Effects of Promotility Agents on Gastric Emptying and Symptoms: A Systematic Review and Meta-analysis

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Background Non‐ulcer dyspepsia (NUD) is a heterogeneous disorder, which is characterized by upper gastrointestinal symptoms and sensorimotor disturbances, including abnormal gastric emptying (GE) and increased intestinal chemosensitivity, and associated with greater plasma glucagon‐like peptide‐1 (GLP‐1) levels during duodenal lipid infusion. However, the relationship(s) between these disturbances and daily symptoms in NUD is variable. We hypothesize that abnormal GE and symptoms during a GE study and during duodenal lipid infusion are associated with the severity of daily symptoms and that GLP‐1 mediates symptoms during duodenal lipid infusion in NUD. Methods Gastric emptying of solids, symptoms during the GE study and duodenal lipid infusion, and daily gastrointestinal symptoms (2 week diary) were measured in 24 healthy controls and 40 NUD patients. During duodenal lipid infusion, participants received the GLP‐1 antagonist exendin 9‐39 or placebo. Key Results In controls and patients, GE of solids was normal in 75% and 75%, delayed in 8% and 12.5%, or rapid in 17% and 12.5%, respectively. No controls but 26 patients (65%) had severe symptoms during the GE study. During lipid infusion, gastrointestinal symptoms were greater (P = .001) in patients and not affected by exendin. Symptoms during GE study and lipid infusion accounted for respectively 62% and 37% of variance in daily symptom severity. Conclusions In NUD, symptoms during a GE study and to a lesser extent during lipid infusion explain the variance in daily symptoms. Intestinal chemosensitivity is not reduced by GLP‐1 antagonist. Assessment of symptoms during a GE study may provide a useful biomarker for NUD in research and clinical practice.

Section: Discussioncontrasting

confidence: 40%

Relationship between symptoms during a gastric emptying study and intestinal chemosensitivity with daily symptoms

Chakraborty

Desai

Halland

et al. 2019

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“… MA, SR (2019) RC, PC—accelerated gastric emptying (2002) RC, DB, PC, XO—no difference (1999) RC, DB, PC, XO—no difference (1999) RC, DB, PC—accelerated gastric emptying but no improvement in symptoms (1993) DB, PC—accelerated gastric emptying but no improvement in symptoms (1989) RC, DB, XO—accelerated gastric emptying but no improvement in symptoms (1987) RC, vs metoclopramide, PC—accelerated gastric emptying with both, significant with cisapride (1987) DB, PC, XO—no difference (1987) …”

Section: Treatment Optionsmentioning

confidence: 99%

“…Several adult studies comparing metoclopramide to placebo have found that metoclopramide improves symptoms and gastric emptying time . A recent systematic review and meta‐analysis demonstrated that metoclopramide significantly improved gastric emptying and upper GI symptoms . However, studies have shown that central nervous system side effects are more notable with metoclopramide when compared with other medications used for GP .…”

Section: Treatment Optionsmentioning

confidence: 99%

“…• SR a (2003) 59 • SA a (1999) 58 • DB a , PC a , XO a -improved antroduodenal motor activity (1997) 55 • RC a , DB, PC-accelerated gastric emptying (1995) 56 • OL a (1994) 60 • OL (1994) 61 • OL (1993) 63 • RC, DB, XO with metoclopramide-improved symptoms, more pronounced with erythromycin (1993) 62 77 • OL (1977) 121 • Re (2015) 75 • Re (2012) 14 • RC, DB, PC-accelerated gastric emptying in infants with regurgitation and infants with GP following abdominal surgery, no change in infants with GP related to prematurity (1988) 83 Domperidone Dopamine D2 receptor antagonist but with lower central side effects when compared to metoclopramide • MA, SR (2019) 80 • RC, PC, vs metoclopramide-equally effective but more pronounced CNS side effects with metoclopramide (1999) 81 • RC, PC, withdrawal study-improved symptoms (1998) 90 • OL (1997) 86 • Re(1990) 87 • OL (1989) 88 • RC, PC, XO-improved symptoms (1989) 91 • OL (1985) 89 • OL (1985) 85 • RC, PC, XO-accelerated gastric emptying (1983) 92 • RC, PC, XO-no difference (1981) 93 • Re (2012) 14 • RC, PC, XO (2010) 95 • RC, PC vs cisapride-domperidone superior to cisapride in improving symptoms and accelerating gastric emptying (2002) but the results are conflicting ( Table 2). [65][66][67][68][69][70][71][72] Consequently, a recent systematic review recommended using erythromycin only for highrisk preterm neonates with persistent feeding intolerance.…”

Section: Motilin Receptor Agonistmentioning

confidence: 99%

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Childhood gastroparesis is a unique entity in need of further investigation

Febo‐Rodriguez

Chumpitazi

Shulman

2019

Background Despite increasing knowledge regarding gastroparesis (GP) in adults, little is known regarding the incidence, prevalence, and natural history of childhood GP. Exacerbating the knowledge gap in pediatric GP is both the lack of normative data for gastric emptying scintigraphy in children and lack of GP‐specific pediatric reported outcome measures. Purpose The aim of this article was to review the available literature on pediatric GP and identify similarities and differences with studies in adults. We performed a comprehensive search in MEDLINE and Google Scholar from inception to April 2019 for articles published in English using the following combination of keywords: gastroparesis, pediatric gastroparesis, outcomes, metoclopramide, erythromycin, domperidone, cisapride, and gastric neurostimulator. The limited available pediatric data, often retrospective, suggest marked differences between adult and pediatric GP in several aspects including etiology, concomitant co‐morbidities (eg, psychiatric disorders), clinical symptom presentation, diagnostic evaluation, response to therapies, and clinical outcome. Further research in pediatric GP is needed and holds the promise to further elucidate the mechanisms of this disorder in children and lead to pediatric‐focused therapies.

“…In the USA, approved therapy is restricted to a single prokinetic dopamine‐2 receptor antagonist (metoclopramide) that carries a black box warning, as chronic use (>12 weeks) may lead to extrapyramidal side effects and potential irreversible tardive dyskinesia . Therefore, gastroenterologists resort to a combination of nutritional recommendations, herbal therapy, off‐label antiemetics, prokinetics and antidepressants, and endoscopic pyloric interventions (botox injections or myotomies) to best manage and prevent symptom flares . Currently, several agents are under various stages of clinical trials including selective serotonin 5‐HT4 receptor agonists, neurokinin‐1 receptor antagonists, and ghrelin receptor agonists .…”

Section: Discussionmentioning

confidence: 99%

Open‐label pilot study: Non‐invasive vagal nerve stimulation improves symptoms and gastric emptying in patients with idiopathic gastroparesis

Gottfried-Blackmore

Adler

Fernandez‐Becker

et al. 2019

Background Gastroparesis, a chronic motility disorder characterized by delayed gastric emptying, abdominal pain, nausea, and vomiting, remains largely unexplained. Medical therapy is limited, reflecting the complex physiology of gastric sensorimotor function. Vagus nerve stimulation is an attractive therapeutic modality for gastroparesis, but prior methods required invasive surgery. In this open‐label pilot study, we aimed to assess the benefit of non‐invasive vagal nerve stimulation in patients with mild to moderate idiopathic gastroparesis. Methods Patients self‐administered the gammaCore vagal nerve stimulator for 4 weeks. The gastroparesis cardinal symptom index daily diary (GCSI‐dd) was assessed during a two‐week run‐in period, ≥4 weeks of therapy, and 4 weeks after therapy was completed. Gastric emptying and autonomic function testing were also performed. The primary endpoint was an absolute reduction in CGSI‐dd of 0.75 after nVNS. Results There was a total improvement in symptom scores (2.56 ± 0.76 to 1.87 ± 1.05; P = .01), with 6/15 (40%) participants meeting our primary endpoint. Therapy was associated with a reduction in gastric emptying (T1/2 155 vs 129 minutes; P = .053, CI −0.4 to 45). Therapy did not correct autonomic function abnormalities, but was associated with modulation of reflex parasympathetic activity. Conclusions Short‐term non‐invasive vagal nerve stimulation led to improved cardinal symptoms and accelerated gastric emptying in a subset of patients with idiopathic gastroparesis. Responders had more severe gastric delay at baseline and clinical improvement correlated with duration of therapy, but not with improvements in gastric emptying. Larger randomized sham‐controlled trials of greater duration are needed to confirm the results of this pilot study.