New perspectives in functional dyspepsia

Functional dyspepsia (FD), a disorder characterized by symptoms though to originate from the gastroduodenum in the absence of organic changes, is one of the most prevalent functional gastrointestinal disorders. In the most recent iteration of the Rome criteria, Rome III, FD was subdivided into epigastric pain syndrome (EPS) and postprandial distress syndrome (PDS).

The underlying pathophysiology of functional dyspepsia is probably multifactorial, involving disordered gastrointestinal motor function, visceral hypersensitivity, mucosal immune activation and alterations of the brain-gut axis. A source of long-standing controversy is whether symptoms arise in the perpiphery or in the brain. Cognitive-affective processes including anticipation of pain and its associated anxiety interfere with pain modulatory mechanisms in the brain in FD, leading to increased pain sensitivity and symptom levels. While these findings indicate a central mechanism for symptom generation in FD, there is increasing and compelling evidence for a contribution of peripheral mechanisms, with a recent focus on changes in mucosal integrity in the duodenum. The contributing factors there could be stressors as well as changes in duodenal acid clearance.

In FD, currently available treatment modalities include acid suppressive drugs, gastroprokinetic drugs, H. pylori eradication therapy, tricyclic antidepressants or psychological therapies. There is evidence, although not always of high quality, of efficacy in subgroups of patients. Drugs currently under evaluation include novel 5-HT4 agonists and motilin and ghrelin receptor agonists. Novel approaches include fundus-relaxing drugs such as 5-HT1A agonists, and guanylate-cyclase-c agonists. The most recent therapeutic advance is the development of acotiamide (Z-338). Acotiamide acts on muscarinic receptors and inhibits cholinesterase, and these effects lead to stimulation of gastric emptying and enhancement of gastric accommodation in FD. In rat models, acotiamide also counteracts the inhibitory effect of stress on gastric emptying rate and food intake. A phase 3 study program in Japan confirmed efficacy over placebo in patients closely reflecting PDS according to the Rome 3 definition. The drug is approved for treatment of FD in Japan since 2013 and a phase 3 program is ongoing in Be.