|Systematic (IUPAC) name|
|sodium [(2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazol-4-yl)methylamino] methanesulfonate|
|Legal status||Varies by country (see article)|
|CAS number||(sodium salt)|
|Mol. mass||333.337 g/mol|
| (what is this?)
Metamizole (INN), or dipyrone, is an analgesic (pain reliever) and antipyretic (fever reducer). Metamizole sodium is marketed under various trade names, including Algozone, Algocalmin, Algopyrin, Analgin, Dipirona, Novalgin, Neo-Melubrina and Optalgin. Metamizole was first synthesized by the German company Hoechst AG (now part of Sanofi) in 1920, and its mass production started in 1922. It remained available worldwide until the 1970s, when it was linked with a small risk of causing agranulocytosis, a potentially fatal condition. Those results have been disputed in meta-analyses conducted in the 2000s. Regardless, several national medical authorities have withdrawn metamizole from the market altogether or have restricted it to be available only with a prescription, although it remains available over the counter in many countries.
Risk of agranulocytosis
According to comments made in 2002 by Dr. Anthony Wong of the University of São Paulo in a World Health Organization newsletter, recent studies estimate that the incidence rate of metamizole-induced agranulocytosis is between 0.2 and 2 cases per million person days of use, with approximately 7% of all cases fatal (provided that all patients have access to urgent medical care). In other words, one should expect 60 to 600 deaths annually due to metamizole in a country of 300 million, assuming that every citizen takes the drug once a month. This is not a very high rate compared to other drugs - for example, the prescription drug clozapine is known to be at least 50 times more likely to trigger agranulocytosis. However, at the time[clarification needed] the risk was assumed to be much greater and, as such, excessive for an over-the-counter analgesic, especially considering the existence of safer alternatives (e.g., aspirin and ibuprofen).[clarification needed]
In 1998, Andrade et al. conducted a meta-analysis to compare epidemiologic studies from 1975 to 1995 and estimated that the excess mortality per million from community acquired cases of agranulocytosis, aplastic anaemia, anaphylaxis and serious upper gastrointestinal complications was 592 for diclofenac, 185 for aspirin, 25 for metamizole, and 20 for paracetamol. CIOMS IV in the same year reported the excess mortality risk for the same conditions to be: diclofenac = 5.92; aspirin = 2.03; metamizole = 0.20; and paracetamol=0.25. These studies certainly suggest that the risks from adverse reactions to metamizole are similar to those posed by paracetamol, a drug widely reputed to be fairly safe. According to the CIOMS IV conclusion “Newer methods of epidemiological studies have shown that the risk of agranulocytosis (1.7 per million) due to metamizole was exaggerated in the 70’s”.
A study in Sweden published in 2002 estimated the total risk during metamizole therapy for patients in hospitals (inpatients) and outside of hospital (outpatients) about 3 to 100 times greater than that estimated by Dr. Wong: "Given certain assumptions including the actual amounts prescribed the calculated risks of agranulocytosis would be approximately one out of every 31,000 metamizole-treated inpatients and one of every 1400 metamizole-treated outpatients."
When considering the data available on the risks and benefits of metamizole, it is noteworthy that this generic non-steroidal anti-inflammatory drug is very inexpensive when compared to newer COX-2 selective preparations. This has the potential to reduce profits for pharmaceutical companies, theoretically producing financial motivation for its discontinuation.
A randomized, double blind, multinational study involving 555 children showed that metamizole was significantly more effective than ibuprofen in achieving normal body temperatures; metamizole produced a significantly greater temperature reduction than ibuprofen, and helped maintain low temperatures for a longer duration.
Metamizole received a brief period of attention by American media in 2001, when a Latino boy was admitted into a Salt Lake City clinic with symptoms of agranulocytosis. It was discovered that the drug remained freely available in Latino shops and highly popular among Mexican immigrants, despite the ban. The ongoing "LATIN" Study, a multicenter international case-control study, is examining the incidence of agranulocytosis in Latin America and the role of metamizole.
Availability around the world
Metamizole was banned in Sweden in 1974, and in the United States in 1977. Since then, more than 30 countries (including Japan, Australia, Iran, and several of the European Union member nations) have followed suit. In these countries, metamizole is still occasionally used as a veterinary drug. In Germany, Austria, Hungary, Italy, Portugal and Spain it is a prescription drug. Some European pharmaceutical companies, notably Hoechst and Merck Serono, continue to develop metamizole-containing drugs and market them in some countries. In Sweden, the ban was lifted in 1995 only to be re-introduced in 1999.
In other countries including Brazil, Bulgaria, Chile, Egypt, Israel, the Republic of Macedonia, Mexico, Poland, Russia, Cuba, Spain and Turkey, metamizole is still widely available over-the-counter, remains one of the most popular analgesics, and plays an important role in self-medication. For example, metamizole and metamizole-containing drugs account for 80% of OTC analgesic market in Russia, whereas ibuprofen accounts for 2.5%. In Israel, metamizole is often used as a first line analgesic in hospitals. As of April 1, 2011, drugs containing metamizole cannot be sold over the counter in Romania.
In Brazil, metamizole products, although over-the-counter, carry warnings to avoid usage by those under 19 years old, and include some information about early detection and treatment of agranulocytosis. Metamizole is widely used in Brazil, from pediatrics (specially the drops 500 mg/ml presentations) to geriatrics (tablets and intravenous). It has such high usage in Brazil, that in late 2008 Sanofi-Aventis released a new version of the product with 1 g of metamizole per tablet (twice the normal 500 mg dosage available before), still under the Novalgina name.
In Argentina it is available over the counter
- 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: Dioxadol
- Czech Republic: Algifen (combined with pitofenone), Novalgin
- Dominican Republic: Neo-Melubrina
- Egypt: Novalgin
- Estonia: Analgin
- Finland: Litalgin (combined with pitofenone)
- 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
- Macedonia: Analgin, Jakagin, Novalgetol, Refalgin, Benalgin (combined with thiamine and caffeine)
- Mexico: Neo-Melubrina, Prodolina, Conmel
- 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
- Turkey: Novalgin, Adepiron
- Uruguay: Novemina
- Venezuela: Novalgina, Bral
- Andrade SE, Martinez C, Walker AM. Comparative safety evaluation of non-narcotic analgesics. J Clin Epidemiol 1998; 51: 1357-1365.
- CCIOMS WORKING GROUP IV – Geneva, 1998 – Benefit-Risk Balance of Marketed Drugs: Evaluating Drug Signals.
- 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.
- Dr. Anthony Wong in WHO Pharmaceuticals Newsletter No. 1, 2002, p.15
- Bäckström, M; Hägg S, Mjörndal T, Dahlqvist R (April–May 2002). "Utilization pattern of metamizole in northern Sweden and risk estimates of agranulocytosis". Retrieved 2007-08-21.
- The Pharmaceutical Industry — Prices and Progress. F.M. Scherer, Ph.D. N Engl J Med 2004; 351:927-932August 26, 2004
- Wong A, Sibbald A, Ferrero F et al. Antipyretic effects of dipyrone versus ibuprofen versus acetaminophen in children: results of a multinational, randomized, modified double blind study. Clin Pediatr 2001; 40: 313-324.
- Metamizole Use by Latino Immigrants: A Common and Potentially Harmful Home Remedy
- FDA Information regarding Dipyrone (Metamizole) http://www.dipyrone.com/fda_info.html
- Rupali Mukherjee (Jun 27, 2013). "Govt bans popular diabetes drug and analgin". Times of India. Retrieved 28 June 2013.