HERE AND NOW: CLINICAL PRACTICE Charles J. Kahi, Section Editor Beyond Metoclopramide for Gastroparesis Michael Camilleri Clinical Enteric Neuroscience Translational and Epidemiological Research, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota Introduction: The Clinical Problem Gastroparesis is characterized by diverse upper gastrointestinal symptoms including nausea, vomiting, early satiety, postprandial fullness, bloating, and upper abdominal pain; slow gastric emptying of solids; and absence of gastric outlet or intestinal obstruction. In clinical practice, diabetes mellitus, and idiopathic and iatrogenic (postsurgical or medication) gastroparesis are the most frequently encountered forms. In addition, diseases affecting the neural control of the upper gut (such as Parkinson’s disease, or effects of dopaminergic agents), and diseases that damage intrinsic nerves or smooth muscle also cause gastroparesis due to tissue infiltration (such as in scleroderma) or muscle degen- eration (as in amyloidosis). Severely delayed gastric emptying of a 2% fat, 255-kcal meal was associated with worse vomiting, more severe anorexia, and overall gas- troparesis symptoms, 1 as well as with stomach fullness, postprandial fullness, and early satiety. 2 Gastroparesis and delayed gastric emptying may be associated with diverse pathophysiological scenarios: antral hypo- motility, increased pyloric contractility or spasm, or decreased distensibility. Recently, evidence has been published showing that increased gastric accommoda- tion or postprandial gastric volume are associated with retardation in the gastric emptying of solids. 3 At present in the United States, metoclopramide is still the only approved medication for gastroparesis; this review addresses what treatments are available for gastroparesis in addition to metoclopramide. Diagnosis and Management Diagnosis requires exclusion of obstruction or medication-induced symptoms (especially GLP-1 [glucagon-like peptide 1] drugs used for diabetes) and documentation of delayed gastric emptying by scintig- raphy or stable isotope breath test, both conducted for at least 3 hours. It is relevant to note that retained food in the stomach at upper gastrointestinal endoscopy is of limited predictive value 4 unless there is underlying dis- ease predisposing to gastric retention such as diabetic neuropathy. It is critically important to compare patient results with extensive normal control data; at our center, we use a 300-kcal, 30% fat meal and have normal values for 319 healthy control subjects, and the abnormal value for gastric retention at 4 hours is >24%. Although the 95th percentile for retention of a 256-kcal egg substitute with 2% fat was >10% at 4 hours based on 123 healthy control subjects in a multicenter study, a recent obser- vation in 31 healthy control subjects at one center showed a 75th percentile of 13% and a 95th percentile of >23% retained at 4 hours (Henry Parkman, MD personal communication, August 2021). In addition, estimated gastric emptying time with the wireless motility capsule is not as accurate as scintigraphy with a radiolabeled, digestible solid meal, as the capsule most often empties with the re-establishment of interdigestive migrating motor complexes, typically a variable period of time after the food has emptied completely from the stomach. The principles of management are restoration of hy- dration, support of nutrition, symptom relief (chiefly by antiemetics), prokinetic medications, and pyloric in- terventions (M. Camilleri, MD, and K. Sanders, PhD, un- published data, August 2021). 5 The first step is to institute a small-particle diet, cooking of nondigestible fiber, and homogenization of solids to a small particle size. 6 Patients with severe gas- troparesis may require hospitalization for intravenous hydration and correction of metabolic derangements (ketoacidosis, uremia, hypoglycemia, hyperglycemia), nasoenteric decompression, or enteral nutrition to manage vomiting and nutritional requirements. 5 Current and investigational prokinetic drugs for gastric motility disorders are summarized in Table 1. 6 Table 2 summarizes published studies on gastric peroral endo- scopic myotomy (G-POEM) for gastroparesis (M. Camilleri, MD, and K. Sanders, PhD, unpublished data, August 2021). Metoclopramide is a peripheral cholinergic and antidopaminergic agent, approved for use up to 12 weeks, 10 mg, 3 times a day, administered 30 minutes before meals. Long-term use is associated with a Most current article © 2022 by the AGA Institute 1542-3565/$36.00 https://doi.org/10.1016/j.cgh.2021.08.052 Clinical Gastroenterology and Hepatology 2022;20:19–24
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Beyond Metoclopramide for GastroparesisHERE AND NOW: CLINICAL PRACTICE Charles J. Kahi, Section Editor
Beyond Metoclopramide for Gastroparesis
Introduction: The Clinical Problem
Gastroparesis is characterized by diverse upper gastrointestinal symptoms including nausea, vomiting, early satiety, postprandial fullness, bloating, and upper abdominal pain; slow gastric emptying of solids; and absence of gastric outlet or intestinal obstruction. In clinical practice, diabetes mellitus, and idiopathic and iatrogenic (postsurgical or medication) gastroparesis are the most frequently encountered forms. In addition, diseases affecting the neural control of the upper gut (such as Parkinson’s disease, or effects of dopaminergic agents), and diseases that damage intrinsic nerves or smooth muscle also cause gastroparesis due to tissue infiltration (such as in scleroderma) or muscle degen- eration (as in amyloidosis). Severely delayed gastric emptying of a 2% fat, 255-kcal meal was associated with worse vomiting, more severe anorexia, and overall gas- troparesis symptoms,1 as well as with stomach fullness, postprandial fullness, and early satiety.2 Gastroparesis and delayed gastric emptying may be associated with diverse pathophysiological scenarios: antral hypo- motility, increased pyloric contractility or spasm, or decreased distensibility. Recently, evidence has been published showing that increased gastric accommoda- tion or postprandial gastric volume are associated with retardation in the gastric emptying of solids.3
At present in the United States, metoclopramide is still the only approved medication for gastroparesis; this review addresses what treatments are available for gastroparesis in addition to metoclopramide.
Most current article
https://doi.org/10.1016/j.cgh.2021.08.052
Diagnosis and Management
Diagnosis requires exclusion of obstruction or medication-induced symptoms (especially GLP-1 [glucagon-like peptide 1] drugs used for diabetes) and documentation of delayed gastric emptying by scintig- raphy or stable isotope breath test, both conducted for at least 3 hours. It is relevant to note that retained food in the stomach at upper gastrointestinal endoscopy is of limited predictive value4 unless there is underlying dis- ease predisposing to gastric retention such as diabetic neuropathy. It is critically important to compare patient
results with extensive normal control data; at our center, we use a 300-kcal, 30% fat meal and have normal values for 319 healthy control subjects, and the abnormal value for gastric retention at 4 hours is >24%. Although the 95th percentile for retention of a 256-kcal egg substitute with 2% fat was >10% at 4 hours based on 123 healthy control subjects in a multicenter study, a recent obser- vation in 31 healthy control subjects at one center showed a 75th percentile of 13% and a 95th percentile of >23% retained at 4 hours (Henry Parkman, MD personal communication, August 2021). In addition, estimated gastric emptying time with the wireless motility capsule is not as accurate as scintigraphy with a radiolabeled, digestible solid meal, as the capsule most often empties with the re-establishment of interdigestive migrating motor complexes, typically a variable period of time after the food has emptied completely from the stomach.
The principles of management are restoration of hy- dration, support of nutrition, symptom relief (chiefly by antiemetics), prokinetic medications, and pyloric in- terventions (M. Camilleri, MD, and K. Sanders, PhD, un- published data, August 2021).5
The first step is to institute a small-particle diet, cooking of nondigestible fiber, and homogenization of solids to a small particle size.6 Patients with severe gas- troparesis may require hospitalization for intravenous hydration and correction of metabolic derangements (ketoacidosis, uremia, hypoglycemia, hyperglycemia), nasoenteric decompression, or enteral nutrition to manage vomiting and nutritional requirements.5
Current and investigational prokinetic drugs for gastric motility disorders are summarized in Table 1.6 Table 2 summarizes published studies on gastric peroral endo- scopic myotomy (G-POEM) for gastroparesis (M. Camilleri, MD, and K. Sanders, PhD, unpublished data, August 2021).
Metoclopramide is a peripheral cholinergic and antidopaminergic agent, approved for use up to 12 weeks, 10 mg, 3 times a day, administered 30 minutes before meals. Long-term use is associated with a
5-HT4 receptor agonist
Felcisetrag IG and DG [ GE Not studied
Tegaseroda FD [ GA Mixed effects
D2/3 receptor antagonist
Trazpiroben IG and DG [ volume to fullness, no D in GE Improved
Ghrelin receptor agonist
Motilin receptor agonist
Erythromycina IG and DG [ GE, [ fundic and antral contractions, Y pyloric contractions
Improved
NK1 receptor agonist
Aprepitanta IG and DG [ GA, no D in GE Improved
Tradipitant IG and DG Not studied Improved
Opioid antagonists (NS or peripherally active [PAMORA])
Naloxone (NS)a FD and IG No D in GE Not studied
MNTX (PAMORA)a Opioid-induced gastric delay No D in GE Not studied
Naloxegol (PAMORA)a Opioid-induced gastric delay No D in GE Not studied
Phosphodiesterase-5 inhibitor
Sildenafila GP with uremia No D in GE Not studied
Adapted from Camilleri and Atieh.7
D, change; DG, diabetic gastroparesis; FD, functional dyspepsia; GA, gastric accommodation; GE, gastric emptying; GP, gastroparesis; IG, idiopathic gastro- paresis; MNTX, methylnaltrexone; NS, nonselective; PAMORA, peripherally active m-opioid receptor antagonist. aMarketed drug.
20 Michael Camilleri Clinical Gastroenterology and Hepatology Vol. 20, No. 1
decline in efficacy and by possible central nervous system side effects, most commonly reversible invol- untary movements and, rarely, irreversible tardive dyskinesia. Intranasal formulation of metoclopramide8
has been approved for treatment of adults with gas- troparesis. Because gastroparesis is a chronic disease lasting beyond 3 months, clinicians, including myself, have balanced the Food and Drug Administration recommendation with the need to manage patients’ symptoms, malnutrition, and other complications by using the liquid formulation at the lowest effective dose (often 5–10 mg, 3 times a day, 15 minutes before meals) over longer than 12 weeks under supervision, with a 10-day interruption of treatment, during which patients are instructed to take a completely liquid or blenderized diet. In this interruption of metoclopra- mide treatment, patients who become symptomatic or have problems maintaining hydration or nutrition are also supported with antiemetics (such as ondansetron, 4 mg oral dissolving tablets) or short-term macrolide
treatment (such as erythromycin, 40–200 mg 3 times a day as tolerated). The rationale for the longer overall duration of metoclopramide use is based on the anal- ysis of the true risks of 2.5 per 100,000 patient years for a neuromusculoskeletal side effect, which includes 1.7 per 100,000 patient-years for a strictly neurological side effect and 0.14 per 100,000 patient-years for tar- dive dyskinesia.9 These data are based on a report from the Swedish Medical Products Agency9 of annual pre- scription rate of 123,935 and daily defined doses in a mean 60,255 patients each year, over the years 2006–2017.
Other medications are marketed and are used in gastroparesis for nonapproved indications. These include domperidone, prucalopride, and macrolides.
Domperidone is available through the Food and Drug Administration’s program for Expanded Access to Investigational Drugs (https://www.fda.gov/drugs/ investigational-new-drug-ind-application/how-request- domperidone-expanded-access-use). The recommended
No. of Patients, ref. # Types of Gastroparesis Changes in
Gastric Emptying Changes in Symptoms Duration of Follow-Up Adverse Events
29, ref.10 Diabetic ¼ 7; Idiopathic ¼ 15; Postsurgical ¼ 5; Scleroderma ¼ 2
70% Normalized 79% at 3 mo; 69% at 6 mo; GCSI improved from 3.5 to 0.9 at 3 mo
3 and 6 mo 17% (n ¼ 2 of 12) pneumoperitoneum requiring decompression
16, ref.11 Diabetic ¼ 9 Idiopathic ¼ 5 Postsurgical ¼ 1 Postinfectious ¼ 1
75% normalized, 25% improved
81% improvement. GCSI improved from baseline of 3.4 to 1.46 (12 mo later)
12 mo None
47, ref.12 Diabetic ¼ 12 Idiopathic ¼ 27 Postsurgical ¼ 8
4-h retention improved: from 37.2% to 20.4%
GCSI improved from 4.6 to 3.3
3 mo (follow-up in 31 of 47)
1 death (unrelated)
30, ref.13 Diabetic ¼ 11 Idiopathic ¼ 7 Postsurgical ¼ 12
47% normalized No validated outcome measure available
6 mo 2 of 30 (6%): 1 prepyloric ulcer and 1 capnoperitoneum
13, ref.14 Diabetic ¼ 1 Idiopathic ¼ 4 Postsurgical ¼ 8
4 of 6 improved; retention at 4 h improved from 49% to 33%
In 11: 4 considerably, 4 somewhat better,
1 no change, 2 worse
3 mo 3 mucosotomy closed with clips; 1 pulmonary embolism
16, ref.15 Diabetes ¼ 3 Postsurgical ¼ 13
Mean retention (bread) at 2 h from 69.3% to 33.4%
Mean total symptom score from 24.25 to 6.37; 13 of 16 improved
3 mo 1 pyloric stenosis at day 45
20, ref.16 Diabetic ¼ 10 Nondiabetic¼ 10
Retention at 4 h improved: 57.5% to 15%; and 30% normalized
GCSI improved from 3.5 to 1.3; QOL improved
3 mo 3 mild hemorrhage, 3 gastric perforation, 1 moderate dyspepsia
40, ref.17 Diabetic ¼ 15 Nondiabetic ¼25 (of which
18 were idiopathic)
% retention at 4h reduced by 41.7%
Improved GCSI, nausea/ vomiting, not bloating
Median 15 mo 1 tension capnoperitoneum,1 exacerbation of COPD; 1 (EDS) disrupted mucosotomy þ ulcer
22, ref.18 Diabetic ¼ 8, idiopathic¼ 14, all with GES þ diverse other procedures
7 of 11 with post–G- POEM GE were normal
GCSI improved (reduction 1.63 points); improved all subscores
1 and 3 mo 1 laparoscopy for pain due to capnoperitoneum and adhesions
January 2022
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22 Michael Camilleri Clinical Gastroenterology and Hepatology Vol. 20, No. 1
dose of domperidone is 10–20 mg, 3 times a day, and at bedtime. Domperidone has been associated with cardiac dysrhythmias; it should be avoided if the QTc interval is >470 ms in males and >450 ms in females.
Prucalopride is approved for the treatment of chronic constipation but not for gastroparesis. In a randomized, placebo-controlled, crossover study involving 28 idio- pathic and 6 diabetic patients with gastroparesis, pru- calopride 2 mg once daily was efficacious in relieving symptoms based on total Gastroparesis Cardinal Symp- tom Index, subscales of nausea or vomiting, fullness or satiety, and bloating or distention, as well as improving Patient Assessment of Upper Gastrointestinal Disorders–Quality of Life score.
For acute gastroparesis, typically in hospitalized pa- tients, treatment is with erythromycin 1.5–3 mg/kg infused intravenously over 1 hour every 8 hours, or neostigmine 1 mg, intramuscular, every 4–6 hours (the latter with electrocardiography monitoring to intervene with atropine if there is symptomatic bradycardia). When given orally, erythromycin is associated with tachyphylaxis within a few days or weeks. Azithromycin and clarithromycin are other macrolides used in the treatment of chronic gastroparesis with similar concerns about potential for tachyphylaxis.
Symptom relief is predominantly in the form of an- tiemetics. In a placebo-controlled trial, the NK1 receptor antagonist, aprepitant (which is approved for chemotherapy-induced emesis), improved multiple symptoms of gastroparesis including nausea. The benefit may reflect NK1 receptor antagonist effects on the vomiting center in the brainstem or increased gastric volumes of the stomach without retardation of gastric emptying. Many patients with gastroparesis use D9THC for symptomatic relief; however, marijuana and the nonselective cannabinoid receptor agonist, dronabinol, retard gastric emptying.
If pain is the predominant symptom, the diagnosis of gastroparesis should be questioned. Opioids should be avoided at all costs; central neuromodulators may be tried, although nortriptyline was not efficacious in a randomized, controlled trial, and its anticholinergic ef- fects may actually retard gastric emptying.
The advent of procedures directed at the pylorus (botulinum toxin injection, surgical or endoscopic pylo- romyotomy) has renewed interest in the role of the py- lorus in the pathophysiology of gastroparesis. Studies show that fasting pyloric distensibility (based on measured pressure and pyloric diameter) was decreased in patients with gastroparesis and was associated with delayed gastric emptying, more severe symptoms, and impaired quality of life. These data provide the rationale for pyloric dilation, botulinum toxin injection, or pylo- romyotomy in patients with gastroparesis.
Multiple open-label trials of intrapyloric botulinum toxin injections for gastroparesis suggested efficacy, but 2 relatively small, randomized, controlled trials failed to show any improvement in symptoms, although one trial
January 2022 Beyond Metoclopramide for Gastroparesis 23
confirmed improved gastric emptying compared to placebo.
In several case series, surgical pyloroplasty has been associated with short-term improvements in symptom severity scores and with accelerated gastric emptying when appraised 3 months postprocedure. The standard Heineke-Mikulicz pyloroplasty divides both longitudinal and circular muscle layers. G-POEM divides the pylorus from the mucosal surface and cuts predominantly the circular muscle layer, leaving the longitudinal muscle intact to avoid perforation. Improved gastric emptying with G-POEM has also been documented. Current evi- dence on the efficacy of G-POEM for gastroparesis is summarized in Table 1, which shows exclusively un- controlled trials. These individual studies and published systematic reviews and meta-analyses based on 10 studies involving 292 patients have documented early andmedium-term efficacy of G-POEM in the treatment of gastroparesis and improvement of gastric emptying, as well as the superiority of this approach to gastric elec- trical stimulation for gastroparesis and equivalence of results to surgical pyloroplasty based on 332 patients with G-POEM (11 studies) and 375 patients who under- went surgical pyloroplasty (7 studies). Two studies have shown average pylorus diameter increase by about 2mm or 1.2 mm after G-POEM, questioning whether merely widening the pyloric diameter may be sufficient, espe- cially if there is also antral hypomotility. In one study, the average post–G-POEM change in the diameter of the py- lorus in those with clinical success was estimated to be 7.46mm, and in thosewith clinical failure it was 1.92mm with the EndoFLIP device (Medtronic, Minneapolis, MN) distended to 50 mL.
There is a critical need for a sham-controlled study of G-POEM in patients with well-characterized baseline and posttreatment measurements of antropyloroduodenal motor function and coordination, and with the diameter and distensibility index of the pylorus measured using EndoFLIP. Such studies would identify predictors of responsiveness to G-POEM and optimal candidates for this treatment.
It has been suggested that changes in diameter and distensibility index of the pylorus after G- POEM are associated with improved therapeutic outcome.
Description of the Figures and Tables
Current and investigational prokinetic drugs for gastric motility disorders are summarized in Table 1. Table 2 summarizes published studies on G-POEM for gastroparesis.
Take-Home Message
It is important to distinguish gastroparesis from func- tional dyspepsia with a well-validated gastric emptying
study measured over 4 hours with robust normal values. Gastroparesis requires multidisciplinary management, and the clinical gastroenterologist and endoscopist are pivotal in helping patients with this challenging disease.
References
1. Parkman HP, Hallinan EK, Hasler WL, et al. Nausea and vom-
iting in gastroparesis: similarities and differences in idiopathic and diabetic gastroparesis. Neurogastroenterol Motil 2016; 28:1902–1914.
2. Parkman HP, Hallinan EK, Hasler WL, et al. Early satiety and postprandial fullness in gastroparesis correlate with gastro- paresis severity, gastric emptying, and water load testing. Neurogastroenterol Motil 2017;29. https://doi.org/10.1111/nmo. 12981.
3. Wang XJ, Burton DD, Breen-Lyles M, Camilleri M. Gastric ac- commodation influences proximal gastric and total gastric emptying in concurrent measurements conducted in healthy volunteers. Am J Physiol Gastrointest Liver Physiol 2021; 320:G759–G767.
4. Bi D, Choi C, League J, et al. Food residue during esoph- agogastroduodenoscopy is commonly encountered and is not pathognomonic of delayed gastric emptying. Dig Dis Sci. Pub- lished online November 2020;25. https://doi.org/10.1007/ s10620-020-06718-0.
5. Camilleri M. Clinical practice. Diabetic gastroparesis. N Engl J Med 2007;356:820–829.
6. Olausson EA, Störsrud S, Grundin H, et al. A small particle size diet reduces upper gastrointestinal symptoms in patients with diabetic gastroparesis: a randomized controlled trial. Am J Gastroenterol 2014;109:375–385.
7. Camilleri M, Atieh J. New developments in prokinetic therapy for gastric motility disorders. Frontiers Pharmacol. Published online August 24, 2021. https://doi.org/10.3389/fphar.2021.711500
8. Parkman HP, Carlson MR, Gonyer D. Metoclopramide nasal spray reduces symptoms of gastroparesis in women, but not men, with diabetes: results of a phase 2B randomized study. 12 weeks. Clin Gastroenterol Hepatol 2015;13:1256–1263.
9. Al-Saffar A, Lennernäs H, Hellström PM. Gastroparesis, meto- clopramide, and tardive dyskinesia: risk revisited. Neuro- gastroenterol Motil 2019;31:e13617.
10. Gonzalez JM, Benezech A, Vitton V, et al. G-POEM with antro- pyloromyotomy for the treatment of refractory gastroparesis: mid-term follow-up and factors predicting outcome. Aliment Pharmacol Ther 2017;46:364–370.
11. Dacha S, Mekaroonkamol P, Li L, et al. Outcomes and quality- of-life assessment after gastric per-oral endoscopic pylo- romyotomy (with video). Gastrointest Endosc 2017;86:282–289.
12. Rodriguez JH, Haskins IN, Strong AT, et al. Per oral endoscopic pyloromyotomy for refractory gastroparesis: initial results from a single institution. Surg Endosc 2017;31:5381–5388.
13. Khashab MA, Ngamruengphong S, Carr-Locke D, et al. Gastric per-oral endoscopic myotomy for refractory gastro- paresis: results from the first multicenter study on endoscopic pyloromyotomy (with video). Gastrointest Endosc 2017; 85:123–128.
14. Malik Z, Kataria R, Modayil R, et al. Gastric per oral endoscopic myotomy (G-POEM) for the treatment of refractory gastro- paresis: early experience. Dig Dis Sci 2018;63:2405–2412.
15. Xu J, Chen T, Elkholy S, et al. Gastric peroral endoscopic myotomy (G-POEM) as a treatment for refractory gastroparesis:
long-term outcomes. Can J Gastroenterol Hepatol 2018; 2018:6409698.
16. Jacques J, Pagnon L, Hure F, et al. Peroral endoscopic pylo- romyotomy is efficacious and safe for refractory gastroparesis: prospective trial with assessment of pyloric function. Endos- copy 2019;51:40–49.
17. Mekaroonkamol P, Patel V, Shah R, et al. Association between duration or etiology of gastroparesis and clinical response after gastric per-oral endoscopic pyloromyotomy. Gastrointest Endosc 2019;89:969–976.
18. Strong AT, Rodriguez J, Kroh M, et al. Safety and feasibility of per-oral pyloromyotomy as augmentative therapy after prior gastric electrical stimulation for gastroparesis. J Am Coll Surg 2019;229:589–595.
19. Strong AT, Landreneau JP, Cline M, et al. Per-oral pylo- romyotomy (POP) for medically refractory post-surgical gastro- paresis. J Gastrointest Surg 2019;23:1095–1103.
20. Vosoughi K, Ichkhanian Y, Benias P, et al. Gastric per-oral endoscopic myotomy (G-POEM) for refractory gastroparesis:
results from an international prospective trial. Gut. Published online March 19, 2021. https://doi.org/10.1136/gutjnl-2020- 322756.
Reprint Requests Address requests for reprints to: Michael Camilleri, MD, Mayo Clinic, Charlton 8-110, 200 First Street SW, Rochester, MN 55905. e-mail: camilleri.michael@ mayo.edu.
Acknowledgments The author thanks Mrs. Cindy Stanislav for excellent secretarial assistance.
Conflicts of interest The author discloses the following: Michael Camilleri has served as an advisor to Takeda and Allergan, with the consulting fees paid to his employer, the Mayo Clinic; and has received single-center research grants from Takeda to study TAK-954 and from Vanda to study tradipitant.
Funding Michael Camilleri is supported by grant R01-DK122280 from National Institutes of Health.
Take-Home Message
Beyond Metoclopramide for Gastroparesis
Introduction: The Clinical Problem
Gastroparesis is characterized by diverse upper gastrointestinal symptoms including nausea, vomiting, early satiety, postprandial fullness, bloating, and upper abdominal pain; slow gastric emptying of solids; and absence of gastric outlet or intestinal obstruction. In clinical practice, diabetes mellitus, and idiopathic and iatrogenic (postsurgical or medication) gastroparesis are the most frequently encountered forms. In addition, diseases affecting the neural control of the upper gut (such as Parkinson’s disease, or effects of dopaminergic agents), and diseases that damage intrinsic nerves or smooth muscle also cause gastroparesis due to tissue infiltration (such as in scleroderma) or muscle degen- eration (as in amyloidosis). Severely delayed gastric emptying of a 2% fat, 255-kcal meal was associated with worse vomiting, more severe anorexia, and overall gas- troparesis symptoms,1 as well as with stomach fullness, postprandial fullness, and early satiety.2 Gastroparesis and delayed gastric emptying may be associated with diverse pathophysiological scenarios: antral hypo- motility, increased pyloric contractility or spasm, or decreased distensibility. Recently, evidence has been published showing that increased gastric accommoda- tion or postprandial gastric volume are associated with retardation in the gastric emptying of solids.3
At present in the United States, metoclopramide is still the only approved medication for gastroparesis; this review addresses what treatments are available for gastroparesis in addition to metoclopramide.
Most current article
https://doi.org/10.1016/j.cgh.2021.08.052
Diagnosis and Management
Diagnosis requires exclusion of obstruction or medication-induced symptoms (especially GLP-1 [glucagon-like peptide 1] drugs used for diabetes) and documentation of delayed gastric emptying by scintig- raphy or stable isotope breath test, both conducted for at least 3 hours. It is relevant to note that retained food in the stomach at upper gastrointestinal endoscopy is of limited predictive value4 unless there is underlying dis- ease predisposing to gastric retention such as diabetic neuropathy. It is critically important to compare patient
results with extensive normal control data; at our center, we use a 300-kcal, 30% fat meal and have normal values for 319 healthy control subjects, and the abnormal value for gastric retention at 4 hours is >24%. Although the 95th percentile for retention of a 256-kcal egg substitute with 2% fat was >10% at 4 hours based on 123 healthy control subjects in a multicenter study, a recent obser- vation in 31 healthy control subjects at one center showed a 75th percentile of 13% and a 95th percentile of >23% retained at 4 hours (Henry Parkman, MD personal communication, August 2021). In addition, estimated gastric emptying time with the wireless motility capsule is not as accurate as scintigraphy with a radiolabeled, digestible solid meal, as the capsule most often empties with the re-establishment of interdigestive migrating motor complexes, typically a variable period of time after the food has emptied completely from the stomach.
The principles of management are restoration of hy- dration, support of nutrition, symptom relief (chiefly by antiemetics), prokinetic medications, and pyloric in- terventions (M. Camilleri, MD, and K. Sanders, PhD, un- published data, August 2021).5
The first step is to institute a small-particle diet, cooking of nondigestible fiber, and homogenization of solids to a small particle size.6 Patients with severe gas- troparesis may require hospitalization for intravenous hydration and correction of metabolic derangements (ketoacidosis, uremia, hypoglycemia, hyperglycemia), nasoenteric decompression, or enteral nutrition to manage vomiting and nutritional requirements.5
Current and investigational prokinetic drugs for gastric motility disorders are summarized in Table 1.6 Table 2 summarizes published studies on gastric peroral endo- scopic myotomy (G-POEM) for gastroparesis (M. Camilleri, MD, and K. Sanders, PhD, unpublished data, August 2021).
Metoclopramide is a peripheral cholinergic and antidopaminergic agent, approved for use up to 12 weeks, 10 mg, 3 times a day, administered 30 minutes before meals. Long-term use is associated with a
5-HT4 receptor agonist
Felcisetrag IG and DG [ GE Not studied
Tegaseroda FD [ GA Mixed effects
D2/3 receptor antagonist
Trazpiroben IG and DG [ volume to fullness, no D in GE Improved
Ghrelin receptor agonist
Motilin receptor agonist
Erythromycina IG and DG [ GE, [ fundic and antral contractions, Y pyloric contractions
Improved
NK1 receptor agonist
Aprepitanta IG and DG [ GA, no D in GE Improved
Tradipitant IG and DG Not studied Improved
Opioid antagonists (NS or peripherally active [PAMORA])
Naloxone (NS)a FD and IG No D in GE Not studied
MNTX (PAMORA)a Opioid-induced gastric delay No D in GE Not studied
Naloxegol (PAMORA)a Opioid-induced gastric delay No D in GE Not studied
Phosphodiesterase-5 inhibitor
Sildenafila GP with uremia No D in GE Not studied
Adapted from Camilleri and Atieh.7
D, change; DG, diabetic gastroparesis; FD, functional dyspepsia; GA, gastric accommodation; GE, gastric emptying; GP, gastroparesis; IG, idiopathic gastro- paresis; MNTX, methylnaltrexone; NS, nonselective; PAMORA, peripherally active m-opioid receptor antagonist. aMarketed drug.
20 Michael Camilleri Clinical Gastroenterology and Hepatology Vol. 20, No. 1
decline in efficacy and by possible central nervous system side effects, most commonly reversible invol- untary movements and, rarely, irreversible tardive dyskinesia. Intranasal formulation of metoclopramide8
has been approved for treatment of adults with gas- troparesis. Because gastroparesis is a chronic disease lasting beyond 3 months, clinicians, including myself, have balanced the Food and Drug Administration recommendation with the need to manage patients’ symptoms, malnutrition, and other complications by using the liquid formulation at the lowest effective dose (often 5–10 mg, 3 times a day, 15 minutes before meals) over longer than 12 weeks under supervision, with a 10-day interruption of treatment, during which patients are instructed to take a completely liquid or blenderized diet. In this interruption of metoclopra- mide treatment, patients who become symptomatic or have problems maintaining hydration or nutrition are also supported with antiemetics (such as ondansetron, 4 mg oral dissolving tablets) or short-term macrolide
treatment (such as erythromycin, 40–200 mg 3 times a day as tolerated). The rationale for the longer overall duration of metoclopramide use is based on the anal- ysis of the true risks of 2.5 per 100,000 patient years for a neuromusculoskeletal side effect, which includes 1.7 per 100,000 patient-years for a strictly neurological side effect and 0.14 per 100,000 patient-years for tar- dive dyskinesia.9 These data are based on a report from the Swedish Medical Products Agency9 of annual pre- scription rate of 123,935 and daily defined doses in a mean 60,255 patients each year, over the years 2006–2017.
Other medications are marketed and are used in gastroparesis for nonapproved indications. These include domperidone, prucalopride, and macrolides.
Domperidone is available through the Food and Drug Administration’s program for Expanded Access to Investigational Drugs (https://www.fda.gov/drugs/ investigational-new-drug-ind-application/how-request- domperidone-expanded-access-use). The recommended
No. of Patients, ref. # Types of Gastroparesis Changes in
Gastric Emptying Changes in Symptoms Duration of Follow-Up Adverse Events
29, ref.10 Diabetic ¼ 7; Idiopathic ¼ 15; Postsurgical ¼ 5; Scleroderma ¼ 2
70% Normalized 79% at 3 mo; 69% at 6 mo; GCSI improved from 3.5 to 0.9 at 3 mo
3 and 6 mo 17% (n ¼ 2 of 12) pneumoperitoneum requiring decompression
16, ref.11 Diabetic ¼ 9 Idiopathic ¼ 5 Postsurgical ¼ 1 Postinfectious ¼ 1
75% normalized, 25% improved
81% improvement. GCSI improved from baseline of 3.4 to 1.46 (12 mo later)
12 mo None
47, ref.12 Diabetic ¼ 12 Idiopathic ¼ 27 Postsurgical ¼ 8
4-h retention improved: from 37.2% to 20.4%
GCSI improved from 4.6 to 3.3
3 mo (follow-up in 31 of 47)
1 death (unrelated)
30, ref.13 Diabetic ¼ 11 Idiopathic ¼ 7 Postsurgical ¼ 12
47% normalized No validated outcome measure available
6 mo 2 of 30 (6%): 1 prepyloric ulcer and 1 capnoperitoneum
13, ref.14 Diabetic ¼ 1 Idiopathic ¼ 4 Postsurgical ¼ 8
4 of 6 improved; retention at 4 h improved from 49% to 33%
In 11: 4 considerably, 4 somewhat better,
1 no change, 2 worse
3 mo 3 mucosotomy closed with clips; 1 pulmonary embolism
16, ref.15 Diabetes ¼ 3 Postsurgical ¼ 13
Mean retention (bread) at 2 h from 69.3% to 33.4%
Mean total symptom score from 24.25 to 6.37; 13 of 16 improved
3 mo 1 pyloric stenosis at day 45
20, ref.16 Diabetic ¼ 10 Nondiabetic¼ 10
Retention at 4 h improved: 57.5% to 15%; and 30% normalized
GCSI improved from 3.5 to 1.3; QOL improved
3 mo 3 mild hemorrhage, 3 gastric perforation, 1 moderate dyspepsia
40, ref.17 Diabetic ¼ 15 Nondiabetic ¼25 (of which
18 were idiopathic)
% retention at 4h reduced by 41.7%
Improved GCSI, nausea/ vomiting, not bloating
Median 15 mo 1 tension capnoperitoneum,1 exacerbation of COPD; 1 (EDS) disrupted mucosotomy þ ulcer
22, ref.18 Diabetic ¼ 8, idiopathic¼ 14, all with GES þ diverse other procedures
7 of 11 with post–G- POEM GE were normal
GCSI improved (reduction 1.63 points); improved all subscores
1 and 3 mo 1 laparoscopy for pain due to capnoperitoneum and adhesions
January 2022
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22 Michael Camilleri Clinical Gastroenterology and Hepatology Vol. 20, No. 1
dose of domperidone is 10–20 mg, 3 times a day, and at bedtime. Domperidone has been associated with cardiac dysrhythmias; it should be avoided if the QTc interval is >470 ms in males and >450 ms in females.
Prucalopride is approved for the treatment of chronic constipation but not for gastroparesis. In a randomized, placebo-controlled, crossover study involving 28 idio- pathic and 6 diabetic patients with gastroparesis, pru- calopride 2 mg once daily was efficacious in relieving symptoms based on total Gastroparesis Cardinal Symp- tom Index, subscales of nausea or vomiting, fullness or satiety, and bloating or distention, as well as improving Patient Assessment of Upper Gastrointestinal Disorders–Quality of Life score.
For acute gastroparesis, typically in hospitalized pa- tients, treatment is with erythromycin 1.5–3 mg/kg infused intravenously over 1 hour every 8 hours, or neostigmine 1 mg, intramuscular, every 4–6 hours (the latter with electrocardiography monitoring to intervene with atropine if there is symptomatic bradycardia). When given orally, erythromycin is associated with tachyphylaxis within a few days or weeks. Azithromycin and clarithromycin are other macrolides used in the treatment of chronic gastroparesis with similar concerns about potential for tachyphylaxis.
Symptom relief is predominantly in the form of an- tiemetics. In a placebo-controlled trial, the NK1 receptor antagonist, aprepitant (which is approved for chemotherapy-induced emesis), improved multiple symptoms of gastroparesis including nausea. The benefit may reflect NK1 receptor antagonist effects on the vomiting center in the brainstem or increased gastric volumes of the stomach without retardation of gastric emptying. Many patients with gastroparesis use D9THC for symptomatic relief; however, marijuana and the nonselective cannabinoid receptor agonist, dronabinol, retard gastric emptying.
If pain is the predominant symptom, the diagnosis of gastroparesis should be questioned. Opioids should be avoided at all costs; central neuromodulators may be tried, although nortriptyline was not efficacious in a randomized, controlled trial, and its anticholinergic ef- fects may actually retard gastric emptying.
The advent of procedures directed at the pylorus (botulinum toxin injection, surgical or endoscopic pylo- romyotomy) has renewed interest in the role of the py- lorus in the pathophysiology of gastroparesis. Studies show that fasting pyloric distensibility (based on measured pressure and pyloric diameter) was decreased in patients with gastroparesis and was associated with delayed gastric emptying, more severe symptoms, and impaired quality of life. These data provide the rationale for pyloric dilation, botulinum toxin injection, or pylo- romyotomy in patients with gastroparesis.
Multiple open-label trials of intrapyloric botulinum toxin injections for gastroparesis suggested efficacy, but 2 relatively small, randomized, controlled trials failed to show any improvement in symptoms, although one trial
January 2022 Beyond Metoclopramide for Gastroparesis 23
confirmed improved gastric emptying compared to placebo.
In several case series, surgical pyloroplasty has been associated with short-term improvements in symptom severity scores and with accelerated gastric emptying when appraised 3 months postprocedure. The standard Heineke-Mikulicz pyloroplasty divides both longitudinal and circular muscle layers. G-POEM divides the pylorus from the mucosal surface and cuts predominantly the circular muscle layer, leaving the longitudinal muscle intact to avoid perforation. Improved gastric emptying with G-POEM has also been documented. Current evi- dence on the efficacy of G-POEM for gastroparesis is summarized in Table 1, which shows exclusively un- controlled trials. These individual studies and published systematic reviews and meta-analyses based on 10 studies involving 292 patients have documented early andmedium-term efficacy of G-POEM in the treatment of gastroparesis and improvement of gastric emptying, as well as the superiority of this approach to gastric elec- trical stimulation for gastroparesis and equivalence of results to surgical pyloroplasty based on 332 patients with G-POEM (11 studies) and 375 patients who under- went surgical pyloroplasty (7 studies). Two studies have shown average pylorus diameter increase by about 2mm or 1.2 mm after G-POEM, questioning whether merely widening the pyloric diameter may be sufficient, espe- cially if there is also antral hypomotility. In one study, the average post–G-POEM change in the diameter of the py- lorus in those with clinical success was estimated to be 7.46mm, and in thosewith clinical failure it was 1.92mm with the EndoFLIP device (Medtronic, Minneapolis, MN) distended to 50 mL.
There is a critical need for a sham-controlled study of G-POEM in patients with well-characterized baseline and posttreatment measurements of antropyloroduodenal motor function and coordination, and with the diameter and distensibility index of the pylorus measured using EndoFLIP. Such studies would identify predictors of responsiveness to G-POEM and optimal candidates for this treatment.
It has been suggested that changes in diameter and distensibility index of the pylorus after G- POEM are associated with improved therapeutic outcome.
Description of the Figures and Tables
Current and investigational prokinetic drugs for gastric motility disorders are summarized in Table 1. Table 2 summarizes published studies on G-POEM for gastroparesis.
Take-Home Message
It is important to distinguish gastroparesis from func- tional dyspepsia with a well-validated gastric emptying
study measured over 4 hours with robust normal values. Gastroparesis requires multidisciplinary management, and the clinical gastroenterologist and endoscopist are pivotal in helping patients with this challenging disease.
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Reprint Requests Address requests for reprints to: Michael Camilleri, MD, Mayo Clinic, Charlton 8-110, 200 First Street SW, Rochester, MN 55905. e-mail: camilleri.michael@ mayo.edu.
Acknowledgments The author thanks Mrs. Cindy Stanislav for excellent secretarial assistance.
Conflicts of interest The author discloses the following: Michael Camilleri has served as an advisor to Takeda and Allergan, with the consulting fees paid to his employer, the Mayo Clinic; and has received single-center research grants from Takeda to study TAK-954 and from Vanda to study tradipitant.
Funding Michael Camilleri is supported by grant R01-DK122280 from National Institutes of Health.
Take-Home Message
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