|Systematic (IUPAC) name|
|[(2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazol-4-yl)methylamino] methanesulfonic acid|
|Trade names||Analgin, Berlosin|
|Routes||Oral, IM, IV, rectal|
|Bioavailability||100% (active metabolites)|
|Protein binding||48%-58% (active metabolites)|
|Half-life||14 minutes (parent compound; parenteral); metabolites: 2–4 hours|
|Excretion||Urine (96%, IV; 85%, oral), faeces (4%, IV).|
|CAS number||(sodium salt)|
|Mol. mass||333.337 g/mol|
|(what is this?)|
Metamizole (INN), or dipyrone (BAN, USAN), is an ampyrone sulfonate analgesic (pain reliever), antispasmodic (spasm reliever) and antipyretic (fever reducer) similar to paracetamol in that it has minimal anti-inflammatory effects and which is most commonly given orally or parenterally (by injection) to prevent and treat pain related to surgery or for the treatment of acute pain. It was first introduced into clinical use in Germany in 1921 and for many years it was available over-the-counter in most countries, until its toxicities became so readily apparent, although in some countries it is available over-the-counter, its use is usually restricted in developed countries, due to its potential for causing toxic reactions.
Metamizole is marketed under various trade names, including Algozone, Algocalmin, Algopyrin, Analgin, Dipirona, Novalgin, Neo-Melubrina and Optalgin. Metamizole has been used for decades in many European (excluding the UK, but including most of continental Europe, including Germany, Italy, Russia and Spain), Asian (China, India, Indonesia and Thailand included), African (including South Africa) and South American (including Argentina and Brazil) countries, despite this, it has been found to have a potentially fatal side effect of agranulocytosis (a dangerously compromised immune system; its rate varies significantly country-to-country), aplastic anaemia and hypersensitivity reactions (like allergic reactions such as anaphylaxis).
It was once widely combined with various other active ingredients, but since concerns over its safety have been raised in the late 1960s and 1970s its use in combination products has been in decline and in some countries, banned. Regardless, some national medical authorities (such as in Australia and United States of America) have withdrawn metamizole from the market altogether or have restricted it to be available only with a prescription, although it remains available over the counter in some countries.
Despite its potential haematologic (blood-related) toxicity (that is potential for causing blood dyscrasias) it produces no clinically relevant effects in the way of kidney toxicity, cardiovascular toxicity and GI toxicity when compared to non-steroidal anti-inflammatory drugs (NSAIDs). Unlike paracetamol and similarly to the NSAIDs it can trigger bronchospasm or anaphylaxis, especially in those with asthma.
It is primarily used for perioperative pain, although the clinical trial data to support this use is limited at best. It is also used for acute injury, colic, cancer pain, other acute/chronic forms of pain and high fever unresponsive to other agents.
Its use in pregnancy is advised against, although animal studies are reassuring in that they show minimal risk of birth defects; its use in the elderly or those with liver/kidney impairment is advised against, but if these groups of people must be treated a lower dose and caution is usually advised; its use in lactation is advised against as it is excreted in breast milk.
It is known to cause minimal side effects in most people given it; serious side effects include agranulocytosis, aplastic anaemia, hypersensitivity reactions (like anaphylaxis and bronchospasm), toxic epidermal necrolysis and it may provoke acute attacks of porphyria, as it is chemically related to sulfonamides. The relative risk for agranulocytosis appears to greatly vary according to the country of estimates on said rate.
Previous hypersensitivity (such as agranulocytosis or anaphylaxis) to metamizole or any of the excipients (e.g. lactose) in the preparation used, acute porphyria, impaired haematopoiesis (such as due to treatment with chemotherapy agents), third trimester of pregnancy (potential for adverse effects in the newborn), lactation, children with a body weight below 16 kg, history of aspirin-induced asthma and other hypersensitivity reactions to analgesics.
|Drug(s)||Interaction/reason for theoretical potential for interaction|
|Ciclosporin||Decreased serum levels of ciclosporin.|
|Chlorpromazine||Additive hypothermia (low body temperature) may result.|
|Methotrexate||Additive risk for haematologic (blood) toxicity.|
Oral anticoagulants (blood thinners), lithium, captopril, triamterene and antihypertensives may also interact with metamizole, as other pyrazolones are known to interact adversely with these substances.
It is considered fairly safe on overdose, but in these cases supportive measures are usually advised as well as measures to limit absorption (such as activated charcoal) and accelerate excretion (such as haemodialysis).
It is a sulfonic acid and comes in calcium, sodium and magnesium salt forms. Its sodium salt monohydrate form is a white/almost crystalline powder that is unstable in the presence of light, highly soluble in water and ethanol but practically insoluble in dichloromethane.
Its precise mechanism of action is unknown, although it is believed that inhibiting brain and spinal cord prostaglandin (fat-like molecules that are involved in inflammation, pain and fever) synthesis might be involved. Recently, researchers uncovered another potential mechanism involving metamizole being a prodrug. In this proposal, not yet verified by other researchers, the metamizole itself breaks down into other chemicals that are the actual active agents. The result is a couple of cannabinoid and NSAID arachidonic acid conjugates[clarification needed] (although not in the strict chemical meaning of the word) of metamizole's breakdown products. Despite this studies in animals have found that the first cannabinoid receptor is not involved in the analgesia induced by metamizole. Although it seems to inhibit fevers caused by prostaglandins, especially prostaglandin E2. It appears to produce its therapeutic effects by means of its metabolites, especially N-methyl-4-aminoantipyrine (MAA) and 4-aminoantipyrine (AA).
|Metabolite||Acronym||Biologically active?||Pharmacokinetic properties|
|MAA||Yes||Bioavailability≈90%. Plasma protein binding: 58%. Excreted in the urine as 3±1% of the initial (oral) dose|
|AA||Yes||Bioavailability≈22.5%. Plasma protein binding: 48%. Excreted in the urine as 6±3% of the initial (oral) dose|
|FAA||No||Plasma protein binding: 18%. Excretion in the urine as 23±4% of the initial oral dose|
|AAA||No||Plasma protein binding: 14%. Excretion in the urine as 26±8% of the initial oral dose|
Society and culture
Countries where it has been withdrawn from the market include: Australia, Norway, United States of America, Denmark, Saudi Arabia, Malaysia, Ghana, Nepal, Syrian Arab Republic, Yemen, Zimbabwe, Sweden, Morocco, Lithuania, Armenia, Bahrain, Ireland and Singapore; it was never approved for use in Venezuela; is prescription-only in: Philippines (extensive warning labels; oral and parenteral use still permitted), Kuwait (single ingredient only; parenteral use and only in emergencies), Italy (parenteral use only with less than or equal to one gram dose, single ingredient only; extensive warning labels), Sudan (parenteral use for limited indications only), Bangladesh (single ingredient injectable only), Egypt (single-ingredient injectables only with no more than a gram of metamizole), Belgium (single-ingredient products that must carry an easily-identifiable [even without speaking the language] warning symbol and extensive warning labels), Germany (single ingredient only; combination products withdrawn), Switzerland (single ingredients only; indicated for strong refractory pain and/or fever) Spain (single ingredient only, for specific indications; combination products withdrawn), Czech Republic, Thailand (single ingredient products only; warning labels required and restricted to limited indications), Greece (injectables only, up to a dose of 1 gram) and Peru (warning labels required); is available over-the-counter, although warning labels may be required in: Pakistan (although combination products are banned), Colombia (warning labels required), Mexico (warning labels required) and Israel (single ingredients only, injectables require suitable facilities for resuscitation). Note all these countries are listed in order of the date these respective changes were made.
- Albania: Analgina
- Argentina: Novalgina, Migral, Buscapina Compositum,
- Austria: Novalgin, Inalgon Neu. In combination with other drugs: Buscopan compositum, Spasmo-Inalgon Neu. As veterinary products: Novalgin, Buscopan compositum, Novacocc
- Barbados: Baralgin, Baralgin M
- Bolivia: Dioxadol
- Bosnia and Herzegovina: Analgin, Bosalgin
- Brazil: Novalgina, Dorflex(combined with orphenadrine citrate and caffeine), Neosaldina (combined with isometheptene mucate and caffeine), Sedalgina (combined with isometheptene mucate and caffeine), Doridina (combined with isometheptene mucate and caffeine), Migranette (combined with isometheptene mucate and caffeine), Benegrip (combined with chlorphenamine maleate and caffeine), Anador, Magnopyrol, Conmel, Difebril, Termopirona, Dipifarma, Dorona, Hynalgin, Lisador (combined with adiphenine hydrochloride and promethazine hydrochloride), Mionevrix (combined with Carisoprodol).
- Bulgaria: Analgin, Algozone, Proalgin, Hexalgin, Tonialgin, Benalgin (combined with thiamine and caffeine), Spasmalgon (combined with pitofenone and fenpiverinium)
- Chile: Dipirona, Baralgina, Piretanyl, Buscapina Compositum, Migranol, Migratam, Cinabel, Migragesic, Cefalmin, Fredol (former six combined with caffeine and ergotamine as antimigranous preparations.
- China: An Nai Jin
- Colombia: Novalgina"dipirona"
- Costa Rica: Lisalgil
- Croatia: Analgin
- Cuba: Dioxadoldipirona
- Czech Republic: Algifen (combined with pitofenone), Novalgin
- Dominican Republic: Neo-Melubrina
- Egypt: Novalgin
- Estonia: Analgin
- Finland: Litalgin (combined with pitofenone)
- France: Calmagine
- Germany: Novalgin, Analgin, Berlosin, Metalgin, Metamizol-Puren, Novaminsulfon
- Hungary: Algopyrin, Algozone, Optalgin. In combination with others drugs: Quarelin, Algopyrin Complex
- India: Novalgin
- Indonesia: Proneuron (combined with diazepam)
- Israel: Optalgin, V-DALGIN
- Italy: Novalgina
- Lithuania: Analginas L, Neoanalginas
- Republic of Macedonia: Analgin, Jakagin, Novalgetol, Refalgin, Benalgin (combined with thiamine and caffeine)
- Mexico: Neo-Melubrina, Prodolina, Conmel
- Moldova: Analgina
- Montenegro: Analgin
- Nicaragua: Novalgina
- Panama Novalgina
- Paraguay: Dolanet, Novalgina, Difebril.
- Peru: Antalgina. Novalgina
- Poland: Pyralgina, Pyralginum, Pyralgin, Pyrahexal. In combination with others drugs: Scopolan compositum, Spasmalgon, Tolargin
- Portugal: Nolotil
- Romania: Algocalmin, Algozone, Nevralgin, Novocalmin, Piafen (combined with pitofenone and fenpipramide), Queralin (combined with caffeine and drotaverine)
- Russia: Analgin, Baralgin, Spazmalgon, Tempalgin (combined with triacetonamine)
- Slovakia: Novalgin, Algifen (combined with pitophenone), Quarelin (In combination with drotaverine and caffeine)
- Slovenia: Analgin
- Serbia: Analgin, Baralgin M, Novalgetol
- Spain: Nolotil, Neo Melubrina, Algi-Mabo, Dolemicin, Lasain, Metamizol pensa, Buscapina Compositum (combination drug; metamizole is one of its components)
- Switzerland: Novalgin, Minalgin
- Turkey: Novalgin, Adepiron
- Uruguay: Novemina
- Venezuela: Novalcina, Bral
- Brayfield, A, ed. (13 December 2013). "Dipyrone". Martindale: The Complete Drug Reference. Pharmaceutical Press. Retrieved 19 April 2014.
- "Fachinformation (Zusammenfassung der Merkmale des Arzneimittels) Novaminsulfon injekt 1000 mg Lichtenstein Novaminsulfon injekt 2500 mg Lichtenstein". Winthrop Arzneimittel GmbH (in German). Zinteva Pharm GmbH. February 2013. Retrieved 19 April 2014.
- Jage, J; Laufenberg-Feldmann, R; Heid, F (20 March 2008). "Medikamente zur postoperativen Schmerztherapie: Bewährtes und Neues" [Drugs for postoperative analgesia: routine and new aspects. Part 1: non-opioids]. Der Anaesthesist (in German) 57 (4): 382–390. doi:10.1007/s00101-008-1326-x. PMID 18351305.
- United Nations Department of Economic and Social Affairs (2005). Consolidated List of Products Whose Consumption and/or Sale Have Been Banned, Withdrawn, Severely Restricted of Not Approved by Governments (12th ed.). New York: United Nations. pp. 171–5. Retrieved 2013-03-04.
- Brack, A; Rittner, HL; Schäfer (March 2004). "Nichtopioidanalgetika zur perioperativen Schmerztherapie" [Non-opioid analgesics for perioperative pain therapy. Risks and rational basis for use]. Der Anaesthesist (in German) 53 (3): 263–80. doi:10.1007/s00101-003-0641-5. PMID 15021958.
|last4=in Authors list (help)
- Rogosch, T; Sinning, C; Podlewski, A; Watzer, B; Schlosburg, J; Lichtman, AH; Cascio, MG; Bisogno, T; Di Marzo, V; Nüsing, R; Imming, P (January 2012). "Novel bioactive metabolites of dipyrone (metamizol)" (PDF). Bioorganic & Medicinal Chemistry 20 (1): 101–7. doi:10.1016/j.bmc.2011.11.028. PMC 3248997. PMID 22172309.
- ISBN 9789287175274
- Jasiecka, A; Maślanka, T; Jaroszewski, JJ (2014). "Pharmacological characteristics of metamizole". Polish Journal of Veterinary Sciences 17 (1): 207–14. PMID 24724493.
- Elmas, P; Ulugol, A (November 2013). "Involvement of cannabinoid CB1 receptors in the antinociceptive effect of dipyrone". Journal of Neural Transmission 120 (11): 1533–8. doi:10.1007/s00702-013-1052-7. PMID 23784345.
- Malvar, DD; Aguiar, FA; Vaz, AD; Assis, DC; de Melo, MC; Jabor, VA; Kalapothakis,, E; Ferreira, SH; Clososki, GC; de Souza, GE (April 2014). "The dipyrone metabolite 4-MAA induces hypothermia and inhibits PGE2-dependent and -independent fever while 4-AA only blocks PGE2 -dependent fever". British Journal of Pharmacology 171 (15): 3666–79. doi:10.1111/bph.12717. PMID 24712707.