Metoclopramide is used in a variety of GI disorders, but principally for the management of GI motility disorders, especially gastric stasis, for the management of gastroesophageal reflux, for the prevention of cancer chemotherapy-induced nausea and vomiting, and for the prevention of postoperative nausea and vomiting when nasogastric suction is considered undesirable. The drug is also used to facilitate intubation of the small intestine and as an adjunct during radiographic examination of the upper GI tract.
Therapy with the drug should not exceed 12 weeks' duration. Metoclopramide oral solution and tablets are recommended for use in adults only.
Diabetic Gastric Stasis
Metoclopramide is used for the symptomatic treatment of acute and recurrent diabetic gastric stasis (gastroparesis). Treatment of diabetic gastric stasis with metoclopramide is not curative. Since diabetic gastric stasis is a chronic, recurrent disease, successful therapy may often require long-term, intermittent use of metoclopramide.
The motility of the stomach is abnormal in patients with diabetic gastric stasis; fundic and antral contractility are markedly diminished and gastric emptying of liquids and solids is delayed. Although a correlation between gastric stasis and autonomic neuropathy has not been shown in diabetics, these patients may have signs of vagal nerve damage.
In patients with diabetic gastric stasis, metoclopramide increases the rate of gastric emptying and decreases usual symptoms of gastric stasis including nausea, vomiting, heartburn, anorexia, persistent postprandial fullness, abdominal pain and distention, and early satiety. Symptoms of delayed gastric emptying appear to respond to metoclopramide within different time intervals. Relief of nausea usually occurs soon after initiating metoclopramide therapy and continues to improve over a 3-week period. Subsequently, relief of vomiting and anorexia may precede relief of abdominal fullness by 1 week or longer.
In most patients with diabetic gastric stasis, metoclopramide-induced reduction of symptoms does not correlate well with improvement in gastric emptying. In some patients, complete relief of symptoms occurs despite minimal increases in the rate of gastric emptying, while in others, symptoms of gastric stasis persist despite a normalization in gastric emptying.
Postsurgical Gastric Stasis
Metoclopramide has been used for the symptomatic treatment of acute and chronic postsurgical gastric stasis following vagotomy and gastric resection or vagotomy and pyloroplasty. The drug has improved gastric emptying and decreased the usual symptoms of gastric stasis in patients with these conditions.
Prevention of Cancer Chemotherapy-induced Emesis
Metoclopramide is used parenterally in high doses for the prevention of nausea and vomiting associated with emetogenic cancer chemotherapy. The drug also has been administered orally for the prevention of chemotherapy-induced nausea and vomiting.
To prevent chemotherapy-induced nausea and vomiting associated with chemotherapy regimens with a high emetic risk (i.e., incidence of emesis exceeds 90% if no antiemetics are administered), the American Society of Clinical Oncology (ASCO) currently recommends a 3-drug antiemetic regimen consisting of a type 3 serotonin (5-HT3) receptor antagonist (e.g., dolasetron, granisetron, ondansetron, palonosetron, tropisetron [not commercially available in the US]), dexamethasone, and aprepitant.
Antiemetic agents with a lower therapeutic index (i.e., less efficacious and generally associated with more frequent adverse effects), including metoclopramide, cannabinoids (e.g., dronabinol, nabilone), butyrophenones, and phenothiazines are not considered by ASCO to be appropriate first-line antiemetics for any group of patients receiving chemotherapy of high emetic risk; ASCO states that these drugs should be reserved for patients unable to tolerate or refractory to first-line agents.
The antiemetic combination of a 5-HT3 receptor antagonist, dexamethasone, and aprepitant also is preferred in patients receiving combination chemotherapy with an anthracycline and cyclophosphamide.
For patients receiving other chemotherapy of moderate emetic risk (i.e., incidence of emesis without antiemetics exceeds 30% but does not exceed 90%), ASCO recommends a 2-drug antiemetic regimen consisting of a 5-HT3 receptor antagonist and dexamethasone.
For patients receiving chemotherapy regimens with a low emetic risk (i.e., incidence of emesis without antiemetics exceeds 10% but does not exceed 30%), ASCO recommends dexamethasone alone on the first day of chemotherapy.
Antiemetics can be prescribed on an as-needed basis in patients receiving chemotherapy with a minimal emetic risk (incidence of emesis is less than 10% without antiemetics).
In patients experiencing vomiting and nausea despite recommended prophylaxis regimens, ASCO recommends that clinicians consider adding a benzodiazepine (e.g., alprazolam, lorazepam) to the regimen, substituting high-dose intravenous metoclopramide for the 5-HT3 receptor antagonist in the regimen, or adding a butyrophenone or phenothiazine to the regimen.
For the prevention of delayed emesis in patients receiving cisplatin or other chemotherapy associated with a high emetic risk, these authorities currently recommend a 2-drug combination of dexamethasone and aprepitant.
Although antihistamines (e.g., diphenhydramine) and benzodiazepines (e.g., alprazolam, lorazepam) may be useful as adjunctive antiemetic agents, they currently are not recommended as monotherapy as antiemetic agents. However, many clinicians find benzodiazepines useful in the management of anticipatory emesis.
Metoclopramide is used parenterally for the prevention of cisplatin-induced nausea and vomiting. The drug has been used effectively for the prevention of chemotherapy-induced emesis in patients receiving cisplatin alone or in combination with other antineoplastic agents. In patients receiving cisplatin, high-dose metoclopramide (2 mg/kg) reduces the number and duration of vomiting episodes and the volume of emesis. In some patients, cisplatin-induced nausea and vomiting are completely prevented with metoclopramide therapy. Clinical evaluations of metoclopramide in the prevention of cisplatin-induced emesis have shown that the antiemetic effect of metoclopramide is greater than that of placebo, prochlorperazine, or tetrahydrocannabinol (THC). However, it appears that type 3 serotonergic (5-HT3) receptor antagonists (e.g., dolasetron, granisetron, ondansetron, palonosetron, tropisetron [not commercially available in the US]) and aprepitant generally are more effective and better tolerated than metoclopramide, which reportedly is pharmacologically less selective, and therefore, these 5-HT3 receptor antagonists given in combination with dexamethasone and aprepitant may be preferred for the initial prophylaxis of acute emetic effects in many patients; in some cases, these drugs may be effective in treating nausea and emesis that develop despite metoclopramide prophylaxis. Currently available 5-HT3 receptor antagonists (i.e., dolasetron, granisetron, ondansetron, palonosetron, tropisetron [not commercially available in the US]) appear to be comparably effective in preventing acute cisplatin- and other chemotherapy-induced nausea and vomiting. The addition of dexamethasone to monotherapy with a 5-HT3 receptor antagonist or metoclopramide increases the antiemetic efficacy of either drug alone, and such combined therapy may be useful in patients whose nausea and vomiting are refractory to monotherapy. Although addition of diphenhydramine to metoclopramide and dexamethasone therapy may increase the antiemetic efficacy further and decrease metoclopramide-induced adverse effects, combined therapy with a selective 5-HT3 receptor antagonist and dexamethasone appears to be more effective than this triple-drug combination. In addition, some evidence suggests that such combined therapy may be more effective, albeit not optimally, than monotherapy for the prevention and treatment of delayed emesis. Various combinations of antiemetic agents have been used, and comparative efficacy is continually being evaluated.
Remaining most problematic is the management of delayed and anticipatory nausea and vomiting; pending further elucidation of optimal regimens, some clinicians suggest combined regimens of 2 or 3 drugs that include a 5-HT3 receptor antagonist (e.g., dolasetron, granisetron, ondansetron, palonosetron, tropisetron [not commercially available in the US]), aprepitant, a corticosteroid (e.g., dexamethasone), metoclopramide, and/or benzodiazepine (e.g., lorazepam for anxiolytic, amnesic, and possibly antiemetic effects). In several clinical trials, oral metoclopramide has been effective when given in combination with dexamethasone for the prevention of delayed emesis in patients receiving chemotherapy.
Based on limited published data, maximum efficacy of metoclopramide appears to depend greatly on the use of the appropriate dose, route, and schedule during administration of the drug.
(See Prevention of Cancer Chemotherapy-induced Emesis, in Dosage and Administration: Dosage.)The efficacy of lower than currently recommended doses and/or alternate administration schedules for metoclopramide in the prevention of cisplatin-induced emesis remains to be clearly established. In one study in patients receiving cisplatin, optimum antiemetic effect was generally associated with serum metoclopramide concentrations greater than 850 ng/mL.
Metoclopramide is more likely to be effective in patients who were not previously exposed to cancer chemotherapy than in patients whose symptoms are refractory to conventional antiemetic agents. The antiemetic efficacy of metoclopramide appears to be maintained during subsequent doses of cisplatin.
Other Antineoplastic Agents
Metoclopramide is used for prevention of nausea and vomiting associated with other antineoplastic agents (e.g., cyclophosphamide, dacarbazine, doxorubicin, methotrexate) and with cancer chemotherapy regimens that do not include cisplatin. Since various antineoplastic agents may induce emesis by different mechanisms, the efficacy of metoclopramide depends on their relative potential and specific pharmacologic pathways for inducing emesis. In patients receiving dacarbazine, high-dose metoclopramide (2 mg/kg) appears to be an effective antiemetic. When oral metoclopramide (10 mg 1-2 hours before chemotherapy and then every 8 hours for a week) was combined with IV dexamethasone (10 mg immediately before initiation of IV chemotherapy) in patients receiving cyclophosphamide, methotrexate, and fluorouracil for breast cancer (a moderately emetogenic regimen), this antiemetic combination appeared to be comparably effective overall to oral ondansetron (8 mg 1-2 hours before chemotherapy and then every 8 hours for a week) in preventing emesis during the 7-day treatment period but was more effective than ondansetron in reducing the frequency of nausea during the first day of chemotherapy. Additional study is needed to further evaluate the role of metoclopramide alone or combined with other antiemetics in the prevention of nausea and vomiting associated with the many different regimens used for cancer chemotherapy.
Intubation of the Small Intestine
Metoclopramide is used parenterally to facilitate intubation of the small intestine in adults and children in whom the tube (e.g., endoscope, biopsy tube) does not pass through the pylorus with conventional maneuvers. The beneficial effect of metoclopramide on intubation of the small intestine is principally related to the pharmacologic action of the drug on GI motility and contractility.
(See Pharmacology: GI Effects.)Metoclopramide has little influence on the time required for biopsy capsules to reach the pylorus, but substantially reduces the time required for the capsules to pass through the pylorus.
In several controlled trials in patients with or without GI disease (e.g., inflammatory bowel disease, chronic diarrhea, malabsorption, celiac disease, peptic ulcer) undergoing intubation of the small intestine, IV metoclopramide (10 mg) reduced the time required for intubation and facilitated performance of the procedure; however, administration of the drug generally did not influence patient tolerance of the procedure.
Radiographic Examination of the Upper GI Tract
Metoclopramide is used parenterally to stimulate gastric emptying and intestinal transit of barium in patients in whom delayed emptying interferes with radiographic examination of the stomach and/or small intestine. In patients receiving oral barium, IV metoclopramide increases the rate of gastric emptying and reduces transit time of the barium in the small intestine. Metoclopramide markedly reduces the time required for radiographic examination of the small intestine and is effective in preventing nausea or regurgitation of barium that occurs in some patients with gastric atonia, pylorospasm, or spasm of the duodenal bulb.
Metoclopramide is used orally for the short-term (up to 12 weeks) relief of symptomatic, documented gastroesophageal reflux in adults who are unresponsive to conventional therapy alone, including changes in lifestyle, habits, and/or diet, which may be contributing or precipitating factors, and weight reduction in obese patients. However, agents that suppress gastric acid secretion (e.g., proton-pump inhibitors, histamine H2-receptor antagonists) currently are considered to be the mainstay of treatment for gastroesophageal reflux disease (GERD).
Metoclopramide produces a dose-related increase in the resting tone of the lower esophageal sphincter in healthy adults and in patients with gastroesophageal reflux. There reportedly is substantial interindividual variation in the effect of metoclopramide on lower esophageal sphincter pressure. In patients with gastroesophageal reflux, metoclopramide increases gastric emptying rate both in those with normal or delayed gastric emptying, and reduces daytime and nocturnal heartburn and regurgitation; however, metoclopramide therapy produces greater reductions in severity and occurrence of daytime and postprandial heartburn and regurgitation than in nocturnal symptoms associated with gastroesophageal reflux. If symptoms are associated with particular situations of precipitating factors (e.g., following the evening meal), administration of a single dose of metoclopramide prior to the provocative situation rather than daily administration of multiple doses of the drug should be considered.
Based on data from a limited number of patients, metoclopramide appears to be more effective than an aluminum hydroxide antacid or placebo and about as effective as cimetidine in improving the symptoms of gastroesophageal reflux. Objective parameters (i.e., endoscopy, lower esophageal sphincter pressure, esophageal contraction amplitude) for response were not consistently improved in these patients following short-term (4-8 weeks) administration of metoclopramide; however, in one unpublished study, endoscopic evidence of healing was observed following administration of metoclopramide (15 mg 4 times daily) for 12 weeks. Since there is no documented correlation between symptoms and healing of esophageal lesions in patients with gastroesophageal reflux, therapy in patients with documented lesions should be accompanied by appropriate endoscopic evaluation. In a study comparing single oral doses of metoclopramide (15 mg) with an aluminum hydroxide antacid (30 mL) or placebo in patients with reflux esophagitis, metoclopramide was reportedly more effective than antacid in reducing the symptoms associated with reflux. Metoclopramide increased the resting tone of the lower esophageal sphincter in all patients for at least 1 hour and prevented gastroesophageal reflux following administration of an intragastric acid load. Although metoclopramide may be effective for the short-term relief of gastroesophageal reflux, safety and efficacy of metoclopramide therapy beyond 12 weeks have not been evaluated and such prolonged use is not recommended.
Although metoclopramide appears to provide symptomatic relief and esophageal healing as effectively as a standard dosage of a histamine H2-receptor antagonist, and improved efficacy has been reported when metoclopramide has been used with a histamine H2-receptor antagonist, the potential risks (e.g., severe and potentially irreversible adverse CNS effects) and benefits of metoclopramide relative to other effective therapies must be considered. The American College of Gastroenterology (ACG) states that the frequent occurrence of adverse CNS effects has appropriately decreased the regular use of metoclopramide for treatment of GERD. Furthermore, the American Gastroenterological Association (AGA) recommends against use of metoclopramide for treatment of GERD because of the drug's adverse effect profile and a lack of high-quality data supporting its use. The ACG and AGA state that proton-pump inhibitors provide greater control of acid reflux than do other currently available agents, including prokinetic agents (e.g., cisapride [no longer commercially available in the US], metoclopramide). Suppression of gastric acid secretion is considered by these experts to be the mainstay of treatment for GERD, and a proton-pump inhibitor or histamine H2-receptor antagonist is used to achieve acid suppression, control symptoms, and prevent complications of the disease. Because GERD is considered to be a chronic disease, many patients with GERD will require long-term, even lifelong, treatment. For further information on the treatment of GERD,
Metoclopramide is used parenterally for the prevention of postoperative nausea and vomiting when nasogastric suction is considered undesirable.
Metoclopramide has been used for the management of migraine. Some experts state that IM metoclopramide may be considered as adjunctive therapy for control of nausea in patients with acute migraine attacks and that the IV drug may be considered as monotherapy for relief of migraine pain. For further information on management and classification of migraine headache,
Metoclopramide has been used in a limited number of patients for the treatment of peptic ulcer. Metoclopramide has also been used as an antiemetic for the prevention of nausea and vomiting associated with drugs other than antineoplastic agents, radiation therapy, and other causes. The drug has also been used for the management of anorexia nervosa, vertigo, and intractable hiccups. Metoclopramide has been used to promote postpartum lactation. Metoclopramide has also been used to empty the stomach of blood prior to endoscopy in patients with upper GI hemorrhage. The safety and efficacy of metoclopramide in these conditions have not been established.