New developments in the treatment of functional dyspepsia.
Functional dyspepsia is a clinical syndrome defined by chronic or recurrent pain or discomfort in the upper abdomen of unknown origin. Although generally accepted, investigators differently interpret this definition and clinical trials are often biased by inhomogeneous inclusion criteria. The poorly defined multifactorial pathogenesis of dyspeptic symptoms has hampered efforts to develop effective treatments. A general agreement exists on the irrelevant role played by Helicobacter pylori in the pathophysiology of functional dyspepsia. Gastric acid secretion is within normal limits in patients with functional dyspepsia but acid related symptoms may arise in a subgroup of them. Proton pump inhibitors appear to be effective in this subset of patients with dyspepsia. Non-painful dyspeptic symptoms are suggestive of underlying gastrointestinal motor disorders and such abnormalities can be demonstrated in a substantial proportion of patients. Postprandial fullness and vomiting have been associated with delayed gastric emptying of solids, and early satiety and weight loss to postcibal impaired accommodation of the gastric fundus. Prokinetics have been shown to exert beneficial effects, at least in some patients with dyspepsia. In contrast, drugs enhancing gastric fundus relaxation have been reported to improve symptoms, although conflicting results have also been published. An overdistended antrum may also generate symptoms, but its potential pathogenetic role and the effects of drugs on this abnormality have never been investigated formally. Visceral hypersensitivity plays a role in some dyspeptic patients and this abnormality is also a potential target for treatment. Both chemo- and mechanoreceptors can trigger hyperalgesic responses. Psychosocial abnormalities have been consistently found in functional digestive syndromes, including dyspepsia. Although useful in patients with irritable bowel syndromes (IBS), antidepressants have been only marginally explored in functional dyspepsia. Among the new potentially useful agents for the treatment of functional dyspepsia, serotonin 5-HT(4) receptor agonists have been shown to exert a prokinetic effect. Unlike motilides, 5-HT(4) receptor agonists do not appear to increase the gastric fundus tone and this may contribute to improve symptoms. 5-HT(3) receptor antagonists have been investigated mainly in the IBS and the few studies performed in functional dyspepsia have provided conflicting results. Also, kappa-opioid receptor agonists might be useful for functional digestive syndromes because of their antinociceptive effects, but available results in functional dyspepsia are scanty and inconclusive. Other receptors that represent potential clinical targets for antagonists include purinoceptors (i. e., P2X2/3 receptors), NMDA receptors (NR2B subtype), protease-activated receptor-2, the vanilloid receptor-1, tachykinin receptors (NK(1)/NK(2)) and cholecystokinin (CCK)(1) receptors.