Metoclopramide

Metoclopramide is a medication used mostly for stomach and esophageal problems.[2] It is commonly used to treat and prevent nausea and vomiting, to help with emptying of the stomach in people with delayed stomach emptying, and to help with gastroesophageal reflux disease.[3] It is also used to treat migraine headaches.[4]

Metoclopramide
Clinical data
Pronunciation/ˌmɛtəˈklɒprəmaɪd/
Trade namesPrimperan, Reglan, others[1]
AHFS/Drugs.comMonograph
MedlinePlusa684035
License data
Pregnancy
category
  • AU: A
  • US: B (No risk in non-human studies)
    Routes of
    administration    		By mouth, intravenous, intramuscular
    Drug classD2 receptor antagonist; 5-HT3 receptor antagonist; 5-HT4 receptor agonist; Prolactin releaser
    ATC code
    Legal status
    Legal status
    • AU: S3 (combination with paracetamol), S4 (alone)
    • CA: ℞-only
    • UK: POM (Prescription only)
    • US: ℞-only
    Pharmacokinetic data
    Bioavailability80 ± 15% (by mouth)
    MetabolismLiver
    Elimination half-life5–6 hours
    ExcretionUrine: 70–85%
    Feces: 2%
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    CompTox Dashboard (EPA)
    ECHA InfoCard100.006.058
    Chemical and physical data
    FormulaC14H22ClN3O2
    Molar mass299.80 g·mol−1
    3D model (JSmol)
    Melting point147.3 °C (297.1 °F)
      (verify)

    Common side effects include: feeling tired, diarrhea, and feeling restless. More serious side effects include: movement disorder like tardive dyskinesia, a condition called neuroleptic malignant syndrome, and depression.[3] It is thus rarely recommended that people take the medication for longer than twelve weeks.[3] No evidence of harm has been found after being taken by many pregnant women.[3][5] It belongs to the group of medications known as dopamine-receptor antagonists and works as a prokinetic.[3]

    In 2012, metoclopramide was one of the top 100 most prescribed medications in the United States.[6] It is on the World Health Organization's List of Essential Medicines, the safest and most effective medicines needed in a health system.[7] It is available as a generic medication.[3] The wholesale cost in the developing world as of 2014 is US$0.003 to US$0.08 per pill.[8] In the United States a month worth of medication is generally less than US$25.[9] In 2016 it was the 250th most prescribed medication in the United States with more than 1 million prescriptions.[10]

    Medical uses
    Metoclopramide 5-mg tablets

    Nausea

    Metoclopramide is commonly used to treat nausea and vomiting associated with conditions such as uremia, radiation sickness, cancer and the effects of chemotherapy, labor, infection, and emetogenic drugs.[3][11][12][13] As a perioperative anti-emetic, the effective dose is usually 25 to 50 mg (compared to the usual 10 mg dose).

    It is also used in pregnancy as a second choice for treatment of hyperemesis gravidarum (severe nausea and vomiting of pregnancy).[3]

    It is also used preventatively by some EMS providers when transporting people who are conscious and spinally immobilized.[14]

    Migraine

    In migraine headaches, metoclopramide may be used in combination with paracetamol (acetaminophen) or in combination with aspirin.[15]

    Gastroparesis

    Evidence also supports its use for gastroparesis, a condition that causes the stomach to empty poorly, and as of 2010 it was the only drug approved by the FDA for that condition.[3][16]

    It is also used in gastroesophageal reflux disease.[3][17]

    Lactation

    While metoclopramide is used to try to increase breast milk production, evidence that it is effective for this is poor.[18] Its safety for this use is also unclear.[19]

    Contraindications

    Metoclopramide is contraindicated in pheochromocytoma. It should be used with caution in Parkinson's disease since, as a dopamine antagonist, it may worsen symptoms. Long-term use should be avoided in people with clinical depression, as it may worsen one's mental state.[12] It is contraindicated for people with a suspected bowel obstruction,[3] in epilepsy, if a stomach operation has been performed in the previous three or four days, if the person has ever had bleeding, perforation or blockage of the stomach, and in newborn babies.[13]

    The safety of the drug was reviewed by the European Medicines Agency in 2011, which determined that it should not be prescribed in high doses, for periods of more than five days, or given to children below 1 year of age. They suggested its use in older children should be restricted to treating post-chemotherapy or post-surgery nausea and vomiting, and even then only for patients where other treatments have failed. For adults, they recommended its use be restricted to treating migraines and post-chemotherapy or post-surgery patients.[20]

    Pregnancy

    Metoclopramide has long been used in all stages of pregnancy with no evidence of harm to the mother or unborn baby.[21] In the US, it has been assigned to pregnancy category B by the US FDA.[22] A large cohort study of babies born to Israeli women exposed to metoclopramide during pregnancy found no evidence that the drug increases the risk of congenital malformations, low birth weight, preterm birth, or perinatal mortality.[23] A large cohort study in Denmark found, in addition, no association between metoclopramide exposure and miscarriage.[24] Metoclopramide is excreted into milk.[21]

    Infants

    A systematic review found a wide range of reported outcomes for treatment of gastroesophageal reflux disease (GERD) in infants and concluded a "poor" rating of evidence and "inconclusive" rating of safety and efficacy for the treatment of GERD in infants.[25]

    Side effects
    Plastic ampoule of metoclopramide

    Common adverse drug reactions (ADRs) associated with metoclopramide therapy include restlessness (akathisia), and focal dystonia. Infrequent ADRs include hypertension, hypotension, hyperprolactinaemia leading to galactorrhea, headache, and extrapyramidal effects such as oculogyric crisis.[12][26]

    Metoclopramide may be the most common cause of drug-induced movement disorders.[27] The risk of extrapyramidal effects is increased in people under 20 years of age, and with high-dose or prolonged therapy.[11][12] Tardive dyskinesia may be persistent and irreversible in some people. The majority of reports of tardive dyskinesia occur in people who have used metoclopramide for more than three months.[27] Consequently, the US Food and Drug Administration (FDA) recommends that metoclopramide be used for short-term treatment, preferably less than 12 weeks. In 2009, the FDA required all manufacturers of metoclopramide to issue a black box warning regarding the risk of tardive dyskinesia with chronic or high-dose use of the drug.[27]

    Dystonic reactions may be treated with benzatropine, diphenhydramine, trihexyphenidyl, or procyclidine. Symptoms usually subside with diphenhydramine injected intramuscularly.[17] Agents in the benzodiazepine class of drugs may be helpful, but benefits are usually modest and side effects of sedation and weakness can be problematic.[28]

    In some cases, the akathisia effects of metoclopramide are directly related to the infusion rate when the drug is administered intravenously. Side effects were usually seen in the first 15 min after the dose of metoclopramide.[29]


    Rare side effects

    Diabetes, age, and female gender are risk factors that increase the likelihood of experiencing a neuropsychiatric side effect of metoclopramide.[30]

    Pharmacology

    Pharmacodynamics

    Metoclopramide appears to bind to dopamine D2 receptors with nanomolar affinity (Ki = 28.8 nM),[32] where it is a receptor antagonist, and is also a mixed 5-HT3 receptor antagonist/5-HT4 receptor agonist.[30]

    Mechanism of action

    The antiemetic action of metoclopramide is due to its antagonist activity at D2 receptors in the chemoreceptor trigger zone in the central nervous system — this action prevents nausea and vomiting triggered by most stimuli.[33] At higher doses, 5-HT3 antagonist activity may also contribute to the antiemetic effect.[34]

    The gastroprokinetic activity of metoclopramide is mediated by muscarinic activity, D2 receptor antagonist activity, and 5-HT4 receptor agonist activity.[35][36] The gastroprokinetic effect itself may also contribute to the antiemetic effect. Metoclopramide also increases the tone of the lower esophageal sphincter.[37]

    Metoclopramide might influence on mood because of its blockade action on 5-HT4 and 5-HT3.[30]

    Chemistry

    Metoclopramide is a substituted benzamide; cisapride and mosapride are structurally related.[34]

    History

    Metoclopramide was first described by Louis Justin-Besançon and Charles Laville in 1964, while working to improve the anti-dysrhythmic properties of procainamide.[38][39][40][41] That research project also produced the product sulpiride.[38] The first clinical trials were published by Tourneu et al. in 1964 and by Boisson and Albot in 1966.[41] Justin-Besançon and Laville worked for Laboratoires Delagrange[38] and that company introduced the drug as Primperan in 1964.[42][43] Laboratoires Delagrange was acquired by Synthelabo in 1991[44][45] which eventually became part of Sanofi.[46]

    A.H. Robins introduced the drug in the US under the tradename Reglan in 1979[47] as an injectable[48] and an oral form was approved in 1980.[49] in 1989 A.H. Robins was acquired by American Home Products,[50] which changed its name to Wyeth in 2002.[51]

    The drugs were initially used to control nausea for people with severe headaches or migraines, and later uses for nausea caused by radiation therapy and chemotherapy, and later yet for treating nausea caused by anesthesia.[41] In the US the injectable form was labelled for chemotherapy-induced nausea and the oral form was eventually labelled for gastroesophageal reflux disease.[52]

    It became widely used in the 1980s, becoming the most commonly used drug to treat anesthesia-induced nausea[41] and for treating gastritis in emergency rooms.[53]

    The first generics were introduced in 1985.[52][54]

    In the early 1980s signs began to emerge in pharmacovigilance studies from Sweden that the drug was causing tardive dyskinesia in some patients.[55] The FDA required a warning about tardive dyskinesia to be added to the drug label in 1985 stating that: "tardive dyskinesia . . . may develop in patients treated with metoclopramide,” and warned against use longer than 12 weeks, as that was how long the drug has been tested.[56][57] In 2009 the FDA required that a black box warning be added to the label.[16][27]

    The emergence of this severe side effect led to a wave of product liability litigation against generic manufacturers as well as Wyeth.[58] The litigation was complicated since there was a lack of clarity in jurisdiction between state laws, where product liability is determined, and federal law, which determines how drugs are labelled, as well as between generics companies, which had no control over labelling, and the originator company, which did.[58][59] The litigation yielded at least two important cases. In Conte v. Wyeth in the California state courts, the claims of the plaintiff against the generic companies Pliva, Teva, and Purepac that had sold the drugs that the plaintiff actually took, and the claims against Wyeth, whose product the plaintiff never took, were all dismissed by the trial court, but the case was appealed, and in 2008 the appellate court upheld the dismissal of the cases against the generic companies, but reversed on Wyeth, allowing the case against Wyeth to proceed.[58][59][60] This established an "innovator liability" or "pioneer liability" for pharmaceutical companies.[58] The precedent was not widely followed in California nor in other states.[59] Litigation over the same issues related to metoclopramide also reached the US Supreme Court in PLIVA, Inc. v. Mensing,[61][62] in which the court held in 2011 that generic companies cannot be held liable for information, or the lack of information, on the originator's label.[57][59][63] As of August 2015 there were about 5000 suits pending across the US and efforts to consolidate them into a class action had failed.

    Shortly following the Pliva decision, the FDA proposed a rule change that would allow generics manufacturers to update the label if the originating drug had been withdrawn from the market for reasons other than safety.[64] As of May 2016 the rule, which turned out to be controversial since it would open generic companies to product liability suits, was still not finalized, and the FDA had stated the final rule would be issued in April 2017.[65] The FDA issued a draft guidance for generic companies to update labels in July 2016.[66]

    Society and culture

    Brand names
    List of trade names for metoclopramide[1][67]
    AAdco-Contromet, Aeroflat (Metoclopramide and Dimeticone), Afipran, Anaflat Compuesto (Metoclopramide and Simeticone; Pancreatin), Anausin Métoclopramide, Anolexinon, Antiementin, Antigram (Metoclopramide and Acetylsalicylic Acid), Aswell
    BBalon, Betaclopramide, Bio-Metaclopramide, Bitecain AA
    CCarnotprim, Carnotprim, Cephalgan (Metoclopramide and Carbasalate Calcium), Cerucal, Chiaowelgen, Chitou, Clifar (Metoclopramide and Simeticone), Clodaset (Metoclopramide and Ondansetron), Clodoxin (Metoclopramide and Pyridoxine), Clomitene, Clopamon, Clopan, Cloperan, Cloprame, Clopramel, Clozil
    DDamaben, Degan, Delipramil, Di-Aero OM (Metoclopramide and Simeticone), Dibertil, Digenor (Metoclopramide and Dimeticone), Digespar (Metoclopramide and Simeticone), Digestivo S. Pellegrino, Dikinex Repe (Metoclopramide and Pancreatin), Dirpasid, Doperan, Dringen
    EEgityl (Metoclopramide and Acetylsalicylic Acid), Elieten, Eline, Elitan, Emenil, Emeprid (veterinary use), Emeran, Emetal, Emoject, Emperal, Enakur, Enteran, Enzimar, Espaven M.D. (Metoclopramide and Dimeticone), Ethiferan, Eucil
    FFactorine (Metoclopramide and Simeticone)
    GGastro-Timelets, Gastrocalm, Gastronerton, Gastrosil, Geneprami
    HH-Peran, Hawkperan, Hemibe, Horompelin
    IImperan, Isaprandil, Itan
    J
    KK.B. Meta, Klometol, Klopra
    LLexapram, Linperan, Linwels
    MMalon, Manosil, Maril, Matolon, Maxeran, Maxolon, Maxolone, Meclam, Meclid, Meclomid, Meclopstad, Meniperan, Mepram, Met-Sil, Metajex, Metalon, Metamide, Metilprednisolona Richet, Metoceolat, Metoclor, Metoco, Metocol, Metocontin, Metomide (veterinary use), Metopar (Metoclopramide and Paracetamol), Metopar (Metoclopramide and Paracetamol), Metopelan, Metoperan, Metoperon, Metopran, Metotag, Metozolv, Metpamid, Metsil, Mevaperan, Midatenk, Migaura (Metoclopramide and Paracetamol), Migpriv (Metoclopramide and Acetylsalicylic Acid), Migracid (Metoclopramide and Paracetamol), Migraeflux MCP (Metoclopramide and Paracetamol), Migrafin (Metoclopramide and Aspirin), Migralave + MCP (Metoclopramide and Paracetamol), MigraMax (Metoclopramide and Acetylsalicylic Acid), Migräne-Neuridal (Metoclopramide and Paracetamol), Migränerton (Metoclopramide and Paracetamol), Motilon
    NN-Metoclopramid, Nastifran, Nausil, Nevomitan, Nilatika, Novomit
    OOpram
    PPacimol-M (Metoclopramide and Paracetamol), Pangastren (Metoclopramide and Simeticone), Paramax (Metoclopramide and Paracetamol), Paspertin, Peraprin, Perinorm, Perinorm-MPS (Metoclopramide and Dimeticone), Perone, Piralen, Plamide, Plamine, Plasil, PMS-Metoclopramide, Podokedon, Polun, Poriran, Pradis, Pramidin, Pramidyl, Pramin, Praux, Premig (Metoclopramide and Acetylsalicylic Acid), Premosan, Prenderon, Prevomic, Primadol (Metoclopramide and Paracetamol), Primavera-N, Premier, Primlan, Primperan, Primperil, Primperoxane (Metoclopramide and Dimeticone), Primram, Primran, Primsel, Pripram, Prokinyl, Promeran, Prometin, Prowel, Pulin, Pulinpelin, Pulperan, Pusuan, Putelome, Pylomid
    Q
    RR-J, Raclonid, Randum, Reglan, Reglomar, Reliveran, Remetin, Riamide, Rilaquin, Rowelcon
    SSabax Metoclopramide, Sinprim, Sinthato, Soho, Indonesia, Sotatic, Stomallin, Suweilan
    TTalex (Metoclopramide and Pancreatin), Tivomit, Tomit, Torowilon
    U
    VVertivom, Vilapon, Vitamet, Vomend (veterinary use), Vomesea, Vomiles, Vomipram, Vomitrol, Vosea
    WWei Lian, Winperan
    X
    Y
    ZZudaw

    Veterinary use

    Metoclopramide is also commonly used to prevent vomiting in cats and dogs. It is also used as a gut stimulant in rabbits.[68]

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