Tag Archives: gastroparesis

Prokinetics Have Little Benefit for Gastroparesis

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WL Hasler et al. Clin Gastroenterol Hepatol 2024; 22: 867-877. Open Access! Benefits of Prokinetics, Gastroparesis Diet, or Neuromodulators Alone or in Combination for Symptoms of Gastroparesis

Methods: In this prospective study of patients (n=129) with suspected gastroparesis, the authors examined longitudinal outcomes focusing on responses to prokinetics and other therapies. This included gastroparesis diets and neuromodulators. Patients underwent validated gastric emptying testing (wireless motility capsule and gastric emptying scan) before recommending new treatments.

Prokinetics included dopamine antagonists, motilin agonists, acetylcholinesterase
inhibitors, and pyloric botulinum toxin injection.

Key findings:

  • “Initiating prokinetics as solo new therapy had little benefit for patients with symptoms of
    gastroparesis.”
  • “Neuromodulators as the only new therapy decreased symptoms other than
    nausea and vomiting”
  • Combination therapy of a prokinetic with a neuromodulator appeared to be the most effective
  • Neuromodulators were mainly effective in those without delayed gastric emptying times

My take: Our therapies for gastroparesis are not very good. And, neuromodulators are likely to be more helpful than prokinetics.

Example of a gastroparesis diet: Cleveland Clinic Gastroparesis Diet (7 pages). Part of the diet recommendations are shown below.

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Is Manometry Useful to Determine if Botox Will Help Nausea/Vomiting?

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Before reviewing today’s article, I wanted to make a comment about the blog post on 12/17/23 (Endoscopy of the Ileal Pouch Anal Anastomosis) which was a JPGN topic of the month. The editorial staff encourages author-driven communication and author-driven initiatives for these types of articles. If you have a topic for JPGN, please send an email to the Section Editor Darla Shores (dshores1@jhmi.edu) or to the editor Sandeep Gupta. (skgupta@uabmc.edu). This includes articles that you would like to write (fellow/interested faculty with senior faculty, up to 5 authors, 1500 words, 12 references), or  if you have a topic that you would like to see in JPGN but do not wish to write yourself, please inform the editorial team as well. 

———

PT Osgood et al. JPGN 2023; 77: 726-733. Intrapyloric Botulinum Toxin Injection for Refractory Nausea and Vomiting in Pediatric Patients

In this retrospective review, pediatric patients (n=25) received intrapyloric botox injections: (80-100 IU divided into 4 doses administered via sclerotherapy needle.

Key findings with botox injections:

  • Of 22 patients completing a GE study, 14 had delayed GE with no significant difference between IPBI responders and nonresponders
  • Improvement in vomiting in 80% (16/20), nausea 75% (15/20), abdominal pain 79% (15/19).
  • In those with psychiatric diagnosis, improvement was seen 71%. In those with orthostatic intolerance, improvement was noted in 67%.
  • In those with delayed GE, improvement was noted in 79% compared with 63% (5/8) with normal GE

My take: Botox was associated with improvement in this refractory pediatric group regardless of gastric emptying/manometry. This suggests that relaxation of pylorus is a useful therapeutic modality in a subset of patients.

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If a Gastroparesis Medication Works in the Forest But No One Sees It, Did It Really Work?

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MR Ingrosso et al. Gastroenterol 2023; 164: 642-654. Open Access! Efficacy and Safety of Drugs for Gastroparesis: Systematic Review and Network Meta-analysis

The authors examined  29 RCTs (3772 patients). Key findings:

  • Only two medications (neither available in U.S.) were identified as being more effective than placebo for global symptoms of gastroparesis: clebopride (RR, 0.30) followed by domperidone (RR, 0.68) 
  • Oral metoclopramide ranked first for nausea (RR 0.46), fullness (RR 0.67), and bloating. Though, use may result extrapyramidal adverse effects

In the associated editorial (pg 522-524, Drug Treatments for Gastroparesis—Why Is the Cupboard So Bare?), the authors note that the label “gastroparesis” applies to a heterogeneous population.

Key points:

  • I tend to abide by the recommendation proposed by Masaoka and Tack10 some years ago that one should use the term gastroparesis only “when persistently and severely delayed gastric emptying is found in the absence of mechanical obstruction.” 
  • An obsession with gastroparesis as the basic issue among patients with “gastroparesis-like” symptoms has translated into a therapeutic fixation on the acceleration of gastric emptying. This too has led to frustration and disappointment. As already mentioned, symptoms are a poor predictor of the rate of gastric emptying, and a normalization of delayed emptying has not consistently correlated with symptom responses and vice versa.11,12
  • Oblivious to research illustrating how upper gastrointestinal symptoms can result from several other derangements in foregut physiology, such as impaired accommodation of the upper stomach, visceral hypersensitivity, and antropyloric distensibility and dysmotility,13, 14, 15, 16

My take: Currently, pharmaceutical agents geared towards symptoms like nausea and sensory disorders are much more promising than prokinetic agents for gastroparesis

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Sunset in Tucson, AZ at Tumamoc Hill

Dreaded Nausea (2022) Plus Skills or Pills

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C DiLorenzo. Front Pediatr 2022; https://doi.org/10.3389/fped.2022.848659. Open Access: Functional Nausea Is Real and Makes You Sick

Couple of key pointers:

Diagnosis:

  • ” I tend to refrain from ordering gastric emptying studies in patients with nausea unless vomiting hours after eating occurs.” According to the article, this is mainly due to the overlap symptoms of gastroparesis and functional dyspepsia, the suboptimal reliability of testing, and the uncertain value of testing in targeting therapy.
  • “Much like in most other DGBI, diagnostic tests in patients with chronic nausea should only be indicated in the presence of other alarm signs or features (weight loss, severe pain, bilious vomiting, etc.) (29). Upper endoscopies are particularly unhelpful with 98% reported to be normal in patient with nausea as the predominant symptom”

Treatment:

  • “Most beneficial treatment is hypnotherapy.” Cognitive behavioral therapy is likely helpful.
  • Medications that may be useful: cryproheptadine, STW5 (an herbal supplement), scopolamine patch, and erythromycin (when there is gastroparesis); “use of psychotropic agents such as amitriptyline, buspirone, and mirtazapine (which decrease visceral hyperalgesia, improve accommodation or accelerate gastric emptying may be justified in selected cases.” There is little evidence that classical antiemetics such as ondansetron are beneficial for functional nausea.
  • Also consider wrist acupuncture &/or commercially available devices based on the same principle, endoscopic injection of botulinum toxin in the pylorus; implantation of a gastric pacemaker improves drug-refractory nausea. Treatment of anxiety and depression, if present, is also beneficial.

My take: This is a useful review on a tough disorder to manage.

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Related article: PD Browne et al. Clin Gastroenterol Hepatol 2022; 20: 1847-1856. Open Access! Skills or Pills: Randomized Trial Comparing Hypnotherapy to Medical Treatment in Children With Functional Nausea

This article found that hypnotherapy was more effective than standard medical therapy during the first 6 months and similar subsequently in children with functional nausea. Standard medical therapy was a progression of treatment:

Tweetorial: Refractory Gastroparesis

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Tweetorial from “The Emoroid Digest”(posted 5/2/22):

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Are Gastroparesis and Functional Dyspepsia Part of the Same Problem?

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A recent post (Is A Gastric Emptying Study Helpful in Children?) reviewed data in children indicating that gastric emptying study (GES) results did not correlate with symptom severity in children with functional dyspepsia (FD) symptoms.

Now a 12-year study in adults (n=944) (PJ Pasricha et al. Gastroenterol 2021; 160; 2006-2017. Full text: Functional Dyspepsia and Gastroparesis in Tertiary Care are Interchangeable Syndromes With Common Clinical and Pathologic Features) shows that FD is similar to gastroparesis in terms of clinical and pathological features and that diagnosis of these disorders were NOT fixed. Many patients with FD developed criteria of gastroparesis and many with gastroparesis were later reclassified as FD after followup GES.

Key findings:

  • At 48-weeks, 42% of patients with an initial diagnosis of gastroparesis were reclassified as FD based on gastric-emptying results at this time point; conversely, 37% of patients with FD were reclassified as having gastroparesis
  • In a subset of patients, full-thickness biopsies of the stomach showed loss of interstitial cells of Cajal and CD206+ macrophages in both groups compared with obese controls.
  • The 48-week clinical outcomes were similar. Symptom severity remained “on average unchanged despite the change in gastric-emptying status”

My take (borrowed from authors): This study shows that “patients initially classified as one or the other are not distinguishable by clinical features or by follow-up assessment of gastric emptying…both disorders are unified by characteristic pathologic features, best summarized as a macrophage-driven “cajalopathy” of the stomach.”

While the authors state that a GES lacks reliability, the associated editorial argues that a GES may still be useful (J Tan et al. pg 1931. Full text: Gastroparesis: A Dead-end Street After All?) As individuals with delayed GE “fail to benefiit” from neuromodulators, a GES may influence treatment. However, they note that ACG guidelines indicate that a GES is not needed and all patients with dyspepsia symptoms can be treated in a “uniform sequence of proton pump inhibitors, tricyclic antidepressants and prokinetics as third-line therapy.”

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Islamorada, FL

Trying to Understand Gastroparesis

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…all I know is that I know nothing. –Socrates

Perhaps Socrates was a gastroenterologist.  So much of what we think we know, we are finding out is poorly understood.  This applies to gallbladder dyskinesia, sphincter of Oddi dysfunction and now gastroparesis.

A recent study (PJ Pasricha et al. Gastroenterol 2015; 149: 1762-74, commentary 1666-68) and commentary show how little we understand about gastroparesis.

The study was a large prospective surgery of 262 adult patients with gastroparesis (either diabetic or idiopathic).

Key findings:

  • 28% had improvement in the gastroparesis cardinal symptom index (GCSI) at 48 weeks.  Beyond 48 weeks, there were no significant reductions through week 192.
  • Favorable characteristics: male gender, age 50 and older, initial infectious prodrome (18% of cohort), antidepressant usage, and 4-hour gastric retention greater than 20%.
  • Unfavorable characteristics: obesity, smoking, use of pain modulators, moderate to severe abdominal pain, severe reflux, and moderate to severe depression.

The commentary suggests that those with the higher GCSI improved, in part, because of a regression toward the mean bias.  Other important commentary:

  • “More severely delayed gastric emptying was associated with a greater likelihood of improvement”
  • “There was no differences in outcome between diabetic or idiopathic gastroparesis.”
  • Gastric emptying tests are not reliable:  “Pathophysiologic tests are useful in clinical practice if they are reproducible, explain the symptoms, guide therapeutic choices, and determine response to therapy and long-term prognosis.  Despite its popularity, the gastric emptying test scores low on most of these criteria.”
  • “A metaanalysis found no correlation between the change in gastric emptying rate and the symptom response during prokinetic therapy…A 5-year prospective follow-up study of …functional dyspepsia…found that more than 50% improved…with no relation to the presence of delayed gastric emptying.”
  • “Using the term gastroparesis also can lead to premature closure in our efforts to understand the pathophysiology of symptoms…can lead to botulinum injections into the pylorus or placement of gastric stimulators (formerly called gastric pacemakers) for gastroparesis, both of which have been shown to be nonefficacious in controlled trials.”

My take: It is unclear “when to consider gastric emptying testing and how to use it in patient management.”  For the pediatric population, gastroparesis is more likely to be associated with a prodromal infection which increases the likelihood of recovery.

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Banning Mills

Banning Mills

Looking More Closely at a Persistent Question

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Virtually everyday, families that I care for are trying to ascertain the link between their GI symptoms and the foods in their diet.  Many authoritative recommendations on irritable bowel have concluded that “food allergies (symptoms caused by an immune response) are rarely the culprit in IBS patients. Most IBS patients with food-related symptoms have food sensitivities or intolerances, which are not caused by an immune response.” (From Univ Virginia Irritable Bowel Diet PDF)

Whether the process is a sensitivity or an immune-reaction, many patients are quite sensitive to certain foods and many have had improvement with a low FODMAPs diet.

A much closer look at this problem with confocal laser endomicroscopy (CLE), in a pilot study (Gastroenterol 2014; 147: 1012-20), has shown measurable changes within five minutes of a food challenge that takes place during an endoscopy.  In this study, the researchers examined 36 patients with IBS who had suspected food intolerance and 10 control patients with Barrett’s esophagus.  Then during an endoscopy, the researchers used provoking solutions of cow’s milk, wheat, yeast, or soy.  The subjects had CLE before and after the challenges. To enhance visualization of changes, subjects had fluorescein dye injected intravenously prior to examination of the duodenum.

Results

  • In 22 of 36 patients, the challenges were considered positive.  These patients had mucosal changes including increase in intraepithelial lymphocytes, followed by disruption of the villi tips/shedding of cells, then fluorescein leakage into the lumen.
  • None of the control patients exhibited these changes.
  • 19 of 22 patients with positive challenges had a >50% reduction, after 4-weeks, in symptom score with individualized diet based on inciting antigen.

Bottomline:

This provocative study indicates that subtle mucosal changes can occur in a number of IBS patients in a quick and direct response to food challenges.  Perhaps when we look closer with technologies like CLE we will find more answers as to why certain foods provoke symptoms in adults and children with IBS.

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Also noted –web-based information on gastroparesis:

What to do with delayed gastric emptying/gastroparesis

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More information for pediatric patients with the perplexing problem of poor gastric emptying is available in three articles:

JPGN 2012; 55: 166-72, 185-90, & 194-199.

The first study by Waseem et al describes the “Spectrum of Gastroparesis:”

  • Retrospective chart review included 239 eligible children with mean age of 7.9 years.  Nearly equal numbers of males and females. .
  • Time to empty half of solid or liquid considered abnormal if more than 45-90 minutes for solid and more than 60 minutes for liquid (labelled pediasure)
  • Etiology: idiopathic 70%, drug-induced 18%, postsurgical 12%
  • Treatment in 74% diet and erythromycin (74%)
  • Over 24 months, 60% had significant improvement regardless of treatment

The second study by Rodriguez et al is titled “Clinical Presentation, Response to Therapy, and Outcome of Gastroparesis in Children.”

  • Restrospective study with 230 children, mean age 9 years.  In adolescents, female gender was more common (77%) whereas in infants (n=36), male gender was more common (61%).  Most common causes were postviral in 42%, mitochondrial in 18%, and diabetes in 5%.
  • Delayed gastric emptying was defined as having solids or liquids emptying <40% of the meal at one hour.
  • Resolution occurred in 22% at 6 months, 53% at 18 months, and 61% at 36 months.  Median time to resolution was 14 months; though among resolvers, 84% did so by 12 months.
  • Presence of longer duration of symptoms and mitochondrial disorder was associated with lower rates of resolution.
  • Younger age and response to promotility agents increased likelihood of resolution
  •  Treatment with proton pump inhibitors (PPIs) were used in 79% as first-line agents; only 3% reported resolution of symptoms with PPIs.
  • Prokinetics: Domperidone (0.1-0.2mg/kg/dose qid to max of 10mg) in 33 patients. Tegaserod in 20 patients.  Metoclopropramide in 142 patients. Erythromycin (EES) in 40 patients (3-10 mg/kg/dose qid).  Of these agents, metoclopropramide was inferior with an 80% failure rate.  In contrast, EES was associated with symptom resolution in 5% and symptom improvement in 46%.  Domperidone was associated with symptom resolution in 26% and symptom improvement in 48%.

The third study by Bhardwaj et al highlights “Impaired Gastric Emptying and Small Bowel Transit in Children with Mitochondrial Disorders.”

  • Prospective study enrolled 26 subjects from mitochondrial clinic.  58 patients were screened but the majority were not eligible; the most common reasons included the following: 14 were receiving enteral feedings, 1 was receiving parenteral nutrition, 6 had no GI symptoms.
  • Delayed gastric emptying was considered if >50% at 90 minutes of a solid meal was present, at 60 minutes for semisolid, and at 40 minutes for liquid meal. For small bowel transit, delayed transit was considered if radiotracer had not reached cecum within 4 hours.  Severely prolonged transit was diagnosed if transit time exceeded 6 hours.
  • In this cohort, 18 (69%) had delayed gastric emptying and 12 (46%) had prolonged small bowel transit.  Common symptoms included abdominal pain and vomiting.
  • In the small numbers of patients who received prokinetics,there was a poor response.  One of three patients with bethanecol and two of five patients with metoclopropramide had normalized GE time; one patient treated with azithromycin continued with abnormal GE time

Additional references:

  • -Gastroenterol 2011; 140: 101.  Clinical features -mostly females, often incr BMI.  Defined as severe gastroparesis if >35% at 4hrs, moderate if 20-35%, and mild if <20%.
  • -Clincal Gastro & Hep 2011; 9: 5.  Review of diabetic gastroparesis & mgt.
  • -Clin Gastro & Hep 2009; 7: 823. Radiation from gastric emptying is ~10mrad, CXR is 12mrad, yearly background is 300mrad.
    Norms:
    1 hr 37-90%
    2 hr 30-60%
    4 hr 0-10%
  • -Gastroenterol 2009; 136: 1526.  Tests of gastric emptying -review.
  • -Clin Gastro & Hep 2008; 6: 1309. algorithm for nausea & delayed GE.  REC;
    1. small meals, low fiber/fat
    2. prokinetic: reglan, EES, ?domperidone
    3. Antiemetics: zofran, prochloroperazine
    4. TCA
    5. ?Botox injection
    6. jejunal feeds
  • -Gastroenterol 2009; 136: 1526.  Tests of gastric emptying -review.  Consider domperidone, reglan, ?gastric stimulation, ?surgery, discusses novel Rxs.
  • -Gastroenterol 2009; 136: 1225.  Review of prevalence and outcomes in Olmsted County.
  • -Am J Gastro 2008; 103: 416-23.  Botox is NOT effective for gastroparesis/delayed GE.
  • Need to distinguish delayed gastric emptying from rumination. Treatment for rumination and belching