Metoclopramide

Sasank Isola; Azhar Hussain; Anterpreet Dua; Karampal Singh; Ninos Adams

Metoclopramide

Earn CME/CE in your profession:

Free Review Questions

Continuing Education Activity

Metoclopramide is a dopamine receptor antagonist and has been approved by the FDA to treat nausea and vomiting in patients with gastroesophageal reflux disease or diabetic gastroparesis by increasing gastric motility. It is also used to control nausea and vomiting in chemotherapy patients. Additionally, metoclopramide can be administered prophylactically to prevent nausea and vomiting in postoperative patients when nasogastric suction is contraindicated or unavailable and has shown surprising success in treating migraines; however, the FDA has not explicitly approved it for these other conditions. This activity will highlight the mechanism of action, adverse event profile, pharmacology, monitoring, and relevant interactions of metoclopramide, pertinent for interprofessional team members in treating patients with conditions that are of clinical value.

Objectives:

Explain the mechanisms of action of metoclopramide.
Identify the approved and off-label indications for metoclopramide.
Review the potential adverse events associated with metoclopramide.
Summarize the contraindications to therapy with metoclopramide.

Indications

The FDA has approved metoclopramide to treat nausea and vomiting in patients with gastroesophageal reflux disease (in patients who fail to respond to established therapy) and diabetic gastroparesis by increasing gastric motility.[1][2] Parenteral metoclopramide is also FDA approved to control nausea and vomiting in chemotherapy patients.[3][4]

Metoclopramide is used off-label prophylactically to prevent nausea and vomiting in postoperative patients when nasogastric suction is contraindicated or unavailable. It is particularly useful in this role because it does not cause any concomitant increase in gastric secretions.[5] Metoclopramide is also used off-label to treat acute migraine in the emergency department. It is an effective adjunctive agent for acute nausea and vomiting and reduces headache intensity; hence it is a valuable agent for the short-term treatment of acute migraine in the ED. It is important to recognize that FDA has not explicitly approved it for acute migraine. Still, it is a valuable alternative to opioids due to the potential for opioid use disorder.[6][7]

Metoclopramide can also be used off-label to treat hyperemesis gravidarum in pregnant patients; still, it should be used cautiously because of the lack of studies on the effects of the drug in pregnant women.[8][9] Recent studies have also shown evidence of metoclopramide’s efficacy in treating Diamond Blackfan syndrome.[10][11] Metoclopramide has also been efficacious in treating nausea in critically ill advanced liver disease patients.[12]

Mechanism of Action

Metoclopramide works by antagonizing central and peripheral dopamine-two receptors (D2) in the medullary chemoreceptor trigger zone in the area postrema, usually stimulated by levodopa or apomorphine. It achieves this by decreasing the sensitivity of visceral afferent nerves that transmit from the gastrointestinal system to the vomiting center in the area postrema in the chemoreceptor trigger zone.[13] In addition to antagonizing dopamine receptors, metoclopramide is an antagonist at 5HT3 (type 3 serotonin receptors) and an agonist at 5HT4 receptors.[14][15] Metoclopramide also blocks the antiperistaltic effects of apomorphine, allowing metoclopramide to slow apomorphine's inhibition of gastric emptying, thereby accelerating gastric emptying by increasing the amplitude and duration of esophageal contractions. Consequently, it increases the resting tone of the lower esophageal sphincter while simultaneously relaxing the duodenal bulb and pyloric sphincter, thereby increasing the peristalsis of the duodenum and jejunum.[16][17]

Pharmacokinetics

Absorption: Metoclopramide is rapidly and well absorbed from the gastrointestinal tract, and peak plasma concentrations are attained about 1 to 2 hours after the oral dose. Metoclopramide is lipid-soluble, giving it a large half-life and a large volume of distribution. Its half-life can range from 4.5 hours to 8.8 hours.[18]

Distribution: The volume of distribution is high (approximately 3.5 L/kg), which suggests the extensive distribution of drugs to the tissues.[19]

Metabolism: Metoclopramide is metabolized by oxidation primarily via cytochrome P450 2D6 (CYP2D6), glucuronide, and sulfate conjugation.[20]

Excretion: In a study, approximately 85% of the radioactivity of an orally administered dose is recovered in the urine, and half of it is present as a parent or conjugated metoclopramide. Around 18–22% of the dose is recovered as free metoclopramide in urine. Metoclopramide's elimination half-life in adults with normal renal function has been reported to be ~ 6 hours. In adults with severe renal impairment, there is a reduced metoclopramide clearance, increasing the elimination half-life (7.7 to 17.8 hours).[14]

Administration

Metoclopramide is generally administered orally in a tablet or solution form. The dosage of the tablets and solutions is generally 5 to 10 mg. It is usually taken before meals and before sleep. However, it can be administered intramuscularly or intravenously in severely nauseous patients; the intravenous route takes effect much more quickly.[13] Parenteral metoclopramide is also 5 mg. Rectal administration is also an option, as is an intraperitoneal injection in patients undergoing peritoneal dialysis.[21] The USFDA also approved metoclopramide nasal spray for symptomatic relief in adults with acute and recurrent diabetic gastroparesis. The nasal formulation has a unique benefit; it can be absorbed without depending on the absorption in the state of gastroparesis, thus ensuring the delivery of a therapeutic dose of metoclopramide.[22]

Metoclopramide dosing for various indications is as follows:

Diabetic Gastroparesis: 10 mg orally/IV/IM four times daily for a maximum duration of 12 weeks; max dose is 40 mg daily. Start at 5 mg four times daily for geriatric patients. For patients who are poor CYP2D6 metabolizers, give 5 mg four times daily (30 minutes before meals and at bedtime) with a max dose of 20 mg daily.[2]

GERD (chronic): 10 to 15 mg orally/IM/IV four times daily for a maximum duration of 12 weeks; maximum dose of 60 mg daily. Start at 5 mg four times daily for geriatric patients; max dose 30 mg daily. For patients who are poor CYP2D6 metabolizers, give 5 mg four times daily (30 minutes before meals and at bedtime) or 10 mg three times daily (30 minutes before meals).

GERD (intermittent): Up to 20 mg orally/IV/IM for one dose before symptoms begin.

Prophylaxis of Chemotherapy-related Nausea and Vomiting: 1 to 2 mg/kg/dose IV every 2 to 3 hours; the first dose is given 30 minutes before starting chemotherapy, then repeated for two doses every 2 hours, then three doses every 3 hours. Pretreat with diphenhydramine to reduce extrapyramidal symptoms. Metoclopramide is not a first-line agent for this purpose.

Use in Specific Patient Populations

Patients with Hepatic Impairment: Reduce the dose of metoclopramide in patients with moderate or severe hepatic impairment (Child-Pugh B or C). The recommended dose for diabetic gastroparesis is 5 mg four times daily.

Patients with Renal Impairment: In patients with kidney failure, it is generally recommended that metoclopramide maintenance doses be reduced to avoid drug accumulation.[23] Use caution in moderate or severe renal impairment (creatinine clearance<60 mL/minute). In patients with end-stage renal disease requiring hemodialysis, the maximum recommended dose is 5 mg twice daily. Lifestyle modification in the form of smaller and more frequent meals is first-line therapy. According to the American society of nephrology guidelines, metoclopramide can be used at 2.5 mg every four hours in refractory cases.[24]

Pregnancy Considerations: Metoclopramide can cross the placental barrier. Maternal administration of metoclopramide during delivery can lead to extrapyramidal signs and methemoglobinemia in neonates. According to ACOG(The American College of Obstetricians and Gynecologists) guidelines, metoclopramide should be used only in refractory cases of nausea and vomiting during pregnancy, 5 to 10 mg every 6 to 8 hours, orally or intramuscularly, in adequately hydrated patients. The preferred pharmacological management is pyridoxine(vitamin B6) or pyridoxine in combination with doxylamine.[25]

Breastfeeding Considerations: Metoclopramide is used as a galactagogue, but the clinical value of metoclopramide in increasing milk supply is uncertain. A meta-analysis of eight clinical trials indicated that metoclopramide increased serum prolactin but did not increase milk supply. Metoclopramide use increases the risk of postpartum depression and tardive dyskinesia. Use with caution.[26]

Adverse Effects

Adverse effects of metoclopramide use include extrapyramidal symptoms.[27][28] These include the following:

Acute dystonic reactions
- Torticollis
- Trismus
- Opisthotonus
- Akathisia
- Dystonia
- Oculogyric crisis
- Laryngospasm
- Hyperprolactinemia
- Tardive dyskinesia
- Parkinson symptoms
- Neuroleptic malignant syndrome

Neuroleptic malignant syndrome is a rare adverse effect.[29] It is among the most serious adverse reactions because it manifests as follows:

Hyperthermia
Lead pipe rigidity
Leukocytosis
Elevated creatine phosphokinase levels
Altered consciousness
Symptoms of autonomic instability (potentially)

Diaphoresis
Tachycardia
Incontinence
Pallor
Irregular blood pressure or pulse
Cardiac arrhythmias

Thus, any patient on metoclopramide who develops neuroleptic malignant syndrome should have metoclopramide immediately discontinued and undergo treatment with dantrolene. These adverse effects stem from metoclopramide’s anti-dopaminergic mechanism of action. It is important to note that these adverse effects are dose-independent and generally reversible following discontinuation of the drug.[30] Furthermore, it is important to keep in mind that oculogyric crises caused by metoclopramide can resemble the following:

Seizures
Cranial nerve palsies
Paroxysmal tonic upward gaze
Encephalopathy[31]

Metoclopramide-induced hyperprolactinemia can cause the following:

Gynecomastia
Galactorrhea
Amenorrhea
Impotence
Hypogonadism

In patients with glucose-6-phosphate dehydrogenase deficiency or nicotinamide adenine dinucleotide cytochrome b5 reductase deficiency, metoclopramide can cause methemoglobinemia and sulfhemoglobinemia.[32][33] Additionally, metoclopramide can increase serum aldosterone levels, potentially causing fluid retention and volume overload. Therefore, it must be used with caution in patients with heart failure or cirrhosis of the liver.[34] Metoclopramide has also been shown to cause a non-thrombocytopenic purpuric rash that subsides upon discontinuation of the drug.[35]

Less acute adverse effects of metoclopramide, generally reversible and observed in children, include the following:

Sedation
Diarrhea[36]

Rarer psychiatric side effects that have developed following brief exposure to metoclopramide include:

Panic disorder
Major depressive disorder
Agoraphobia[37]

Drug-Drug Interactions

Reduced efficacy of dopamine agonists(like bromocriptine and cabergoline)[38] Furthermore, metoclopramide can increase serum aspirin levels by increasing the absorption of aspirin, potentially causing salicylate toxicity.[39] In addition to increasing the absorption of aspirin, metoclopramide can also increase serum levels of bupropion and its metabolite hydroxybupropion because it aids gastric emptying and thus bupropion absorption in the small intestine.[40] This can increase the serum levels of other drugs, given that bupropion and hydroxybupropion, in turn, inhibit the effects of the CYP2D6 metabolic enzyme.[41]

Concurrent administration of metoclopramide and antipsychotic drugs should be avoided due to the potential for additive effects and neuroleptic malignant syndrome(NMS).[42] Metoclopramide should not be administered with CYP2D6 inhibitors like fluoxetine as there is an increased risk of extrapyramidal symptoms.[43]

Contraindications

Metoclopramide is contraindicated in patients with the following:

Known hypersensitivity to metoclopramide or excipients[44]
Gastrointestinal bleeding
Obstruction
Perforation[30]

Other contraindications include the following:

Pheochromocytoma
Seizures
Depression
Parkinson disease

Metoclopramide is contraindicated in patients with depression because it can cause major depressive disorder.[37] It is contraindicated in patients with seizures because it lowers the seizure threshold and can result in longer and more frequent seizures.[45] It is contraindicated in patients with depression and Parkinson disease because of the aforementioned adverse effects of major depressive disorder and parkinsonian symptoms. It is contraindicated in pheochromocytoma because it releases catecholamines and can exacerbate pheochromocytoma, causing a hypertensive crisis, which can be treated with phentolamine.[46][45]

US Boxed Warning: Metoclopramide can cause tardive dyskinesia, a serious movement disorder. Tardive dyskinesia risk increases with the total treatment duration and total cumulative exposure. Therefore, avoid treatment with metoclopramide tablets for longer than 12 weeks. Discontinue metoclopramide in patients who develop clinical signs or symptoms of tardive dyskinesia. In some patients, symptoms may decrease or resolve after metoclopramide is discontinued.[47][48]

Monitoring

It is also important to note that the efficacy of metoclopramide can be diminished if the patient takes anticholinergics or narcotic analgesic medications because these drugs decrease the gastric emptying rate.[49] Metoclopramide decreases the absorption rate of drugs generally absorbed from the stomach, like digoxin, while increasing the absorption of drugs absorbed from the small intestine, like cyclosporine.[50][51]

Metoclopramide is included in the KIDS list (Key Potentially Inappropriate Drugs in Pediatrics), a reference tool to identify medications associated with a high risk for adverse drug reactions. Monitor when metoclopramide is used in pediatric patients.[52] Metocloclopramide is also recognized as a potentially inappropriate medication for older adults per the American Geriatrics Society 2019 updated Beers criteria. Monitor elderly patients for extrapyramidal symptoms and tardive dyskinesia.[53]

Toxicity

The following are the primary symptoms of metoclopramide overdose:

Sedation[54]
Diarrhea[55]
Extrapyramidal adverse effects (particularly tardive dyskinesia)[27]

Tardive dyskinesia is an adverse effect, often seen in antipsychotic medications, that generally manifests as grimacing, lip-smacking, tongue flicking, and general choreoathetoid movements of the body.[56] Because it can sometimes be irreversible, it is the most threatening potential complication of metoclopramide overdose, and metoclopramide treatment should be discontinued in any patient who develops tardive dyskinesia. Extrapyramidal adverse effects have been observed in metoclopramide overdose, particularly in infants and the elderly, who are at the most significant risk.[57] Retrospective analysis has shown that pediatric emergency room visits leading to extrapyramidal symptoms can be caused by metoclopramide syrup overdose.[58]

Though there is no specific treatment for metoclopramide overdose, its extrapyramidal effects are among the most common adverse effects. They can be alleviated with anticholinergics like benztropine and antihistamines like diphenhydramine.[59] Supportive therapy is recommended, while dialysis is generally ineffective in treating metoclopramide overdose.[23]

Enhancing Healthcare Team Outcomes

Metoclopramide is widely used in most hospitals and is an effective drug for gastroparesis and postoperative nausea and vomiting. However, the drug does have several side effects that all healthcare practitioners must be familiar with, so an interprofessional team approach is necessary. The nurse and pharmacist are in a prime position to monitor the drug and, hopefully, reduce its adverse effects by closely monitoring the patient and recommending discontinuation when symptoms arise. Of all the side effects, the most concerning are the extrapyramidal reactions that are more likely to occur in diabetics, children, seniors, and those already taking antipsychotic medications. The risk of developing tardive dyskinesia from metoclopramide varies from 1 to 15%, and the condition is quite debilitating. Hence, before using this drug, the nurse, pharmacist, and prescriber should obtain informed consent from the patient. All patients should be told about the potential for developing dyskinesias before treatment. If the patient has an adverse risk profile, the pharmacist should offer another agent option to the prescriber for consideration.

All interprofessional team members are also responsible for communicating concerns with other team members. They must also maintain accurate and updated records of their observations and interventions with the patient so that all team members have the most recent data on the case. Closely monitoring the patient is critical, and the interprofessional team, including clinicians, nursing, and pharmacy, will drive optimal outcomes.[60] [Level 5]

Outcomes

Metoclopramide has proven valuable in managing diabetic gastroparesis, postoperative nausea, and vomiting. However, the potential risk for dyskinesias has led to a re-evaluation of this agent. Experts indicate that metoclopramide should be started with the lowest possible dose and the shortest duration of time. The drug is effective in the short term, but its CNS adverse drug reactions are worrisome.[61] [Level 5]

Details

References

[1]

Rettura F, Bronzini F, Campigotto M, Lambiase C, Pancetti A, Berti G, Marchi S, de Bortoli N, Zerbib F, Savarino E, Bellini M. Refractory Gastroesophageal Reflux Disease: A Management Update. Frontiers in medicine. 2021:8():765061. doi: 10.3389/fmed.2021.765061. Epub 2021 Nov 1 [PubMed PMID: 34790683]

[2]

Shakhatreh M, Jehangir A, Malik Z, Parkman HP. Metoclopramide for the treatment of diabetic gastroparesis. Expert review of gastroenterology & hepatology. 2019 Aug:13(8):711-721. doi: 10.1080/17474124.2019.1645594. Epub 2019 Jul 30 [PubMed PMID: 31314613]

[3]

Adel N. Overview of chemotherapy-induced nausea and vomiting and evidence-based therapies. The American journal of managed care. 2017 Sep:23(14 Suppl):S259-S265 [PubMed PMID: 28978206]

Level 3 (low-level) evidence

[4]

Flank J, Robinson PD, Holdsworth M, Phillips R, Portwine C, Gibson P, Maan C, Stefin N, Sung L, Dupuis LL. Guideline for the Treatment of Breakthrough and the Prevention of Refractory Chemotherapy-Induced Nausea and Vomiting in Children With Cancer. Pediatric blood & cancer. 2016 Jul:63(7):1144-51. doi: 10.1002/pbc.25955. Epub 2016 Mar 9 [PubMed PMID: 26960036]

[5]

De Oliveira GS Jr, Castro-Alves LJ, Chang R, Yaghmour E, McCarthy RJ. Systemic metoclopramide to prevent postoperative nausea and vomiting: a meta-analysis without Fujii's studies. British journal of anaesthesia. 2012 Nov:109(5):688-97. doi: 10.1093/bja/aes325. Epub 2012 Sep 25 [PubMed PMID: 23015617]

Level 1 (high-level) evidence

[6]

Najjar M, Hall T, Estupinan B. Metoclopramide for Acute Migraine Treatment in the Emergency Department: An Effective Alternative to Opioids. Cureus. 2017 Apr 20:9(4):e1181. doi: 10.7759/cureus.1181. Epub 2017 Apr 20 [PubMed PMID: 28533997]

[7]

Eigenbrodt AK, Ashina H, Khan S, Diener HC, Mitsikostas DD, Sinclair AJ, Pozo-Rosich P, Martelletti P, Ducros A, Lantéri-Minet M, Braschinsky M, Del Rio MS, Daniel O, Özge A, Mammadbayli A, Arons M, Skorobogatykh K, Romanenko V, Terwindt GM, Paemeleire K, Sacco S, Reuter U, Lampl C, Schytz HW, Katsarava Z, Steiner TJ, Ashina M. Diagnosis and management of migraine in ten steps. Nature reviews. Neurology. 2021 Aug:17(8):501-514. doi: 10.1038/s41582-021-00509-5. Epub 2021 Jun 18 [PubMed PMID: 34145431]

[8]

Tan PC, Khine PP, Vallikkannu N, Omar SZ. Promethazine compared with metoclopramide for hyperemesis gravidarum: a randomized controlled trial. Obstetrics and gynecology. 2010 May:115(5):975-981. doi: 10.1097/AOG.0b013e3181d99290. Epub [PubMed PMID: 20410771]

Level 1 (high-level) evidence

[9]

Abas MN, Tan PC, Azmi N, Omar SZ. Ondansetron compared with metoclopramide for hyperemesis gravidarum: a randomized controlled trial. Obstetrics and gynecology. 2014 Jun:123(6):1272-1279. doi: 10.1097/AOG.0000000000000242. Epub [PubMed PMID: 24807340]

Level 1 (high-level) evidence

[10]

Akiyama M, Yanagisawa T, Yuza Y, Yokoi K, Ariga M, Fujisawa K, Hoshi Y, Eto Y. Successful treatment of Diamond-Blackfan anemia with metoclopramide. American journal of hematology. 2005 Apr:78(4):295-8 [PubMed PMID: 15795909]

[11]

Bartels M, Bierings M. How I manage children with Diamond-Blackfan anaemia. British journal of haematology. 2019 Jan:184(2):123-133. doi: 10.1111/bjh.15701. Epub 2018 Dec 4 [PubMed PMID: 30515771]

[12]

Vijayaraghavan R, Maiwall R, Arora V, Choudhary A, Benjamin J, Aggarwal P, Jamwal KD, Kumar G, Joshi YK, Sarin SK. Reversal of Feed Intolerance by Prokinetics Improves Survival in Critically Ill Cirrhosis Patients. Digestive diseases and sciences. 2022 Aug:67(8):4223-4233. doi: 10.1007/s10620-021-07185-x. Epub 2021 Aug 14 [PubMed PMID: 34392492]

[13]

Lee A, Kuo B. Metoclopramide in the treatment of diabetic gastroparesis. Expert review of endocrinology & metabolism. 2010:5(5):653-662 [PubMed PMID: 21278804]

[14]

Ge S, Mendley SR, Gerhart JG, Melloni C, Hornik CP, Sullivan JE, Atz A, Delmore P, Tremoulet A, Harper B, Payne E, Lin S, Erinjeri J, Cohen-Wolkowiez M, Gonzalez D, Best Pharmaceuticals for Children Act - Pediatric Trials Network Steering Committee. Population Pharmacokinetics of Metoclopramide in Infants, Children, and Adolescents. Clinical and translational science. 2020 Nov:13(6):1189-1198. doi: 10.1111/cts.12803. Epub 2020 May 27 [PubMed PMID: 32324313]

[15]

Sanger GJ, Andrews PLR. A History of Drug Discovery for Treatment of Nausea and Vomiting and the Implications for Future Research. Frontiers in pharmacology. 2018:9():913. doi: 10.3389/fphar.2018.00913. Epub 2018 Sep 4 [PubMed PMID: 30233361]

[16]

Ramsbottom N, Hunt JN. Studies of the effect of metoclopramide and apomorphine on gastric emptying and secretion in man. Gut. 1970 Dec:11(12):989-93 [PubMed PMID: 5511820]

[17]

Harada T, Hirosawa T, Morinaga K, Shimizu T. Metoclopramide-induced Serotonin Syndrome. Internal medicine (Tokyo, Japan). 2017:56(6):737-739. doi: 10.2169/internalmedicine.56.7727. Epub 2017 Mar 17 [PubMed PMID: 28321081]

[18]

McGovern EM, Grevel J, Bryson SM. Pharmacokinetics of high-dose metoclopramide in cancer patients. Clinical pharmacokinetics. 1986 Nov-Dec:11(6):415-24 [PubMed PMID: 3542335]

[19]

Bauer M, Barna S, Blaickner M, Prosenz K, Bamminger K, Pichler V, Tournier N, Hacker M, Zeitlinger M, Karanikas G, Langer O. Human Biodistribution and Radiation Dosimetry of the P-Glycoprotein Radiotracer [(11)C]Metoclopramide. Molecular imaging and biology. 2021 Apr:23(2):180-185. doi: 10.1007/s11307-021-01582-4. Epub 2021 Jan 22 [PubMed PMID: 33481175]

[20]

Chua EW, Harger SP, Kennedy MA. Metoclopramide-Induced Acute Dystonic Reactions May Be Associated With the CYP2D6 Poor Metabolizer Status and Pregnancy-Related Hormonal Changes. Frontiers in pharmacology. 2019:10():931. doi: 10.3389/fphar.2019.00931. Epub 2019 Aug 22 [PubMed PMID: 31507424]

[21]

Trapnell BC, Mavko LE, Birskovich LM, Falko JM. Metoclopramide suppositories in the treatment of diabetic gastroparesis. Archives of internal medicine. 1986 Nov:146(11):2278-9 [PubMed PMID: 3778059]

[22]

Gajendran M, Sarosiek I, McCallum R. Metoclopramide nasal spray for management of symptoms of acute and recurrent diabetic gastroparesis in adults. Expert review of endocrinology & metabolism. 2021 Mar:16(2):25-35. doi: 10.1080/17446651.2021.1886922. Epub 2021 Mar 19 [PubMed PMID: 33739209]

[23]

Lehmann CR, Heironimus JD, Collins CB, O'Neil TJ, Pierson WP, Crowe JT, Melikian AP, Wright GJ. Metoclopramide kinetics in patients with impaired renal function and clearance by hemodialysis. Clinical pharmacology and therapeutics. 1985 Mar:37(3):284-9 [PubMed PMID: 3971652]

[24]

Davison SN, Tupala B, Wasylynuk BA, Siu V, Sinnarajah A, Triscott J. Recommendations for the Care of Patients Receiving Conservative Kidney Management: Focus on Management of CKD and Symptoms. Clinical journal of the American Society of Nephrology : CJASN. 2019 Apr 5:14(4):626-634. doi: 10.2215/CJN.10510917. Epub 2019 Feb 28 [PubMed PMID: 30819670]

[25]

Committee on Practice Bulletins-Obstetrics. ACOG Practice Bulletin No. 189: Nausea And Vomiting Of Pregnancy. Obstetrics and gynecology. 2018 Jan:131(1):e15-e30. doi: 10.1097/AOG.0000000000002456. Epub [PubMed PMID: 29266076]

[26]

. Metoclopramide. Drugs and Lactation Database (LactMed®). 2006:(): [PubMed PMID: 30000411]

[27]

Moos DD, Hansen DJ. Metoclopramide and extrapyramidal symptoms: a case report. Journal of perianesthesia nursing : official journal of the American Society of PeriAnesthesia Nurses. 2008 Oct:23(5):292-9. doi: 10.1016/j.jopan.2008.07.006. Epub [PubMed PMID: 18926476]

Level 3 (low-level) evidence

[28]

Donnet A, Harle JR, Dumont JC, Alif Cherif A. Neuroleptic malignant syndrome induced by metoclopramide. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 1991:45(10):461-2 [PubMed PMID: 1820178]

[29]

Gupta S, Nihalani ND. Neuroleptic Malignant Syndrome: A Primary Care Perspective. Primary care companion to the Journal of clinical psychiatry. 2004:6(5):191-194 [PubMed PMID: 15514687]

Level 3 (low-level) evidence

[30]

Ponte CD, Nappi JM. Review of a new gastrointestinal drug--metoclopramide. American journal of hospital pharmacy. 1981 Jun:38(6):829-33 [PubMed PMID: 7018232]

[31]

Koban Y, Ekinci M, Cagatay HH, Yazar Z. Oculogyric crisis in a patient taking metoclopramide. Clinical ophthalmology (Auckland, N.Z.). 2014:8():567-9. doi: 10.2147/OPTH.S60041. Epub 2014 Mar 19 [PubMed PMID: 24672222]

[32]

Mary AM, Bhupalam L. Metoclopramide-induced methemoglobinemia in an adult. The Journal of the Kentucky Medical Association. 2000 Jun:98(6):245-7 [PubMed PMID: 10870338]

[33]

Tanishima K, Tanimoto K, Tomoda A, Mawatari K, Matsukawa S, Yoneyama Y, Ohkuwa H, Takazakura E. Hereditary methemoglobinemia due to cytochrome b5 reductase deficiency in blood cells without associated neurologic and mental disorders. Blood. 1985 Dec:66(6):1288-91 [PubMed PMID: 4063522]

[34]

Nagahama S, Fujimaki M, Kawabe H, Nakamura R, Saito I, Saruta T. Effect of metoclopramide on the secretion of aldosterone and other adrenocortical steroids. Clinical endocrinology. 1983 Mar:18(3):287-93 [PubMed PMID: 6861367]

[35]

Upputuri S, Prasad S. Metoclopramide-induced delayed non-thrombocytopenic purpuric rash. Clinical drug investigation. 2006:26(12):745-7 [PubMed PMID: 17274681]

[36]

Lau Moon Lin M, Robinson PD, Flank J, Sung L, Dupuis LL. The Safety of Metoclopramide in Children: A Systematic Review and Meta-Analysis. Drug safety. 2016 Jul:39(7):675-87. doi: 10.1007/s40264-016-0418-9. Epub [PubMed PMID: 27003816]

Level 1 (high-level) evidence

[37]

Anfinson TJ. Akathisia, panic, agoraphobia, and major depression following brief exposure to metoclopramide. Psychopharmacology bulletin. 2002 Winter:36(1):82-93 [PubMed PMID: 12397849]

[38]

Torre DL, Falorni A. Pharmacological causes of hyperprolactinemia. Therapeutics and clinical risk management. 2007 Oct:3(5):929-51 [PubMed PMID: 18473017]

[39]

Volans GN. The effect of metoclopramide on the absorption of effervescent aspirin in migraine. British journal of clinical pharmacology. 1975 Feb:2(1):57-63 [PubMed PMID: 791318]

[40]

Lai AA, Schroeder DH. Clinical pharmacokinetics of bupropion: a review. The Journal of clinical psychiatry. 1983 May:44(5 Pt 2):82-4 [PubMed PMID: 6406470]

[41]

Joy MS, Frye RF, Stubbert K, Brouwer KR, Falk RJ, Kharasch ED. Use of enantiomeric bupropion and hydroxybupropion to assess CYP2B6 activity in glomerular kidney diseases. Journal of clinical pharmacology. 2010 Jun:50(6):714-20. doi: 10.1177/0091270009353031. Epub 2010 Jan 26 [PubMed PMID: 20103693]

[42]

Mazhar F, Akram S, Haider N, Ahmed R. Overlapping of Serotonin Syndrome with Neuroleptic Malignant Syndrome due to Linezolid-Fluoxetine and Olanzapine-Metoclopramide Interactions: A Case Report of Two Serious Adverse Drug Effects Caused by Medication Reconciliation Failure on Hospital Admission. Case reports in medicine. 2016:2016():7128909. doi: 10.1155/2016/7128909. Epub 2016 Jun 28 [PubMed PMID: 27433163]

Level 3 (low-level) evidence

[43]

Igata R, Hori H, Atake K, Katsuki A, Nakamura J. Adding metoclopramide to paroxetine induced extrapyramidal symptoms and hyperprolactinemia in a depressed woman: a case report. Neuropsychiatric disease and treatment. 2016:12():2279-81. doi: 10.2147/NDT.S116686. Epub 2016 Sep 1 [PubMed PMID: 27621638]

Level 3 (low-level) evidence

[44]

Pietrzko P, Zakrzewski A, Matuszewski T, Kruszewski J. Angioneurotic edema: a rare case of hypersensitivity to metoclopramide. Postepy dermatologii i alergologii. 2013 Apr:30(2):117-8. doi: 10.5114/pdia.2013.34163. Epub 2013 Apr 12 [PubMed PMID: 24278059]

Level 3 (low-level) evidence

[45]

Weinstein RB, Fife D, Sloan S, Voss EA, Treem W. Prevalence of Chronic Metoclopramide Use and Associated Diagnoses in the US Pediatric Population. Paediatric drugs. 2015 Aug:17(4):331-7. doi: 10.1007/s40272-015-0136-2. Epub [PubMed PMID: 26014368]

[46]

Guillemot J, Compagnon P, Cartier D, Thouennon E, Bastard C, Lihrmann I, Pichon P, Thuillez C, Plouin PF, Bertherat J, Anouar Y, Kuhn JM, Yon L, Lefebvre H. Metoclopramide stimulates catecholamine- and granin-derived peptide secretion from pheochromocytoma cells through activation of serotonin type 4 (5-HT4) receptors. Endocrine-related cancer. 2009 Mar:16(1):281-90. doi: 10.1677/ERC-08-0190. Epub 2008 Oct 23 [PubMed PMID: 18948374]

[47]

Xu D, Ham AG, Tivis RD, Caylor ML, Tao A, Flynn ST, Economen PJ, Dang HK, Johnson RW, Culbertson VL. MSBIS: A Multi-Step Biomedical Informatics Screening Approach for Identifying Medications that Mitigate the Risks of Metoclopramide-Induced Tardive Dyskinesia. EBioMedicine. 2017 Dec:26():132-137. doi: 10.1016/j.ebiom.2017.11.015. Epub 2017 Nov 22 [PubMed PMID: 29191560]

[48]

Avalos DJ, Sarosiek I, Loganathan P, McCallum RW. Diabetic gastroparesis: current challenges and future prospects. Clinical and experimental gastroenterology. 2018:11():347-363. doi: 10.2147/CEG.S131650. Epub 2018 Sep 25 [PubMed PMID: 30310300]

[49]

Nimmo WS. Drugs, diseases and altered gastric emptying. Clinical pharmacokinetics. 1976:1(3):189-203 [PubMed PMID: 797497]

[50]

Johnson BF, Bustrack JA, Urbach DR, Hull JH, Marwaha R. Effect of metoclopramide on digoxin absorption from tablets and capsules. Clinical pharmacology and therapeutics. 1984 Dec:36(6):724-30 [PubMed PMID: 6499354]

[51]

Wadhwa NK, Schroeder TJ, O'Flaherty E, Pesce AJ, Myre SA, First MR. The effect of oral metoclopramide on the absorption of cyclosporine. Transplantation proceedings. 1987 Feb:19(1 Pt 2):1730-3 [PubMed PMID: 3547879]

[52]

Meyers RS, Thackray J, Matson KL, McPherson C, Lubsch L, Hellinga RC, Hoff DS. Key Potentially Inappropriate Drugs in Pediatrics: The KIDs List. The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG. 2020:25(3):175-191. doi: 10.5863/1551-6776-25.3.175. Epub [PubMed PMID: 32265601]

[53]

By the 2019 American Geriatrics Society Beers Criteria® Update Expert Panel. American Geriatrics Society 2019 Updated AGS Beers Criteria® for Potentially Inappropriate Medication Use in Older Adults. Journal of the American Geriatrics Society. 2019 Apr:67(4):674-694. doi: 10.1111/jgs.15767. Epub 2019 Jan 29 [PubMed PMID: 30693946]

[54]

Gralla RJ. Metoclopramide. A review of antiemetic trials. Drugs. 1983 Feb:25 Suppl 1():63-73 [PubMed PMID: 6682376]

[55]

Sewell DD, Jeste DV. Metoclopramide-associated tardive dyskinesia. An analysis of 67 cases. Archives of family medicine. 1992 Nov:1(2):271-8 [PubMed PMID: 1341603]

Level 3 (low-level) evidence

[56]

Casey DE. Tardive dyskinesia. The Western journal of medicine. 1990 Nov:153(5):535-41 [PubMed PMID: 1979705]

Level 3 (low-level) evidence

[57]

Bateman DN, Rawlins MD, Simpson JM. Extrapyramidal reactions with metoclopramide. British medical journal (Clinical research ed.). 1985 Oct 5:291(6500):930-2 [PubMed PMID: 3929968]

[58]

Chang MY, Lin KL, Wang HS, Wu CT. Drug-Induced Extrapyramidal Symptoms at the Pediatric Emergency Department. Pediatric emergency care. 2020 Oct:36(10):468-472. doi: 10.1097/PEC.0000000000001954. Epub [PubMed PMID: 31790070]

[59]

Pringsheim T, Doja A, Belanger S, Patten S, Canadian Alliance for Monitoring Effectiveness and Safety of Antipsychotics in Children (CAMESA) guideline group. Treatment recommendations for extrapyramidal side effects associated with second-generation antipsychotic use in children and youth. Paediatrics & child health. 2011 Nov:16(9):590-8 [PubMed PMID: 23115503]

[60]

Fog AF, Kvalvaag G, Engedal K, Straand J. Drug-related problems and changes in drug utilization after medication reviews in nursing homes in Oslo, Norway. Scandinavian journal of primary health care. 2017 Dec:35(4):329-335. doi: 10.1080/02813432.2017.1397246. Epub 2017 Nov 2 [PubMed PMID: 29096573]

[61]

Sridharan K, Sivaramakrishnan G. Interventions for treating nausea and vomiting in pregnancy: a network meta-analysis and trial sequential analysis of randomized clinical trials. Expert review of clinical pharmacology. 2018 Nov:11(11):1143-1150. doi: 10.1080/17512433.2018.1530108. Epub 2018 Oct 5 [PubMed PMID: 30261764]

Level 1 (high-level) evidence