Mayo Clinic
Rochester, Minn.
The American College of Gastroenterology recently released a new clinical guideline on gastroparesis (Am J Gastroenterol 2022;117[8]:1197-1220). GEN’s Sarah Tilyou spoke with lead author Michael Camilleri, MD, DSc, a gastroenterologist and professor of medicine, physiology and pharmacology at Mayo Clinic in Rochester, Minn., about the impetus for the guideline and what it means to GI practice.
GEN: What prompted the guideline?
Dr. Camilleri: There are three really important points to make. The first is that the previous guideline from ACG was published in 2013—a decade ago (Am J Gastroenterol 2013;108[1]:18-37). The second is that there still is an unmet need in terms of diagnosis and treatment. And the third is that there’s interest in the guideline for gastroparesis, with the 2013 guideline being cited over 570 times. Although the European Society of Neurogastroenterology and Motility published a consensus document more recently (United Eur Gastroenterol J 2021;9[3]:287-306), it was based on expert opinion, in contrast to the rigor of the ACG guideline based on extensive literature search and GRADE methodology. In addition, some novel diagnostic and therapeutic approaches have come to the fore over the past decade, and they needed to be summarized for clinicians and patients.
GEN: What’s new in the guideline that clinicians need to know?
Dr. Camilleri: The first important point from a clinician standpoint is diagnosis. It’s important for clinicians to appreciate that the diagnosis of gastroparesis requires symptoms, exclusion of obstruction and documentation of the slow emptying of solid foods from the stomach. The state of the art has been evolving. It’s clear that we have to study the emptying of solids for at least three hours with a valid test—either scintigraphy, the stable isotope–labeled spirulina breath test or the wireless motility capsule.
The second important point is reiteration of the importance of diet—both reducing the nondigestible fiber content of the diet and, based on a clinical trial from Sweden, homogenizing the diet (Am J Gastroenterol 2014;109[3]:375-385)—to facilitate the emptying of food from the stomach and provide relief of symptoms.
The third point pertains to therapy. From the pharmacologic standpoint, there have been no real novelties in the past decade, so we needed to guide clinicians regarding the evidence for various treatments—prokinetic agents, antiemetic agents, and central neuromodulators such as nortriptyline. We made specific recommendations with regard to those drugs. Also from a therapeutic standpoint, we summarize the data on gastric electrical stimulation (GES) and gastric per-oral endoscopic myotomy (G-POEM). We were able to incorporate the data from the first randomized controlled trial of active G-POEM versus sham to provide guidance to clinicians (Gut 2022;71[11]:2170-2178).
We also summarized how patients might be selected for the G-POEM procedure. For instance, data suggest that it is important to measure the distensibility and the diameter of the pylorus to help predict a good response to the G-POEM procedure. We know that in gastroparesis, sometimes there is weakness of the distal part of the stomach, so food can’t be broken down. But, if you just open the lower end of the stomach in a patient with weakness of the distal stomach, is it really going to help you to get the food out of the stomach and relieve the patient’s symptoms? This question is still not completely answered, but research is being done to try to uncover some of the physiologic measurements that, in the future, hopefully will help us identify the best candidates for treatment with G-POEM.
GEN: What were some of the hottest points of debate among the guideline panelists, and how did you resolve them?
Dr. Camilleri: Use of the wireless motility capsule in the setting of gastroparesis was an item of debate among the panelists. We all agree that the small bowel and colonic transit measurements with the wireless motility capsule are very accurate. But when we came to assess the diagnostic accuracy of the capsule for gastric emptying, this was an item of controversy. The reason, I think, is that a solid capsule, 8 to 10 mm in size, does not empty the same way ordinary food empties from the stomach. There has been evidence to suggest that it actually empties when the next migrating motor complex comes through the intestine and the stomach, like nondigestible vegetables (Neurogastroenterol Motil 2008;20[4]:311-319). On balance, we agreed that it would be very helpful to measure the rest of the GI tract, but we have to be very careful not to overstate the accuracy for the measurement of gastric emptying. The gold standards remain scintigraphy and the stable-isotope breath test.
A second item of controversy was the use of GES as a means to treat gastroparesis symptoms. This has been around for humanitarian use for about three decades, but the literature is mixed. GES requires surgery, and there could be the need for replacing batteries, etc. As we were going through our study of the literature, a very large multicenter study from France was published, suggesting that GES had a beneficial effect in management, particularly in patients who have very severe vomiting episodes (Clin Gastroenterol Hepatol 2022;20[8]:1857-1866).
A third point of debate centered on the role of the G-POEM procedure. Again, as we were discussing that, the first sham-controlled, randomized study was published, which makes us more optimistic that this would be a useful treatment (Gut 2022;71[11]:2170-2178). However, we have to keep in mind that it’s a relatively small study, and the procedure was most efficacious for patients with diabetic gastroparesis. Its efficacy was not completely proven for idiopathic or postsurgical gastroparesis in the sham-controlled study.
Another thing that was a little controversial was the use of central neuromodulators, such as tricyclic agents and mirtazapine, which can reduce the symptoms in patients with gastroparesis. The problem is that tricyclic antidepressants also have anticholinergic effects that may result in delayed gastric emptying, and a large study of nortriptyline showed no difference from placebo in patients with idiopathic gastroparesis (JAMA 2013;310[24]:2640-2649). So, you may reduce symptoms one way but induce symptoms another way.
GEN: Where are the remaining gaps in evidence, and what can clinicians do in these cases?
Dr. Camilleri: We need to go back to first principles.
Remember to remove any medication that could be aggravating the gastric emptying delay. I often tell my students and my fellows and patients themselves: There is no such thing as an opiate that does not delay gastric emptying. And that’s just one example.
Clinicians also need to make sure that there is a robust diagnosis using a test that’s well validated.
Then, it’s a matter of optimizing the diet and trying the available medications. The only medication actually approved in the United States is metoclopramide. Since the FDA required a black box warning to be added to the metoclopramide labeling, there have been many epidemiological studies showing that the risk for tardive dyskinesia is not 2% to 4%; it is probably closer to one in 1,000. In some cases, people think it’s one in 10,000 patient-years (Neurogastroenterol Motil 2019;31[11]:e13617; Br Med J [Clin Res Ed] 1984;288:545-547). Involuntary movements happen with metoclopramide, but if you stop the medication, it isn’t permanent. It isn’t truly tardive dyskinesia. We wanted to specify that updated information, which appeared in the literature since the last guideline, as well as clarify recommendations on the central neuromodulators, prokinetic agents and antiemetic agents, as mentioned previously.
Finally, clinicians should keep in mind the opportunity for some of those other interventions, including the G-POEM procedure, which appears to be quite safe in carefully selected patients.
The final point was to stress that patients with gastroparesis really are suffering. They often have to go to the emergency room or be admitted for hydration. The condition has a very significant negative impact on quality of life and results in significant expenses and healthcare utilization that has been very well documented in the literature. We wanted to stress, kind of indirectly, to the pharmaceutical companies and the FDA that there is still such a large unmet need for medications for gastroparesis.
Some investigational agents are being tested for the treatment of gastroparesis. For example, I am the principal investigator on a placebo-controlled clinical trial of the cannabinoid type 2 receptor agonist cannabidiol, and we’re hoping to present data in 2023 (ClinicalTrials.gov Identifier: NCT03941288). In addition, the neurokinin-1 receptor antagonist tradipitant (Vanda) is being tested in this setting (Gastroenterology 2021;160[1]:76-87).
Dr. Camilleri reported research funding in the past 36 months for single-center studies related to gastroparesis from Allergan, Takeda and Vanda.
This article is from the March 2023 print issue.