Treatment of gastroparesis

INTRODUCTION — Gastroparesis is a syndrome of objectively delayed gastric emptying in the absence of a mechanical obstruction and cardinal symptoms of nausea, vomiting, early satiety, belching, bloating, and/or upper abdominal pain.

This topic will review the treatment of gastroparesis. The pathophysiology, etiology, and diagnosis of gastroparesis are discussed separately. (See "Pathogenesis of delayed gastric emptying" and "Gastroparesis: Etiology, clinical manifestations, and diagnosis".)

Our recommendations are largely consistent with the guidelines issued by the American Gastroenterological Association and the American College of Gastroenterology [1-3].

INITIAL MANAGEMENT — Initial management of gastroparesis consists of dietary modification, optimization of glycemic control and hydration, and in patients with continued symptoms, pharmacologic therapy with prokinetic and antiemetics. A suggested approach to the management of gastroparesis based on the extent of delay in gastric emptying is outlined in the algorithm (algorithm 1).

Dietary modification — Dietary modification is considered first-line therapy in patients with mild gastroparesis, although in clinical practice it is associated with only a modest improvement in symptoms [1]. Foods that are fatty, acidic, spicy, and roughage-based increase overall symptoms in individuals with gastroparesis [4,5]. Fat slows gastric emptying and nondigestible fiber (eg, fresh fruits and vegetables) require effective interdigestive antral motility that is frequently absent in patients with significantly delayed gastric emptying. Diet should be low in fat and in non-digestible (insoluble) fiber; in general, soluble fiber or fiber that is cooked and reduced to small particle size by homogenization can be digested and emptied from the stomach except in the most severe patients with gastroparesis [1].

For patients who are unable to tolerate solid food, meals should be homogenized, as gastric emptying of liquids is often normal even when emptying of solids is delayed [6-8]. Patients should also be advised to avoid carbonated beverages as they can aggravate gastric distention [6]. Alcohol and smoking should also be avoided as they can decrease antral contractility and delay gastric emptying [9,10].

Hydration and nutrition — Recurrent vomiting and reduced oral intake may result in hypokalemia, metabolic alkalosis, and dehydration. Patients with gastroparesis can also develop micronutrient and vitamin deficiencies [11]. Patients with prior gastric surgery are particularly susceptible to deficiencies in iron, vitamin B12, fat-soluble vitamins, thiamine, and folate. (See "Bariatric surgery: Postoperative nutritional management", section on 'Micronutrient management'.)

Hydration and vitamin supplementation should be provided orally in patients with mild gastroparesis. For patients who are unable to tolerate solids, supplements and vitamins can be added to liquidized or homogenized meals [12]. Patients with refractory symptoms may require enteral or parenteral supplementation. (See 'Decompression and feeding' below.)

Optimize glycemic control — Diabetes mellitus is a common cause of delayed gastric emptying [13]. While glycemic control should be advised in patients with diabetes to decrease the risk of microvascular complications, there are limited and conflicting data regarding the efficacy of long-term glycemic control on gastric emptying rates and symptoms of gastroparesis [14-16]. However, acute hyperglycemia has been demonstrated to slow gastric emptying in patients with diabetes mellitus and healthy controls [17-21]. In addition, hyperglycemia also attenuates the efficacy of prokinetic drugs [22-25].

In patients with diabetes, incretin-based therapies such as pramlintide (amylin analog) and GLP1 analogues or agonists (eg, liraglutide, exenatide) should be avoided as they can delay gastric emptying. In contrast, dipeptidyl peptidase IV inhibitors (eg, vildagliptin, sitagliptin) do not affect gastric emptying. (See "Amylin analogs for the treatment of diabetes mellitus", section on 'Side effects and adverse events' and "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus", section on 'Suggested approach to the use of GLP-1 receptor agonist-based therapies'.)

Prokinetics — Pharmacologic therapy is necessary for patients who continue to have symptoms of gastroparesis despite dietary modification. Prokinetics increase the rate of gastric emptying and should be administered 10 to 15 minutes before meals with an additional dose before bedtime in patients with persistent symptoms. As compared with tablets, liquid formulations allow for easier dose titration and are less likely to accumulate in the stomach and cause erratic absorption (algorithm 1). (See 'Dietary modification' above.)

Metoclopramide — Metoclopramide is first-line therapy for gastroparesis [1]. Metoclopramide, a dopamine 2 receptor antagonist, a 5-HT4 agonist, and a weak 5-HT3 receptor antagonist, improves gastric emptying by enhancing gastric antral contractions and decreasing postprandial fundus relaxation. Metoclopramide is approved by the US Food and Drug Administration (FDA) for treatment of gastroparesis for no longer than 12 weeks unless patients have a therapeutic benefit that outweighs the risks. The side effects associated with metoclopramide include central side effects of anxiety, restlessness, and depression, hyperprolactinemia, and QT interval prolongation. Extrapyramidal side effects, including dystonia in 0.2 percent of patients and tardive dyskinesia in 1 percent of patients, have led to a black box warning [26]. In one observational study that included 479 reports of extrapyramidal side effects associated with metoclopramide, while acute dystonias were more likely in children and young adults and in females, parkinsonian reactions were more likely in older adults [27].

It is important to inform patients of the side effects and to obtain written informed consent before treating patients with metoclopramide. We initiate treatment with a low-dose liquid formulation (eg, 5 mg, 15 minutes before meals and at bedtime), titrating up to identify the lowest effective dose. Many patients can tolerate treatment with up to 40 mg of oral metoclopramide per day, in divided doses, without significant adverse effects. "Drug holidays" or dose reductions (eg, 5 mg, before two main meals of the day) should be implemented whenever clinically possible. It is the author's practice to review these patients every three months to assess medication efficacy and adverse events, before repeat prescription. A drug holiday of two weeks between prescriptions helps to ensure that the patient is really benefitting from the medication, as evidenced by recurrence of gastroparesis symptoms, or inability to tolerate solid or calorie-rich foods. If patients remain asymptomatic while off metoclopramide, the length of the drug holiday is then prolonged. This is particularly relevant with postviral gastroparesis, which may go into remission on average 12 months after onset [28]. Patients should also be advised to inform the clinician of involuntary movements [26]. The management and prognosis of tardive dyskinesia and acute dystonia are discussed separately. (See "Tardive dyskinesia: Prevention, treatment, and prognosis", section on 'Initial management' and "Schizophrenia in adults: Maintenance therapy and side effect management", section on 'Dystonia'.)

Metoclopramide can also be administered by intravenous, intramuscular, or subcutaneous routes. In patients who cannot tolerate oral medications, metoclopramide can be administered subcutaneously, although experience is limited [29]. We suggest that the metoclopramide dose is limited to 5 to 10 mg three times daily [29].

A nasal spray preparation of metoclopramide was approved in the United States for treatment of diabetic gastroparesis in men and women based on data extrapolated from oral administration; one 15 mg spray delivers a dose approximately equivalent to 10 mg of oral metoclopramide [30]. However, comparisons between intranasal and oral administration are limited, and one study in 285 patients found that intranasal metoclopramide was useful for symptom relief in women but not men [31].

Domperidone — Domperidone is an alternative to metoclopramide in patients with gastroparesis [1]. However, domperidone, a dopamine 2 antagonist, is not readily available in the United States but is available in Canada and in other countries. In the United States, domperidone can be prescribed to patients only through an FDA Investigational New Drug application. Use of domperidone is, therefore, reserved to patients whose symptoms fail to respond to metoclopramide or with side effects to metoclopramide.

The efficacy of domperidone in diabetic gastroparesis is likely similar to that of metoclopramide [32,33]. However, trials of domperidone in diabetic gastroparesis have been small and have had methodologic limitations [34]. Studies suggest domperidone may increase the risk of cardiac arrhythmias [35]. Therefore, an electrocardiogram should be performed at baseline and while on treatment. Domperidone should be withheld if the corrected QT is >450 ms in men and >470 ms in women. Domperidone can cause hyperprolactinemia. Drug-drug interactions may occur with concomitant administration of cisapride, azole antifungals, and antiretrovirals (table 1 and table 2). (See "Overview of pharmacogenomics", section on 'CYP isoenzymes and drug metabolism' and "Acquired long QT syndrome: Definitions, pathophysiology, and causes".)

Macrolide antibiotics

Erythromycin — Erythromycin, a motilin agonist, induces high-amplitude gastric propulsive contractions that increase gastric emptying [36,37]. Erythromycin also stimulates fundic contractility, or at least inhibits the accommodation response of the proximal stomach after food ingestion [38]. Patients who fail to respond to a trial of metoclopramide and domperidone should be treated with oral erythromycin (liquid formulation, 40 to 250 mg three times daily before meals) (algorithm 1) [6].

Oral erythromycin should be administered for no longer than four weeks at a time, as the effect of erythromycin decreases due to tachyphylaxis. Use of higher doses (eg, 250 mg, compared with 40 mg) may be more likely to cause abdominal pain or induce tachyphylaxis. Chronic administration of oral erythromycin should be restricted to patients who have failed to respond to other prokinetics and who continue to demonstrate an improvement in symptoms over baseline and tolerance of oral feeding. Intravenous erythromycin should be reserved for acute exacerbations of gastroparesis in which oral intake is not tolerated. (See 'Management of acute exacerbations' below.)

Intravenous erythromycin significantly improves gastric emptying [39]. Although gastric emptying is also improved with oral erythromycin, this improvement is smaller as compared with intravenous administration [39]. In a systematic review of five clinical trials involving oral erythromycin for gastroparesis, 26 of 60 patients (43 percent) had an improvement in symptoms of gastroparesis [40]. However, the studies included were small (≤13 subjects), of short duration (≤4 weeks), and had methodologic limitations.

Tachyphylaxis to erythromycin and potential side effects limit its use in the management of gastroparesis. Side effects of erythromycin include gastrointestinal toxicity, ototoxicity, the induction of resistant bacterial strains, QT prolongation, and sudden death, particularly when used in patients taking medications that inhibit CYP3A4 (table 2). (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes".)

Azithromycin — Azithromycin has a longer half-life, and fewer gastrointestinal adverse effects and drug interactions as compared with erythromycin. However, azithromycin is a weak inhibitor of CYP3A4 and like erythromycin may prolong cardiac repolarization and the QT interval, increasing the risk of cardiac arrhythmias and torsade de pointes.

There are no randomized trials directly comparing azithromycin and erythromycin in patients with gastroparesis. In a case-control study with 120 patients, there was no significant difference in gastric emptying between patients who received azithromycin as compared with erythromycin [41]. A manometric study found that when azithromycin and erythromycin were given in similar doses intravenously, they had a similar positive effect on antral motility [42]. When a higher dose of azithromycin (500 mg) was used, the mean amplitude, duration of antral activity, and motility index were all increased compared with erythromycin (250 mg).

Cisapride — Cisapride, a 5HT4 agonist, stimulates antral and duodenal motility and accelerates gastric emptying of solids and liquids, which in open-label trials has been maintained for up to one year [43-48]. Although cisapride is better tolerated than metoclopramide, its use has been associated with important drug interactions with medications metabolized by the cytochrome P450-3A4 isoenzyme (eg, macrolide antibiotics, antifungals, and phenothiazines) resulting in cardiac arrhythmias and death [43]. In the United States, prescriptions for cisapride can only be filled through an investigational limited access program from the manufacturer after providing documentation as to need for cisapride and assessment of risk factors for cardiac arrhythmias in the individual patient (eg, a QTc >450 ms). However, cisapride is available in several other countries.

If prescribed, cisapride should be administered to patients who have failed a trial of all other prokinetics, at a dose of 10 to 20 mg four times daily, one-half hour before each meal and at bedtime. Cisapride dose should not exceed 1 mg/kg per day or 60 to 80 mg daily as cardiac arrhythmias have been observed when prescribed at high doses (>1 mg/kg per day), or when administered with a drug that inhibits its metabolism (table 2). Other side effects of cisapride, including abdominal discomfort and diarrhea, respond to dose reduction.

Antiemetics — We treat patients with persistent nausea and vomiting despite prokinetics with antihistamines (eg, diphenhydramine 12.5 mg orally or intravenously every six to eight hours as needed) and in patients with persistent symptoms, 5HT3 antagonists (eg, ondansetron 4 to 8 mg orally three times daily). Antiemetics have not been studied in the management of patients with gastroparesis, and their use in gastroparesis is based on their efficacy in controlling nonspecific nausea and vomiting and in chemotherapy-induced emesis. Prolongation of the QT interval and central side effects have limited the use of phenothiazines (eg, prochlorperazine 5 to 10 mg orally three times daily, 5 to 25 mg twice daily per rectum as needed) to patients who remain symptomatic despite antihistamines and 5HT3 antagonists (algorithm 1).

When coadministering antiemetics and prokinetics it is important to consider potential metabolic drug interactions that may result in high blood levels resulting in drug toxicity [49]. First generation 5-HT3 antagonists (eg, ondansetron, granisetron, and dolasetron) are associated with electrocardiographic (ECG) changes. While most changes are small and insignificant, fatal arrhythmias have been reported in association with prolonged QT intervals. ECG monitoring is recommended in patients on 5HT3 antagonists with hypokalemia, hypomagnesemia, heart failure, bradyarrhythmias, or patients taking concomitant medications that prolong the QT interval. In contrast to phenothiazines, 5HT3 antagonists have not been associated with cognitive, psychomotor, or affective disturbances. The side effects of antiemetics are discussed in detail, separately. (See "Characteristics of antiemetic drugs", section on 'Phenothiazines' and "Characteristics of antiemetic drugs", section on 'Antihistamines' and "Characteristics of antiemetic drugs", section on 'Serotonin receptor antagonists'.)

While antihistamines, phenothiazines, and 5T3 antagonists can all be administered orally and parenterally, only antihistamines and phenothiazines can be administered rectally.

REFRACTORY SYMPTOMS — In patients with refractory symptoms of gastroparesis despite dietary modification, prokinetics, and antiemetics, it is important to re-evaluate compliance with dietary modification and pharmacotherapy and to provide nutritional support. We suggest placement of a jejunostomy and venting gastrostomy tube for enteral nutrition and decompression, respectively. We suggest parenteral nutrition only in patients who cannot tolerate enteral nutrition despite concomitant pharmacotherapy. Gastric electrical stimulation should only be used in patients with gastroparesis with intractable nausea and vomiting despite medical therapy for at least one year.

Decompression and feeding — In patients with gastroparesis and abdominal pain or nausea that is refractory to pharmacotherapy with prokinetics and antiemetics, we place a percutaneous endoscopic gastrostomy tube to decompress the upper gastrointestinal tract. In patients with generalized motility disorders, the placement of a gastrostomy tube allows patients to vent gastric contents to relieve symptoms and reduces the need of hospitalization for acute exacerbations of dysmotility [50,51]. In addition, we place a percutaneous endoscopic jejunostomy tube to provide enteral nutrition in patients with unintentional loss of 10 percent or more of the usual body weight during a period of three to six months, and/or repeated hospitalizations for refractory symptoms (algorithm 1).

A jejunal feeding tube provides a means to deliver enteral formula by continuous infusion at a rate that allows for the majority of calories and nutrients to be delivered at night. However, prior to placement of a jejunostomy tube, we perform a trial of nasojejunal feeding for three days to ensure that at least 80 mL of enteral nutrition can be delivered per hour, as this rate is essential if jejunal feeding is to succeed in the long term. The advantages and disadvantages of different feeding tubes in the setting of gastroparesis are outlined in the table (table 3).

Patients on enteral feeding are permitted small-volume liquid meals by mouth during the day. A nutrient formula should be selected in consultation with an expert in nutrition, and guided by the individual patient's caloric, fat, protein, and supplement needs and the caloric density and osmolality of the formula. The concomitant presence of small intestinal disease may reduce the tolerance to high osmolality and high nitrogen-containing formulas. (See "Nutrition support in intubated critically ill adult patients: Enteral nutrition", section on 'Formulations'.)

Parenteral nutrition should be restricted to patients with severe gastric and small intestinal dysmotility who have failed enteral nutrition with prokinetics and antiemetic therapy. Parenteral nutrition is seldom necessary in patients with gastroparesis, unless it is part of a generalized motility disorder (eg, hollow visceral myopathy, progressive systemic sclerosis) [52]. (See 'Prokinetics' above and 'Antiemetics' above and "Gastrointestinal manifestations of systemic sclerosis (scleroderma)".)

Indications for surgery include placement of an enterostomy tube (eg, gastrostomy, jejunostomy) that cannot be placed endoscopically and completion or subtotal gastrectomy to relieve refractory nausea and vomiting in patients with a partial gastrectomy [53-55].

Tricyclic antidepressants — The use of tricyclic antidepressants (TCAs) is limited to treat symptoms of abdominal pain and vomiting despite a venting gastrostomy tube for decompression. In open-label trials, low-dose nortriptyline, a TCA with low anticholinergic effects, has been demonstrated to decrease symptoms of nausea, vomiting, and abdominal pain in patients with diabetic and idiopathic gastroparesis [56,57]. However, TCAs can potentially decrease the rate of gastric emptying. In addition, results from a randomized trial failed to demonstrate a benefit of nortriptyline in improving global symptoms of gastroparesis [58].

An alternative central neuromodulator that can be considered is mirtazapine, which is an antidepressant with central adrenergic and serotonergic activity with direct anti-emetic activity possibly related to 5-HT₃ antagonist activity and demonstrated benefit in patients with gastroparesis [59].

Other therapies with limited or unclear role

Acupuncture — There are limited data to support the use of acupuncture in patients with delayed gastric emptying for symptom control in patients with diabetic gastroparesis [1]. Acupuncture has not been demonstrated to be beneficial in gastroparesis due to other etiologies. In one single-blinded randomized trial, 19 patients with type 2 diabetes were assigned to two weeks of acupuncture or sham control. Acupuncture improved symptoms of postprandial fullness, early satiety, and bloating as compared with sham treatment control both at the end of the two weeks of treatment and at two-week follow-up [60]. Although gastric emptying of solids improved as compared with baseline in patients treated with acupuncture but not in patients treated with sham control, patients in the acupuncture arm had significantly lower gastric emptying times at baseline.

Interventions directed at the pylorus — Randomized sham-controlled trials are required to establish the role of endoscopic approaches (gastric endoscopic pyloromyotomy [G-POEM], transpyloric stent) and laparoscopic (pyloroplasty) approaches in patients with gastroparesis [61,62]. Endoscopic pyloromyotomy and surgical myotomy appear to have comparable efficacy but endoscopic myotomy has been associated with lower postprocedural complication rates and shorter hospital length of stay [1,63,64]. Limited data suggest that functional lumen imaging of the pylorus may predict clinical outcomes of G-POEM [65] as well as outcomes of intra-pyloric botulinum toxin injection [66].

Endoscopic placement of a transpyloric stent, which is anchored by suturing on the gastric side, has been evaluated in patients with gastroparesis. In an open-label trial in which a total of 30 patients with refractory gastroparesis underwent 48 transpyloric stent procedures, clinical response was reported in 21 of 28 patients (75 percent), with greater efficacy in those with predominant nausea and/or vomiting than in those with predominant pain [67].

G-POEM] and laparoscopic pyloroplasty have been successful in small studies in treating gastroparesis [68-71]. G-POEM has the theoretical potential to induce dumping syndrome [3]. G-POEM should be reserved for patients with refractory gastroparesis. There is evidence from a pilot sham-controlled study that G-POEM is efficacious in gastroparesis [72], that G-POEM may be superior to gastric electrical stimulation in the long term [73], and that it can be applied as adjunctive therapy in patients who remain symptomatic after gastric electrical stimulation [74].

Intrapyloric injection of botulinum toxin is not recommended in patients with gastroparesis [1]. Although there have been multiple open-label trials attesting to the efficacy of this approach [75-77], randomized controlled trials failed to show any improvement in symptoms [78,79].

Gastric electrical stimulation — Gastric electrical stimulation is reserved for compassionate treatment in patients with refractory symptoms, particularly nausea and vomiting (eg, with persistence of symptoms despite antiemetic and prokinetic drug therapy for at least one year), who are not on opioids and who do not have pain as a predominant symptom [3]. G-POEM should be reserved for patients with refractory gastroparesis. There is evidence from a pilot sham-controlled study that G-POEM is efficacious in gastroparesis, particularly in patients with diabetic gastroparesis [80]. In the United States, the gastric electrical neurostimulator (Enterra Therapy system) has been approved as a humanitarian exemption device for diabetic and idiopathic gastroparesis. In a randomized cross-over trial of the same device in 172 patients with chronic (>12 months) refractory vomiting, the device reduced vomiting frequency when it was on compared to when the device was off [81]. (See "Electrical stimulation for gastroparesis".)

Investigational agents — Relamorelin (a pentapeptide ghrelin receptor agonist) [82], velusetrag (5HT-4 receptor agonist), and tradipitant (a neurokinin 1 antagonist) [83] are investigational therapies in patients with gastroparesis and type 1 or type 2 diabetes [84-87]. Further studies are needed before they can be routinely recommended. Herbal therapies (eg, STW5 [Iberogast]) should not be used for treatment of gastroparesis [1].

MANAGEMENT OF ACUTE EXACERBATIONS — For acute exacerbations of delayed gastric emptying, we suggest erythromycin 3 mg/kg intravenously (IV) every eight hours. In patients without permanent enterostomy tubes, IV erythromycin relieves acute gastric stasis rapidly, obviating the need for nasogastric decompression. However, IV erythromycin is effective in relieving symptoms in approximately 40 percent of patients [29]. We treat patients who fail IV erythromycin with subcutaneous metoclopramide (5 to 10 mg three times daily).

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Gastroparesis".)

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●Basics topics (see "Patient education: Gastroparesis (delayed gastric emptying) (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Initial management – The initial management of gastroparesis consists of dietary modification, optimization of glycemic control and hydration, and, in patients with continued symptoms, pharmacologic therapy with prokinetics and antiemetics (algorithm 1).

•Dietary modification – We suggest that patients consume small, frequent meals that are low in fat and contain only soluble fiber (Grade 2C). In patients who cannot tolerate solids, meals can be homogenized and liquid meals supplemented with vitamins. (See 'Dietary modification' above.)

•Pharmacologic treatment – In patients who fail to respond to dietary modification, we start pharmacologic treatment with prokinetics to increase the rate of gastric emptying. We use liquid formulations in order to facilitate absorption, if available, and administer prokinetics 10 to 15 minutes before meals, with an additional dose before bedtime in patients with continued symptoms.

We recommend initial pharmacologic treatment with metoclopramide (Grade 1A). In patients who fail to respond to metoclopramide, we suggest a trial of domperidone and subsequently oral erythromycin (Grade 2B).

In patients with nausea and vomiting that fail to respond to metoclopramide, domperidone, and erythromycin, we suggest cisapride if available (Grade 2B). (See 'Metoclopramide' above and 'Domperidone' above and 'Cisapride' above.)

●Patients with refractory symptoms – We suggest a venting gastrostomy tube or decompression in patients with abdominal pain and nausea that is refractory to pharmacotherapy with prokinetics and antiemetics (Grade 2C). We suggest jejunal feeding tubes for enteral nutrition in patients with unintentional loss of 10 percent or more of the usual body weight during a period of three to six months, and/or two or more hospitalizations for refractory symptoms (Grade 2C). (See 'Decompression and feeding' above and 'Prokinetics' above and 'Antiemetics' above.)

●Management of acute exacerbations – For acute exacerbations of delayed gastric emptying, we suggest intravenous erythromycin (erythromycin lactobionate 3 mg/kg intravenously) every eight hours (Grade 2B). In patients who fail to respond to intravenous erythromycin, we suggest subcutaneous metoclopramide (5 to 10 mg three times daily) (Grade 2C). (See 'Management of acute exacerbations' above.)