GASTROINTESTINAL MOTILITY AND FUNCTIONAL BOWEL DISORDERS, SERIES #1 Richard W. McCallum, MD, FACP, FRACP (Aust), FACG Status of Pharmacologic Management of Gastroparesis: 2014 Richard W. McCallum Joseph Sunny, Jr. Gastroparesis is characterized by delayed gastric emptying without mechanical obstruction of the gastric outlet or small intestine. The main etiologies are diabetes, idiopathic and post- gastric and esophageal surgical settings. The management of gastroparesis is challenging due to a limited number of medications and patients often have symptoms, which are refractory to available medications. This article reviews current treatment options for gastroparesis including adverse events and limitations as well as future directions in pharmacologic research. INTRODUCTION astroparesis is a syndrome characterized by documented gastroparesis are increasing.2 Physicians delayed emptying of gastric contents without have both medical and surgical approaches for these Gmechanical obstruction of the stomach, pylorus or patients (See Figure 1). Medical therapy includes both small bowel. Patients can present with nausea, vomiting, prokinetics and antiemetics (See Table 1 and Table 2). postprandial fullness, early satiety, pressure, fullness The gastroparesis population will grow as diabetes and abdominal distension. In addition, abdominal pain increases and new therapies will be required. What located in the epigastrium, and distinguished from the do we know about the size of the gastroparetic term discomfort, is increasingly being recognized population? According to a study from the Mayo Clinic as an important symptom. The main etiologies of group surveying Olmsted County in Minnesota, the gastroparesis are diabetes, idiopathic, and post gastric risk of gastroparesis in Type 1 diabetes mellitus was and esophageal surgeries.1 Hospitalizations from significantly greater than for Type 2. The cumulative proportions developing gastroparesis over a ten year time period was 5.2% in Type 1 and 1.0% in Type 2, Richard W. McCallum, M.D., Professor and Founding compared to 0.2% in controls. They concluded that Chair of Medicine, Department of Internal Medicine gastroparesis is a relatively uncommon complication Director, Center for Neurogastroenterology and GI of diabetes.3 However in recent studies utilizing a Motility. Joseph Sunny, Jr., M.D., Senior Fellow, more “real world” population of diverse cultures and Division of Gastroenterology, Hepatology and socioeconomic status, not represented in Olmsted Nutrition, Texas Tech University Health Sciences County, there is a very different result. This new Center, Paul L. Foster School of Medicine, El Paso, TX (continued on page 22) 20 PRACTICAL GASTROENTEROLOGY • SEPTEMBER 2014 Status of Pharmacologic Management of Gastroparesis: 2014 GASTROINTESTINAL MOTILITY AND FUNCTIONAL BOWEL DISORDERS, SERIES #1 (continued from page 20) Most of the research with metoclopramide occurred study concluded that approximately 165,000 Type as long as thirty years ago. A multi-center placebo 1 diabetes mellitus (14% of US patients with Type controlled trial in 1983 using a dose of 10 mg orally 1 diabetes) and 2.1 million Type 2 diabetes mellitus four times a day showed improved symptom outcomes (9.4%) patients are currently seeking medical therapy and gastric emptying time in patients with diabetic for diabetic gastroparesis symptoms and had moderate gastroparesis.8 Two trials with a total of twenty three to severe symptoms of diabetic gastroparesis within diabetic gastroparesis patients showed improvement the previous seven days of being in the survey.4 The in gastric emptying and symptoms over placebo.9,10 prevalence of diabetic gastroparesis is thus higher than Patients did have symptom improvement as far as previously reported and is significantly underdiagnosed nausea, vomiting, constipation, fullness and bloating; and undertreated. The greater standardization and however, gastric emptying did not improve and did acceptance of radionuclide four hour gastric emptying not correlate with symptom improvement in either and the SmartPill (wireless motility capsule) will study. Therefore, metoclopramide’s clinical efficacy facilitate more confidence in the evaluation of gastric is provided by a combination of pro-kinetic effects emptying and with better recognition the full breadth of peripherally and antiemetic properties centrally.8,9 gastroparesis will be better appreciated as a relatively Metoclopramide is available in oral, suppository, and common and severe complication of Diabetes Mellitus. injectable routes of administration. Oral formulations The predicted number with diabetic gastroparesis in the include tablet, liquid and dissolvable tablets. A trial of US is 4 million and combined with other etiologies of ten patients showed that subcutaneous metoclopramide gastroparesis the overall figure approaches or exceeds (2 cc=10 mg) administration can lead to improvement ten million patients in the USA. This is essentially in gastric emptying and symptoms. In the outpatient 3% of the population. Put in perspective, hepatitis C setting, subcutaneous metoclopramide in doses of 10 to and celiac sprue are now both thought to be present in 40 mg per day can be used as an adjunct to the patient’s approximately 1% of the population. oral medications since the plasma levels achieved are 80% of the intravenous levels thus overcoming Prokinetics the limitations of erratic absorption in the setting Metoclopramide of gastroparesis and vomiting.11 This subcutaneous Approved by the FDA in 1979, metoclopramide is the self administration essentially equates to IV use only gastric prokinetic registered in the United States. in the emergency department. The newly released Metoclopramide blocks dopamine D2 receptors in metoclopramide ODT (Metozolv ODT) is an orally the upper gastrointestinal tract as well as stimulates dissolvable tablet available in 5 mg and 10 mg, which 5-HT4 receptors resulting in augmented acetylcholine facilitates patient compliance. The absorption occurs release which promotes gastric motility by affecting in the small bowel and not through the buccal mucosa. pre-synaptic and post-synaptic receptors in the gut An intranasal route of administration is also being wall. Overall, the medication leads to increased lower developed to address the challenges of gastroparesis esophageal sphincter pressure, gastric tone, intragastric by providing a continuous plasma level for the agent. pressure, as well as coordinates antroduodenal motility Adverse events are a significant detraction for with relaxation of the pylorus, resulting in faster gastric metoclopramide. The United States Food and Drug emptying. Dopamine inhibits lower oesophageal Administration released a warning for metoclopramide sphincter pressure and gastroduodenal motility.5 in 2009 stating the medications risk of tardive dyskinesia, Levodopa was shown to increase gastric retention specifically with patients taking the medications for of a technetium labelled meal compared to placebo. greater than three months.12 Overall, approximately Administration of metoclopramide with levodopa thirty percent of patients cannot maintain long term returned gastric emptying toward normal. This study use. The medication can cross the blood-brain barrier demonstrated the inhibitory effect of dopamine receptors leading to inhibition of central D2 receptors involved on gastric motility.6 Metoclopramide also provides in movement pathways such as the basal ganglion, antiemetic relief through inhibiting D2 dopamine within manifesting in a wide array of involuntary movement the chemoreceptor trigger zone of the brain as well as disorders. An acute dystonic reaction can occur within 7 some antagonism of 5-HT3 receptors. the first few hours typically when given parenterally, 22 PRACTICAL GASTROENTEROLOGY • SEPTEMBER 2014 Status of Pharmacologic Management of Gastroparesis: 2014 GASTROINTESTINAL MOTILITY AND FUNCTIONAL BOWEL DISORDERS, SERIES #1 Figure 1. Algorithm for Gastroparesis Management Gastroparesis suspected based on symptoms Negative for obstruction with EGD and/or small bowel series Gastric scintigraphy to evaluate for delayed gastric emptying -­‐ 4 hour test shows >10% isotope retention Mild Moderate Severe -­‐less than daily symptoms, no -­‐daily symptoms, not continuous, -­‐daily, continuous symptoms, hospitalizations, no impact on work occasional hospitalization, and multiple ED/hospitalizations, and and family functioning some interference with work and inability to work and function family functioning Liquid or t sof diet, glucose control, Diet, prokinetics, one or more Diet, combining prokinetics, multiple antiemetics prn, review of antiemetics and glucose control, antiemetics, address narcotics and medications and metabolic state also question addressing pain and glucose control, plus research trials psychological aspects Inadequate response to therapy Trial of jejunal tube feeding and continue all treatment Botulinum pyloric injection trial in Gastric electrical stimulation device post vagotomy and idiopathic placement combined with patients pyloroplasty +/-­‐ jejunostomy tube placement which will resolve with discontinuation. Within the first The length of treatment prior to symptom development few weeks and months, akathisia, anxiety, tremor, drug- was also variable from 14 to 20 months.3 Careful follow induced Parkinsonism and depression can develop. up of patients on chronic metoclopramide with actual These can be reversible within a few days to a