious against nausea, a major symptom in gastroparesis.

• The rate of gastric emptying is a poor predictor of the severity of nausea and other symptoms in patients with gastroparesis. However, gastroparesis remains a motility disorder, emphasizing the need for more sophisticated methods to look at regional rather than global changes in motility.

• It is hypothesised that repair or control of a damaged network of interstitial cells of Cajal will alleviate symptoms. Approaches include agents which may modulate ion channel functions, prevent damage by invading macrophages or repair by using agents with trophic functions.

• Ghrelin receptor agonists are currently being explored since preliminary evidence suggests that nausea is reduced, perhaps via the same pathways which increase appetite, opening a new avenue for investigation into the mechanisms of nausea in general, an area with high unmet clinical need.

• As more is understood it seems likely that the current definitions of gastroparesis, chronic unexplained nausea and vomiting and functional dyspepsia will increasingly become less distinct.

This box summarizes key points contained in the article.

Declaration of interest

G. J. Sanger currently receives funding from The Dunhill Medical Trust, The research into ageing fund, set up and managed by AgeUK, the BBSRC (Case award with GlaxoSmithKline) and Takeda pharmaceuticals. P. J. Pasricha is supported in part by a grant from the NIH/NIDDK UO1DKO73983. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was not funded.