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A recent article in The American Journal of Gastroenterology acknowledges unmet needs at both the patient care and systems level (e.g., trial design level) related to gastroparesis, with the authors stressing that medical therapy for the treatment of gastroparesis is less than satisfactory. In the article, Brian E. Lacy PhD, MD, FACG, and co-authors, Michael D. Crowell, PhD, FACG and Michael Camilleri, MD, address the challenges of gastroparesis, pointing out deficiencies in study design that do not take into account the diverse disease pathogenesis and unique experience of gastroparesis patients and provides recommendations for critical future improvements in patient care.
Gastroparesis affects approximately 5 million adult Americans, with one study estimating a community prevalence of 1.8% Using a combination of symptoms (e.g., nausea, vomiting, early satiety or postprandial fullness, weight loss, and abdominal pain) and an objective measurement of gastric emptying (e.g., scintigraphy, breath tests), gastroparesis can be readily diagnosed. Long-lasting symptoms debilitate many patients, which can dramatically reduce patients’ quality of life and negatively impact the health care system.
Although, diagnosing gastroparesis is easier due to heightened awareness of the condition and the release of guidelines and consensus statement, persistent unmet needs exist in the treatment of gastroparesis leading to both patient and clinician frustration.
“For clinicians frustrated by a lack of effective therapies, these system level changes should move the field forward and deliver more effective therapies to improve symptoms on an individual level,” said the Mayo Clinic authors Dr. Lacy (Jacksonville, FL), Dr. Crowell (Scottsdale, Arizona) and Dr. Camilleri (Rochester, MN).
The authors suggest that in the meantime, gastroparesis treatment should:
- Focus on the predominant symptom (e.g., nausea or pain or bloating)
- Address co-existing symptoms (e.g., constipation)
- Deemphasize the focus on accelerating gastric emptying
- Stop opioids and other exacerbating medications
- Perform experimental therapies (e.g., G-POEM) at referral centers using standardized protocols
The article outlines a number of reasons why treating gastroparesis symptoms is difficult:
1. Only one medication (e.g., metoclopramide) is FDA-approved for the treatment of gastroparesis. Although metoclopramide improves symptoms of nausea and vomiting in some patients, it is associated with side effects in many patients (e.g., anxiety, restlessness, gynecomastia, galactorrhea, involuntary movements), which led to a “black box” warning from FDA in 2009.
2. Many therapies commonly employed to treat symptoms of gastroparesis have never been tested in prospective, placebo-controlled trials of patients with gastroparesis. For example, clinicians are hamstrung by the lack of data supporting the use of promethazine, prochlorperazine, trimethobenzamide or scopolamine, and these treatments are technically all off-label.
3. Some treatments are frequently used to treat symptoms despite the lack of data. For example, data supporting botulinum toxin injection of the pylorus in diabetic gastroparesis patients is marginal and prospective studies have demonstrated it is not effective in idiopathic gastroparesis patients.
4. Clinicians frequently struggle with gastroparesis treatments because we live in a “data-free” zone. For example, is promethazine more effective than ondansetron? Does scopolamine work better than prochlorperazine? Which medication should be used first, and which should be reserved for second-line or third-line therapy? Unfortunately, these questions cannot be answered because head-to-head studies comparing different treatments have not been performed and no validated treatment algorithm exists.
5. Clinicians frequently receive conflicting information. For example, dronabinol might help nausea and vomiting, although it may slow gastric emptying by binding to cannabinoid receptors. Similarly, transdermal scopolamine (a belladonna alkaloid with anticholinergic properties) helps some patients but potentially could slow gastric emptying.
6. Symptoms do not accurately reflect underlying pathophysiology, although preliminary data support an association between gastric emptying measured by optimal methodology and upper gastrointestinal symptoms (manuscript submitted). A number of studies have demonstrated that accelerating gastric emptying may not improve symptoms of gastroparesis, but the efficacy of the treatments at accelerating gastric emptying, including, for example, gastric electrical stimulation, was questionable.
7. Epigastric pain is reported by a majority of patients with gastroparesis, although this symptom has not been the primary endpoint of clinical trials and is often undertreated clinically. A well-designed prospective study demonstrated that nortriptyline, a tricyclic antidepressant, did not improve symptoms in idiopathic gastroparesis patients, although it has not been tested prospectively in diabetic patients.
Data from randomized controlled trials conducted in patients with gastroparesis show that a small particle diet compared to normal food results in improved symptoms of gastroparesis and the NK1 receptor antagonist aprepitant is associated with reduced secondary outcome measures, although nausea, the primary outcome was not significantly improved compared to placebo. “Unfortunately, we do not have any prospective data from trials involving other anti-nociceptive agents such as gabapentin or pregabalin,” the authors said.
Need to “Dramatically” Change Approach to Treating Gastroparesis
While the authors said it would be speculative to try to determine why so many of the studies performed to date have been less than satisfactory, they did note that likely factors my include:
- the costs of long-term studies
- the difficulty recruiting patients classified as “pure” gastroparesis patients without co-morbid disorders
- the potential confounding effects of concomitant medications (such as antidepressants, anti-histaminics, or opioids)
- the unwillingness of many patients to enter a long-term study in which they may be randomized to placebo are all likely factors.
These factors make it difficult for clinicians to effectively treat patients with gastroparesis, and highlights the need to dramatically change our approach to treating gastroparesis on a global level, according to the authors.
“A first required step is changing study design. Imperfect clinical study design has made it difficult to determine whether current medications are simply not very effective at treating gastroparesis symptoms or whether flawed trials mask medication efficacy.”
Key Change to Study Design to Better Understanding the Disease: Distinguish Three Groups
Gastroparesis symptoms are not one-sized fits all. Given the diverse mechanisms involved, prospective, placebo-controlled trials in gastroparesis should carefully distinguish three essential groups:
- diabetic gastroparesis
- idiopathic gastroparesis
- post-surgical gastroparesis
This classification scheme should enable researchers to gain a better understanding of the complex pathophysiology involved in the generation of symptoms, including nausea and vomiting, postprandial fullness, and upper abdominal pain, according to the authors. “Studies in more homogeneous subgroups of gastroparesis should foster the emergence of therapeutic insights, thereby improving patient care and outcomes.”
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Call to Action
“There is now robust guidance on the optimal definition, study design, methodology, and endpoints for clinical trials in gastroparesis,” said the authors. “This should be a rallying call to basic and clinical researchers, as well as to the pharmaceutical and device industry, to develop robust trials with clinically meaningful, and validated endpoints.”
“This is great news for gastroparesis patients,” said gastroenterologist Patricia Raymond, MD, FACG, who was not an author of the article. “With definition of the specific cause of your gastropareisis, and designing studies specific to that subtype, we will make headway into better treatment and management. I encourage patients to be willing to participate in new drug and device studies if they are available in their area.”
Source: “The Challenges of Gastroparesis: Changing Study Design to Improve Clinical Care,” The American Journal of Gastroenterology, https://doi.org/10.1038/s41395-018-0134-4