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Gastroparesis patients face a series of symptoms for which there is currently a significant void in treatment. With complications and questions aplenty, answers are in high demand as physicians search for suitable medicines to combat this disease.
This article is part of a series on drug development in gastroenterology, brought to you by the American Gastroenterological Association Center for Diagnostics and Therapeutics. If you’re interested in learning more about drug development in this area, join the center for its first Drug Development Conference, Oct. 27-28, 2016, in Washington, DC.
Gastroparesis presents with a constellation of symptoms including nausea, vomiting, early satiety, fullness, bloating and abdominal pain and is diagnosed by documenting delays in gastric emptying. One third of cases result from longstanding diabetes and a small number are complications of fundoplication surgery for gastroesophageal reflux disease (GERD). About 60% percent of patients have idiopathic disease. There is a significant overlap of idiopathic gastroparesis with functional dyspepsia.
Although gastric emptying impairments are required for diagnosis, other pathways may contribute to symptoms in gastroparesis, including CNS nausea pathways and hypersensitive gastric innervation. The poor correlation of symptom intensity with severity of emptying delays emphasizes the importance of these other mechanisms of symptom generation.
Options for treating gastroparesis are limited. Prokinetics that stimulate gastric emptying are traditionally used as first-line agents. However, only metoclopramide is FDA approved for this indication and its use is hampered by prevalent and severe side effects including exacerbation of depression or anxiety and movement disorders, including irreversible tardive dyskinesia. Because of a paucity of effective and approved prokinetic medications, antiemetic drugs are empirically used for symptom control based on their efficacy in other settings including chemotherapy-induced nausea and vomiting. Others have proposed using neuromodulators (mostly antidepressants), which act on CNS pathways and reduce gastric sensation and which have anti-nausea effects in small case series. However, no controlled trials have been published showing benefit of these therapies in gastroparesis.
Until recently, drug development for gastroparesis has been stagnant. Some agents with potential benefit have been beset with cardiovascular complications including serotonin 5-HT4 agonists like cisapride and tegaserod. New motilin agonists, which act similarly to erythromycin, have shown potent effects to accelerate gastric emptying but have shown minimal abilities to reduce symptoms. However, there has been some movement in the field with a publication describing benefits of a novel ghrelin receptor agonist in a placebo-controlled phase IIa trial in diabetic gastroparesis, a report from an international trial of the 5-HT4 agonist prucalopride, and recently a presentation at a GI medical meeting describing effects of the neurokinin antagonist aprepitant for symptoms of gastroparesis.
Several issues complicate research into new pharmaceutical agents for gastroparesis. Symptom outcome measures have not been universally accepted. The importance of medication-induced gastric emptying acceleration for drug efficacy is unproved and the comparative benefits of prokinetics, antiemetics and neuromodulators have not been delineated. There is little consensus on whether new therapies should control all gastroparesis symptoms or if medications that reduce only nausea or pain are worthy of investigation.
To move forward and find suitable treatments for our gastroparesis patients, we need to address these questions. Hopefully, with collaboration from physicians, researchers, pharma, and FDA, we can fill the gap in gastroparesis treatment.
By William L. Hasler, MD, professor, Division of Gastroenterology, University of Michigan Health System