Rethinking Gastroparesis: Controversies in Care and the Search for Better Answers

Gastroparesis, an uncommon and often misunderstood motility disorder, sits at the crossroads of complex physiology and limited treatment options. Unlike other motility conditions, gastroparesis presents unique challenges, from misdiagnosis to a scarcity of effective therapies. Its heterogeneity and overlapping symptoms not only complicate diagnosis but also slow progress in research, leaving patients with few reliable options and clinicians searching for better answers.1,2

“When I think about the field of gastroparesis, the 3 C’s come to mind: challenging, complicated, and controversial,” Brian Lacy, MD, PhD, of the Mayo Clinic in Jacksonville, told HCPLive, citing challenges related to both diagnosis and treatment, the first often due to frequent misdiagnoses and incorrectly performed diagnostic tests.

In 2022, the American Gastroenterological Association (AGA) released a clinical guideline detailing appropriate tests for diagnosing gastroparesis and both pharmacologic and non-pharmacologic therapies for improving gastroparesis symptoms and gastric emptying. In this document, the AGA strongly recommended scintigraphic gastric emptying of a solid meal with a duration of ≥ 3 hours for diagnosis of gastroparesis, advising against shorter studies like gastric emptying studies, which are only 90 minutes long, due to the potential for false negative results.3

“A lot of patients have a normal gastric emptying study, or the gastric emptying study may not have been done correctly,” Douglas Weinstein, MD, a gastroenterologist and director of GI Motility at Hackensack Meridian Jersey Shore University Medical Center, told HCPLive, describing how the size and composition of the meal eaten, medications taken, and patient position may impact test results. “Even if everything's done right, sometimes [the test] will still be normal.”

Adeling Hung, MD, a clinical assistant professor at Rosalind Franklin University Chicago Medical School and director of the IBD program at Sinai Health System Chicago, added that in addition to these potential variations in test protocols and subsequent results, recommended tests like gastric emptying scintigraphy are not widely available outside of specialized centers and do not pinpoint the primary cause of gastroparesis to determine which treatment may be most appropriate.

Of note, the only strong treatment recommendations in the 2022 AGA gastroparesis guideline focused on therapies not supported for use, including neuromodulators, ghrelin agonists, and intrapyloric botox injections. Conversely, small-particle diets, metoclopramide, domperidone, antiemetic agents, and 5HT4 agonists are suggested for symptom control or improvement in gastric emptying.3

Currently, the only FDA-approved gastroparesis treatment is metoclopramide, a dopamine receptor antagonist first approved for diabetic gastroparesis in 1979. In 2020, the FDA approved Evoke Pharma’s metoclopramide (Gimoti) nasal spray as the first and only nasally-administered product indicated for the relief of symptoms in adults with acute and recurrent diabetic gastroparesis. The approval also represented the first novel pharmaceutical treatment for gastroparesis in several decades.4,5

However, several concerns exist regarding the use of metoclopramide for gastroparesis. It is not recommended to be used for durations longer than 12 weeks, and in 2009, the FDA placed a Black Box warning on metoclopramide because of the risk of related side effects, including tardive dyskinesia, with chronic or high-dose use.6

“Metoclopramide is not a good medicine because it can't be used long-term,” Weinstein explained. “There is a nose spray that was recently approved, but it has the same side effects as metoclopramide, or even more because it gets absorbed. It could cause neurological side effects that can be permanent if people are on it long term, so we try not to use it.”

Beyond metoclopramide, erythromycin, a macrolide antibiotic used to treat or prevent a wide range of bacterial infections, is also used off-label to treat gastroparesis because of its prokinetic effects on gastrointestinal motility to stimulate gastric emptying. However, like metoclopramide, erythromycin is not a perfect treatment.7

“The few approved prokinetics, including metoclopramide and erythromycin, have modest efficacy, short durability, and significant side effects, which are both neurologic and cardiac in nature,” Hung told HCPLive.

With a severe unmet need for new and effective pharmacologic treatment options, Vanda Pharmaceuticals sought to add another novel therapy to the limited gastroparesis therapeutic landscape with the Company’s New Drug Application (NDA) for tradipitant, a neurokinin receptor 1 antagonist licensed by Vanda from Eli Lilly and Company. However, in September 2024, the FDA issued a Complete Response Letter (CRL) to the NDA, suggesting Vanda conduct additional studies with a design and duration Vanda described as being inconsistent with the advice of key experts in the field and not appropriate based on the scientific understanding and natural course of gastroparesis.8

With the CRL, metoclopramide remains the only FDA-approved agent indicated specifically for the treatment of gastroparesis, raising questions as to how meaningful progress in bringing effective gastroparesis therapies to market can be achieved.

“Due to [the heterogeneity of the disease and its] multiple mechanisms, it is hard to find one treatment or therapy that can show appropriate efficacy for all patients… In most trials, you need both improvement of symptoms and of gastric emptying times to demonstrate benefit, but in some cases, a treatment may help clinical symptoms while not meeting gastric emptying endpoints,” Hung explained, citing the need for better classification of patients based on mechanism of disease with tests beyond gastric emptying scintigraphy to more appropriately study targeted therapy in trials, which she says should have more flexible endpoints and consider patient-reported outcomes.

Beyond concerns about trial design, the fundamental definition of what gastroparesis entails is another area of controversy potentially impacting treatment development.

“I believe that one of the biggest challenges is that we need to rethink what gastroparesis really is,” Lacy told HCPLive, describing inherent issues with the current mindset that gastroparesis is purely a motor (muscle) disorder of the stomach that can be treated by accelerating gastric emptying. “That may work in some patients, but the data is very clear that it does not work in most patients… If the field is to move ahead, we need to reframe how we think about the underlying physiology of gastroparesis.”

Rather, Lacy points to the likely theory that gastroparesis represents a sensory disorder in many patients, a concept supported by the data showing that accelerating gastric emptying does not improve symptoms as well as data suggesting a strong overlap between gastroparesis and functional dyspepsia, a disorder of gut brain interaction.

Hung adopts a similar perspective, noting symptoms do not always correlate with gastric emptying times and describing how some patients with severe delays may be minimally symptomatic while others with only mild delay are very symptomatic. Because of this, she says improving gastric emptying times does not always relieve symptoms.

Despite not being recommended in the 2022 AGA guidance, in the absence of notable progress regarding pharmacologic treatment options for gastroparesis, advances in neuromodulation and device-based approaches to care have gained traction, with Hung describing them as “shaping the future of gastroparesis care.”

Among these advances are gastric electrical stimulation and vagal nerve stimulation, both of which have shown promising results for nausea/vomiting and neural control of motility for selected patients. Of note, the latest gastric electrical stimulation is programmable to patient-specific parameters and customizable to patient’s needs, which helps personalize therapy.

For neurostimulation, Weinstein describes how he tries to predict which patients are going to respond well by doing a temporary stimulation trial where the patient carries a simulator externally for a week or 2 to determine if their symptoms get better.

“If their symptoms don't improve, then we don't implant the stimulator, and that helps us reduce unnecessary surgery… but it does help a lot of patients by improving electrical activity in the stomach, by improving the vagus nerve function, and by improving brain sensations,” Weinstein said, describing its utility across multiple nausea/vomiting conditions beyond gastroparesis.

However, while recognizing the benefit of such approaches, especially for patients that have not responded to pharmacological or pyloric therapies, Hung was careful to call attention to the need for more standardization on how to best integrate the latest procedures/devices along with pharmacological therapy so that patients can receive the right therapy at the right time.

“This could be an exciting area of research in the future. If we begin to view gastroparesis as a sensory disorder for many, but not all, patients, then new treatment pathways will emerge,” Lacy added. “For example, we know that a small subset of patients with gastroparesis respond well to gastric electrical stimulation. Could more selective devices be employed to better improve symptoms? Or, if we consider this a sensory disorder in some, can we employ new medications to help tamp down these overly sensitive nerves which may be the underlying cause of persistent symptoms of nausea and vomiting?”

As the field continues to grapple with diagnostic complexities, limited pharmacologic options, and the evolving understanding of gastroparesis as more than just a motility disorder, the path forward will require both innovation and collaboration. Redefining disease mechanisms, incorporating patient-reported outcomes into trial design, and integrating novel device-based approaches alongside pharmacotherapy may help bridge long-standing treatment gaps.

While progress has been incremental, growing recognition of gastroparesis’ heterogeneity and the push for more targeted, patient-centered strategies suggest the next chapter in care could bring meaningful advances for patients who have waited decades for better solutions.

Editors’ note: Hung and Weinstein report no relevant disclosures. Lacy reports relevant disclosures with AbbVie, Bausch, Gemelli, Ironwood, Salix, and Sanofi.

References

1. Mount Sinai. Mount Sinai Center for Gastrointestinal Physiology & Motility. Accessed August 27, 2025. https://www.mountsinai.org/care/gastroenterology/services/motility

2. International Foundation for Gastrointestinal Disorders. Motility Disorders. Accessed August 27, 2025. https://iffgd.org/gi-disorders/motility-disorders/

3. Camilleri M, Kuo B, Nguyen L, et al. ACG Clinical Guideline: Gastroparesis. The American Journal of Gastroenterology. doi:10.14309/ajg.0000000000001874

4. Lee A, Kuo B. Metoclopramide in the treatment of diabetic gastroparesis. Expert Rev Endocrinol Metab. 2010;5(5):653-662. doi:10.1586/eem.10.41

5. Evoke Pharma. FDA Approves Evoke’s GIMOTI™. June 19, 2020. Accessed August 27, 2025. https://investor.evokepharma.com/news-releases/news-release-details/fda-approves-evokes-gimotitm

6. Kanto WP. An FDA Warning About Metoclopramide. NEJM Journal Watch. March 18, 2009. Accessed August 27, 2025. https://www.jwatch.org/pa200903180000001/2009/03/18/fda-warning-about-metoclopramide

7. Johns Hopkins Medicine. Gastroparesis Treatment. Accessed August 27, 2025. https://www.hopkinsmedicine.org/health/conditions-and-diseases/gastroparesis/gastroparesis-treatment

8. Brooks A. FDA Issues CRL to Vanda Pharmaceuticals’ Tradipitant for Gastroparesis Symptoms. HCPLive. September 19, 2024. Accessed August 27, 2025. https://www.hcplive.com/view/fda-issues-crl-vanda-pharmaceuticals-tradipitant-gastroparesis-symptoms