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Treatment Options for Gastroparesis
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Thomas Abell, MD

 

This article was adapted from the transcript of a webinar Dr. Abell presented for the Oley Foundation in July 2017, at the Oley conference in Old Greenwich, Connecticut. This and another webinar by Dr. Abell were recorded and can be viewed at www.oley.org.

 

               I have been interested in GI motility disorders, including gastroparesis, for fifty years. My initial interest stemmed from my observations of migraine-related nausea and vomiting in friends and family members. While studying at Yale University in 1968, I was assured that these disorders were psychosomatic, that is, physical symptoms caused by psychological factors. I set out to see how this could be possible. As you’ll see, I found out they are not psychosomatic; they are organic disorders.

 

Symptoms of Gastroparesis

               The vast majority of patients with gastroparesis (Gp) have one or more of these symptoms: nausea, vomiting, abdominal pain. They may also have bloating (distension) and/or loss of appetite (anorexia). They may have constipation and/or diarrhea, or fecal incontinence; urinary hesitancy and/or urinary frequency; or interstitial cystitis, which is an inflammatory disease. Other patients have autonomic symptoms, such as dizziness, cold intolerance, and/or heat intolerance.

 

               About half of the patients we see with severe disorders have migraine headaches. They may have muscle pains and are often diagnosed with fibromyalgia. Or they may have autoimmune diseases. Some have overly flexible joints. Others may have seizures or other neurologic disorders.

 

               Some patients have symptoms that come in cycles: they do well for a few days, and then they don’t do well for a few days. Many have a family history of symptoms.

 

               What are all these symptoms from? Many are seen with acute illness or viral infections, but with Gp, they may be recurrent or chronic. Unfortunately, most providers, including myself, never learned about this in medical school, training, or practice; thus they may not value these symptoms, or the illness behind them. Patients have taught me that this leaves them suffering from what I call the five Ms: miserable, misunderstood, misdiagnosed, mismanaged, and mistreated. Hopefully, those days are largely behind us.

Quality of Life with Gp

               I’ve been impressed at how little we know about Gp, as well as how much patients are able to tell us, if we’ll just listen. I’ve been impressed, too, at how much suffering, which is now called the “disease burden,” exists.

 

               In the 1990s, my colleague Dr. Teresa Cutts, a psychologist, and I held nearly a hundred focus groups for patients with the symptoms of gastroparesis. Over the last twenty-five years we’ve looked at the data collected, much of it prospectively.

 

               One article we published based on this data looked at quality of life (QoL) with Gp using the SF-36, a standard generic tool that helps rate QoL. The SF-36 allows you to look at physical functioning, pain, social functioning, and general health. Based on a large sample of people with Gp, we found there are a lot of problems with physical and social functioning, and a lot of pain and general health issues. (See figure 1.)

 

               We have learned several things since we started these groups: (1) the team approach to Gp is crucial for helping patients; (2) the autonomic nervous system is part of the illness, and the GI tract may not be the only system that is involved; (3) providers often underestimate the effect of the illness on QoL; (4) for some patients, Gp is associated with increased levels of anxiety and depression, likely due to the trauma of the illness (as opposed to being the cause of the illness); and (5) well-intentioned providers often make things worse while trying to make things better.

 

Gp Research Consortium

               Federal involvement in Gp is quite important. The National Institutes of Health (NIH) Gp Clinical Research Consortium (GpCRC) was set up in response to patient needs, with patients contacting their congressmen and senators and NIH saying, “We need help.” The impetus behind the GpCRC was literally a discussion in a patient’s kitchen; it is now in its eleventh year.

               The GpCRC has defined the disease burden by providing descriptions, diagnoses, details of illness, and distinctive pathophysiology of Gp. The NIH GpCRC has also helped stimulate concomitant interest in Gp at the FDA and supported proposals on Medicare coverage, some of which have been enacted (though not enough). FDA has been very helpful in defining what should be measured and reported in trials for Gp.

 

Diagnosing Gp

               The GpCRC looked at people who have the symptoms of Gp with, and without, delayed gastric emptying. We found that people with what we call gastroparesis-like syndrome (GLS) who have non-delayed gastric emptying are identical in every way to those with Gp except for emptying. I mean in every way—age, sex, underlying illness, if known, etc. So gastric emptying studies may not be the best way to differentiate patients to make a diagnosis of gastroparesis.

 

               When placing a j-tube or gastric stimulator, we often have the opportunity to do full-thickness gastric biopsies. The GpCRC has set up a core laboratory to examine these biopsies, looking at things like the interstitial cells of Cajal (ICC), which are decreased in almost all patients with symptoms of Gp. As those numbers get lower, the gastric emptying becomes more delayed.

 

               In figure 2, the circular muscle is on the upright axis (the Y axis). This is the number of ICC per high power field (a common standard of magnification). On the right are the healthy control patients. They

have about five or six ICC per high power field. The Gp patients (on the left) have less than two or three per high power field and have delayed emptying. The patients in the middle have chronic unexplained nausea and vomiting (CUNV). They have a decreased number of ICC, but not enough decrease in ICC to be delayed.

 

               A lot of patients are non-delayed in their emptying study. A doctor might say to these patients, “You can’t really be sick, because you don’t have Gp. You’re not delayed.” To me, that’s a little bit like saying to a patient with heart disease and angina, “Come back and see me when you have your heart attack. Then I’ll know you are really sick and I’ll take care of you.”

 

               Of course that would be crazy. No one would intend to treat patients that way. But patients with nausea and vomiting are treated that way at times. So in my opinion, this is really a spectrum. There is decrease in ICC for a number of reasons that are not fully understood; when finally the ICC get low enough, there is delayed emptying.

 

               While in my and others’ view, Gp and GLS can be viewed as part of a spectrum, many others would not agree with us. Many people in Europe would not agree with us for example, so there is no general agreement or consensus.

 

               A couple of years ago, the Diabetes Complications Consortium, also NIH-funded and related to the GpCRC, funded our center to look at a small group of diabetic and nondiabetic patients with the symptoms of Gp. This resulted in new work that has not been widely circulated. We found that these patients were systemically inflamed and had abnormal autonomic nervous system measures. We then looked at their enteric (gastrointestinal) nervous system by full thickness biopsies, as well as other biopsies, and found they were abnormal as well.

 

               We also looked at electrophysiology, which is what I’ve worked on for decades, and found these patients had abnormal activity. (Just like with the heart, you can have electric abnormalities in the stomach.) We also found hormonal abnormality; even if not diabetic, many patients with Gp have abnormal metabolic and appetite hormones. My conclusion is that Gp can be looked at as a systemic disease with variable presentations of symptoms. The work is not yet published, but the investigation is registered on clinicaltrials.gov for anyone who is interested.

 

               In this study, we also looked for the effects of gastric electrical stimulation (GES), and showed several possible mechanisms of action related to pathophysiology. I could talk much more about GES now, but won’t do so, due to limited space. So I’d like to switch to a discussion of therapies. I’ll use the abbreviation COPS: C for chronic disease, O for options for therapy, P for particulars, and S for electronic searches.

 

COPS

               Chronic illness care, the first of what I call the “Cs,” starts with home care and primary care. Then there’s internet care, which I think almost everybody uses next these days, as well as acute care, chronic care, and hospital care. Many patients have experienced all of these, but they need to be integrated, in my opinion, for optimal patient care.

 

               Team work, with ongoing communication, is essential. It’s gotten a little easier with texting and pagers, but it is amazing to me, as a former primary care doctor, how many people are seen and taken care of by others without all team members being informed. Unfortunately, electronic medical records haven’t solved this problem—or not yet anyway.

 

               I’m going to spend more time on “O,” the options for therapy, because that’s the primary focus of this article. I will subdivide the “Os” into the “Ds”: diet and nutritional support; drugs; devices; disrupt/divert; and detoxify. I’ll discuss each one separately.

 

               Why are there not more treatments? One of the many reasons is that there is still the belief that Gp is not a real disease, that it is not a biologic problem. But beliefs are about religion, and science should be about data. In addition, there is a lack of understanding of mechanisms. As we discussed, the GpCRC and many others are starting to understand the mechanisms of Gp much better.

 

               There are limited resources for new drugs, though that, too, is changing. And there is often a narrow view about the range of therapeutic options available for patients. All of these contribute to the current lack of good treatment options for Gp. Let me spend time on the “Ds” in more detail.

 

Diet and Nutritional Support

               The traditional approach is to advise frequent small meals of limited digestibility. However, this only works for certain patients. Also, the majority of people with Gp—you won’t be shocked by this, but I think many were—are never seen by a nutritionist, even in referral centers. Part of the reason for this is we don’t work with nutrition colleagues enough, part of it is reimbursement, and part of it is we (providers) don’t think of it.

 

               Eating by mouth is the best option, but not everyone can do this. Small bowel (jejunal) feedings, as with a j-tube, are the next best option. We usually try an endoscopic nasojejunal (NJ) tube before placing a more long-term j-tube. But there is limited expertise with feeding tubes, and not everyone can have successful small bowel feedings. Some patients don’t have a complete and functioning small bowel so it doesn’t work. My own concern is that most people who get tubes never had a small bowel (or gastric) full-thickness biopsy. To me that’s kind of like treating cancer and never having a tissue diagnosis. You don’t know what’s there, what the nerve and muscle abnormality is, so it is really going to be hard to treat it appropriately.

 

               For many patients, parenteral nutrition (PN) is the only option. A full discussion of home PN (HPN) is beyond the scope of this article. For now, I’ll say that it is wonderful to have this option, but HPN is not easy, inexpensive, or risk-free. And, unfortunately, expertise in HPN varies widely, although there are many excellent HPN pharmacies. Support groups like the Oley Foundation are crucial for people on HPN.

 

Drugs

Drugs can be discussed by class: antiemetics, prokinetics, and others (see table 1). Not all of these drugs are available in the U.S., and some are investigational. Fortunately, there is renewed interest by pharmaceutical companies in drugs for Gp.

 

               Antiemetic drugs are helpful. Unfortunately, a nationwide shortage of promethazine (Phenergan®) has been ongoing; a lot of our patients at home can’t get it at times. Aprepitant, which addresses the symptoms of Gp, has documented efficacy, but is quite expensive.

 

               We have only one approved drug for Gp in the U.S.: metoclopramide (Reglan®). It is a prokinetic but has a number of safety issues, both short- and long-term, and so it is recommended for a maximum of about six to eight weeks. Erythromycin can be also helpful, but it may not work long-term and some people can’t tolerate it. Other drugs have not been studied systematically.

 

               There are also investigational drugs not approved in the U.S., like domperidone. It is safer than metoclopramide, but complex to obtain. Other investigational drugs are in clinical trials, all under FDA guidelines. The FDA, as always, is trying to respond to patients and patient groups with new ways to get drugs more quickly.

 

               Most of these are oral drugs. Most are small tablets. Some are available as capsules, suppositories, or liquids. Some can be given intravenously. IV therapies are, again, beyond the scope of this talk. There are real risks with IV therapies, including IV access issues, blood clots, bleeding, and infections, some of which can be life-threatening, but there are benefits as well. There are some coverage issues by insurers for IV therapies, and you need a dedicated team to administer.

 

Drugs for Pain in Gp

               This is a very complex issue. It is difficult for most patients and most providers, and the discussion is beyond the scope of this paper. We try to get every patient with Gp with pain to see a pain specialist, with the idea that pain should be able to be treated—even though we realize that doesn’t often happen in practice. A separate communication about this important topic is needed and will hopefully follow by experts in the field, as there exist other ways to treat pain, such as neuromodulation. [Editor’s note: We are working on a follow-up article on this topic.]

 

Devices for Gp

               Devices for Gp are of limited availability. Medtronic’s Enterra™ neurostimulator is the only FDA-approved device. There are many regulatory, insurance, and other issues with neurostimulators. This is primarily what I have worked on for the past twenty-five years. The first current neurostimulator was implanted in 1992. It was approved by the FDA in 2000 as a Humanitarian Use Device, which has some limitations on use. GES was recommended for compassionate use by the American College of Gastroenterology Gp guidelines in 2013. This neuromodulation therapy can be very helpful, but it is beyond the scope of this article.

 

Diverting and Disrupting

               What do I mean by this? The stomach has an inlet, upper and lower parts, and an outlet. There is increased interest in the lower, pyloric outlet function. This lower outlet dysfunction is clearly an issue for many patients, especially those with delayed emptying. There are many new approaches, including endoscopic approaches, but all attempt to divert/disrupt the pyloric sphincter. None of these have been shown conclusively to consistently help, but I try to discuss them with patients and say we can try to do something about your pylorus. This is something the GpCRC and others are actively looking at.

 

Detoxify

               Many patients have systemic issues, generalized symptoms, and disordered physiology. But some have neuromuscular issues, as measured by blood and/or tissue, which we think is in part due to systemic inflammation. Therapies like IV immunoglobulin (IVIG) act on the immune system, and although this is an off-label use for IVIG, can be quite helpful for some patients. There are three peer-reviewed published studies, many case reports, and other articles in the works. It is something to at least be aware of.

Particulars

               The “Ps” include the patient and protectors (by which I mean the family), providers, partnerships, pharmacies, and professional companies and insurance companies—working together. We really need a true team, with any chronic illness; it is crucial. I don’t think I need to explain to this audience how important this is. Without it, we just can’t deliver good care.

 

Searches

               This could have been called “COPES,” for electronic searches, but I don’t mean Internet searches. I mean what I call, first, “PreSearch,” which is talking about the issues important to patients. Then there is “ReSearch,” which is formal work like that done by GpCRC and others. “ProSearch” is the education of providers. I knew nothing about Gp after my first residency, and I was well educated in primary care, both internal medicine and family medicine. “FuSearch” is how we can get to the future. As part of this, support groups are crucial, and federal resources—NIH, FDA, Medicare, and others—are very important. It all boils down to education, teams, funding, and working together.

 

Summary

               Most things in medicine are opinions, not facts. I have given you my opinions. As I see it, over the past fifty years we’ve gone from bad, to better, and to now good in many areas. The future, I hope, will be better yet.

 

               I have tried to focus on therapies, but also tried to offer background—why things are the way they are right now—and a bit about the physiology of the GI tract. Several important areas, such as medications and other treatments for pain associated with gastroparesis, are not discussed here.

 

               Teams and support groups, in the context of the illness we call Gp, which, when severe, is GI tract failure, are the key in my opinion. A number of our patients end up getting PN or small bowel transplants. If you have severe Gp, you have GI tract failure.

 

My Bottom Lines

               Gp has been misunderstood, which is not unusual in the history of medicine. It takes decades (or longer) to understand many illnesses. Gp is generally now accepted as a “legitimate” illness, although still not everyone agrees. The U.S. NIH and FDA are engaged in work on this problem. Medicare (i.e., as part of the government) can be lobbied, by patients, and their family, friends, and representatives. Institutions don’t always listen to me as a physician, but patients are voters.

 

               Much has been learned, especially over the last decade, about Gp and gut failure, but much more work needs to be done. Partnerships of patients, protectors, and providers may be the key to making this happen. Web access is very important. The GpCRC website and others, support groups like Oley, IFFGD, G-PACT, AMGD, and others, are all important.

Lifeline Letter, January/February 2018

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2/9/2019
Oley Regional Conference - Dallas, Texas

This website is an educational resource. It is not intended to provide medical advice or recommend a course of treatment. You should discuss all issues, ideas, suggestions, etc. with your clinician prior to use. Clinicians in a relevant field have reviewed the medical information; however, the Oley Foundation does not guarantee the accuracy of the information presented, and is not liable if information is incorrect or incomplete. If you have questions please contact Oley staff.

 

Updated in 2015 with a generous grant from Shire, Inc. 

 

This website was updated in 2015 with a generous grant from Shire, Inc. This website is an educational resource. It is not intended to provide medical advice or recommend a course of treatment. You should discuss all issues, ideas, suggestions, etc. with your clinician prior to use. Clinicians in a relevant field have reviewed the medical information; however, the Oley Foundation does not guarantee the accuracy of the information presented, and is not liable if information is incorrect or incomplete. If you have questions please contact Oley staff.
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