Metoclopramide, Paracetamol/metoclopramide, Witch’s Milk, Lactating Men and Homicidal Maniacs?

March 21, 2023
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Metoclopramide is a medication used for stomach and esophageal problems. 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. It is also used to treat migraine headaches.

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. It is thus rarely recommended that people take the medication for longer than twelve weeks. No evidence of harm has been found after being taken by many pregnant women. It belongs to the group of medications known as dopamine-receptor antagonists and works as a prokinetic.

In 2012, metoclopramide was one of the top 100 most prescribed medications in the United States. It is available as a generic medication. It is on the World Health Organization’s List of Essential Medicines. In 2020, it was the 352nd most commonly prescribed medication in the United States, with more than 600,000 prescriptions.

Medical uses

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.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).

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

  • “Ambulance Victoria Clinical Guideline A0701”“Oxygen Therapy” (PDF). Ambulance Victoria. 2013. Archived from the original (PDF) on 12 March 2015. Retrieved 5 December 2014.

Migraine

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

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.

It is also used in gastroesophageal reflux disease.

Lactation

While metoclopramide is used to try to increase breast milk production, evidence for its effectiveness for this is poor. Its safety for this use is also unclear.

Procedures

Intravenous metoclopramide is used in small-bowel follow-through, small-bowel enema, and radionuclide gastric-emptying studies to reduce the time taken for barium to go through the intestines, thus reducing the total time needed for the procedures. Metoclopramide also prevents vomiting after oral ingestion of barium.

  • Watson N, Jones H (2018). Chapman and Nakielny’s Guide to Radiological Procedures. Elsevier. pp. 48, 55, 87. ISBN 9780702071669.

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. It is contraindicated for people with a suspected bowel obstruction, 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.

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.

Pregnancy

Metoclopramide has long been used in all stages of pregnancy with no evidence of harm to the mother or foetus. 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. A large cohort study in Denmark found, in addition, no association between metoclopramide exposure and miscarriage. Metoclopramide is excreted into milk.

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.

Side effects

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.

Metoclopramide may be the most common cause of drug-induced movement disorders. The risk of extrapyramidal effects is increased in people under 20 years of age, and with high-dose or prolonged therapy. 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. 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.

Dystonic reactions may be treated with benzatropine, diphenhydramine, trihexyphenidyl, or procyclidine. Symptoms usually subside with diphenhydramine injected intramuscularly. 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.

  • Olanow C, Schapira AV (2012). “Chapter 372. Parkinson’s Disease and Other Movement Disorders.”. In Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson J, Loscalzo J (eds.). Harrison’s Principles of Internal Medicine (18th ed.). New York, NY: McGraw-Hill.
  • “Reglan- metoclopramide hydrochloride tablet”. DailyMed. 19 June 2020. Retrieved 22 November 2020.

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.

Rare side effects

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

Panic disorder

  • Isola S, Adams N (2020). “Metoclopramide”. Statpearls. PMID 30137802.

Major depressive disorder

  • Isola S, Adams N (2020). “Metoclopramide”. Statpearls. PMID 30137802.

Agoraphobia

  • Isola S, Adams N (2020). “Metoclopramide”. Statpearls. PMID 30137802.

Agranulocytosis, supraventricular tachycardia, hyperaldosteronism, neuroleptic malignant syndrome, akathisia and tardive dyskinesia.

Methaemoglobinaemia*

Galactorrhea

Galactorrhea (also spelled galactorrhoea) is the spontaneous flow of milk from the breast, unassociated with childbirth or nursing.

Galactorrhea is reported to occur in 5–32% of women. Much of the difference in reported incidence can be attributed to different definitions of galactorrhea. Although frequently benign, it may be caused by serious underlying conditions and should be properly investigated. Galactorrhea also occurs in males, newborn infants and adolescents of both sexes.

Galactorrhea can take place as a result of dysregulation of certain hormones. Hormonal causes most frequently associated with galactorrhea are hyperprolactinemia and thyroid conditions with elevated levels (which may also suggest Pituitary disease) of thyroid-stimulating hormone (TSH) or thyrotropin-releasing hormone (TRH). No obvious cause is found in about 50% of cases.

Lactation requires the presence of prolactin, and the evaluation of galactorrhea includes eliciting a history for various medications or foods (methyldopa, opioids, antipsychotics, serotonin reuptake inhibitors) and for behavioral causes (stress, breast, and chest wall stimulation), as well as evaluation for gestation, pituitary adenomas (with overproduction of prolactin or compression of the pituitary stalk), and hypothyroidism. Adenomas of the anterior pituitary are most often prolactinomas. Overproduction of prolactin leads to cessation of menstrual periods and infertility, which may be a diagnostic clue. Galactorrhea may also be caused by hormonal imbalances owing to birth control pills.

Galactorrhea is also a side effect associated with the use of the second-generation H2 receptor antagonist cimetidine (Tagamet). Galactorrhea can also be caused by antipsychotics that cause hyperprolactinemia by blocking dopamine receptors responsible for control of prolactin release. Of these, risperidone is the most notorious for causing this complication. Case reports suggest proton-pump inhibitors have been shown to cause galactorrhea.

Galactorrhea in infants is associated with metoclopramide use in the neonatal unit.

  • Paturi, B., Ryan, R., Michienzi, K. et al. Galactorrhea with metoclopramide use in the neonatal unit. J Perinatol 29, 391–392 (2009). https://doi.org/10.1038/jp.2008.246

Witch’s Milk

Witch’s milk or neonatal milk is milk secreted from the breasts of some newborn human infants of either sex. It is thought to be caused by a combination of the effects of maternal hormones before birth, prolactin, and growth hormone passed through breastfeeding and the postnatal pituitary and thyroid hormone surge in the infant.

Breast milk production occurs in about 5% of newborns and can persist for two months though breast buds can persist into childhood. Witch’s milk is more likely to be secreted by infants born at full term, and not by prematurely born infants. The consistency of neonatal milk is estimated to be quite similar to maternal milk. Its production also may be caused by certain medications. 

Pharmacology

Pharmacodynamics

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

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. At higher doses, 5-HT3 antagonist activity may also contribute to the antiemetic effect.

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

  • Sweetman S., ed. (2004). Martindale: The Complete Drug Reference (34th ed.). London: Pharmaceutical Press. ISBN 978-0-85369-550-9.
  • Tonini M, Candura SM, Messori E, Rizzi CA (May 1995). “Therapeutic potential of drugs with mixed 5-HT4 agonist/5-HT3 antagonist action in the control of emesis”. Pharmacological Research. 31 (5): 257–260. doi:10.1016/1043-6618(95)80029-8. PMID 7479521.
  • Feldman M, Friedman LS, Brandt LJ, eds. (2010). “Ch. 43: Gastroesophageal Reflux Disease”. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease (9th ed.). Philadelphia: Saunders. ISBN 978-1-4160-6189-2.

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

Chemistry

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

History

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

A.H. Robins introduced the drug in the US under the brand name Reglan in 1979 as an injectable and an oral form was approved in 1980. in 1989 A.H. Robins was acquired by American Home Products, which changed its name to Wyeth in 2002.

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. In the US the injectable form was labelled for chemotherapy-induced nausea and the oral form was eventually labelled for gastroesophageal reflux disease.

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

The first generics were introduced in 1985.

In the early 1980s signs began to emerge in pharmacovigilance studies from Sweden that the drug was causing tardive dyskinesia in some patients. 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. In 2009 the FDA required that a black box warning be added to the label.

The emergence of this severe side effect led to a wave of product liability litigation against generic manufacturers as well as Wyeth. 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. 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. This established an “innovator liability” or “pioneer liability” for pharmaceutical companies. The precedent was not widely followed in California nor in other states. Litigation over the same issues related to metoclopramide also reached the US Supreme Court in PLIVA, Inc. v. Mensing, 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. As of August 2015 there were about 5000 suits pending across the US and efforts to consolidate them into a class action had failed.[citation needed]

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. 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. The FDA issued a draft guidance for generic companies to update labels in July 2016.

Society and culture

Brand names

AAdco-Contromet, Aeroflat (metoclopramide and dimeticone), Afipran, Anaflat Compuesto (metoclopramide and simeticone; pancreatin), Anagraine (metoclopramide and paracetamol), Anausin Métoclopramide, Anolexinon, Antiementin, Antigram (Metoclopramide and Acetylsalicylic Acid), Aswell (“Anagraine – Drugs.com”. Drugs.com. Retrieved 10 May 2020)
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 Dimethicone), 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, Meclizine, Meclomid, Meclopstad, Meniperan, Mepram, Met-Sil, Metajex, Metalon, Metamide, Metilprednisolona Richet, Metoceolat, Metoclor, Metoco, Metocol, Metocontin, Metomide (veterinary use), Metonia, 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

Paracetamol/metoclopramide

Paracetamol/metoclopramide hydrochloride is an oral fixed dose combination prescription medication containing the analgesic paracetamol (500 mg) and the anti-emetic metoclopramide hydrochloride (5 mg). Formulated as a tablet and as sachets of a water-soluble powder, it is sold under the trade name Paramax by Sanofi-Synthelabo, and in Switzerland as Migraeflux MCP, in Australia it is sold as Meteclomax and Anagraine.

The combination is used to treat the symptoms of migraine, both to relieve headache (the analgesic) and to treat associated nausea and vomiting (the antiemetic). In addition to its direct anti-emetic effect metoclopramide also stimulates gastric emptying (prokinetic), which is often delayed during migraine attacks, and accelerates the absorption of paracetamol. However the improvement in paracetamol absorption has been questioned.

The combination of metoclopramide to the paracetamol has been shown to enhance the analgesia relief when used to treat the pain of arthritis.

  • Matts SG, Boston PF (1983). “Paracetamol plus metoclopramide (‘Paramax’) as an adjunct analgesic in the treatment of arthritis”. Curr Med Res Opin. 8 (8): 547–52. doi:10.1185/03007998309109796. PMID 6653133.

Whilst the individual component drugs may be prescribed individually, as a combination, it is only available as the branded Paramax preparation in the UK. In the UK there are only two other combination analgesics with antiemetics (i.e., anti-nausea) products available: MigraMax (aspirin with metoclopramide) and the over-the-counter drug Migraleve (paracetamol and codeine for analgesia, with buclizine as the antiemetic). The role for these products is between just the use of simple analgesics (paracetamol or ibuprofen) and the triptan class of drugs; although the latter are not options during pregnancy. In the elderly although triptans are generally avoided, so too are antiemetics such as metoclopramide due to higher risks of side effects. In Australia and New Zealand, the combination is available without prescription from pharmacies.

Veterinary use

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

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Medical uses
Pharmacodynamics
Analgesics (N02A, N02B)
Non-steroidal anti-inflammatory drugs (NSAIDs) (primarily M01A and M02A, also N02BA)

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