Metamizole

Not to be confused with methimazole, the antithyroid drug

Metamizole

Systematic (IUPAC) name
Sodium [(2,3-dihydro- 1,5-dimethyl- 3-oxo- 2-phenyl- 1H- pyrazol- 4-yl) methylamino] methanesulfonate
Clinical data
AHFS/Drugs.com	International Drug Names
Pregnancy cat.	?
Legal status	?
Routes	oral, parenteral
Pharmacokinetic data
Half-life	1 - 4 hours
Excretion	renal
Identifiers
CAS number	68-89-3 Y (sodium salt)
ATC code	N02BB02
PubChem	CID 80254
DrugBank	DB04817
ChemSpider	6000 Y
UNII	VSU62Z74ON Y
ChEBI	CHEBI:59033 N
ChEMBL	CHEMBL487894 Y
Chemical data
Formula	C13H16N3NaO4S
Mol. mass	333.337 g/mol
SMILES	eMolecules & PubChem
InChI InChI=1S/C13H17N3O4S.Na/c1-10-12(14(2)9-21(18,19)20)13(17)16(15(10)3)11-7-5-4-6-8-11;/h4-8H,9H2,1-3H3,(H,18,19,20);/q;+1/p-1 Y Key:DJGAAPFSPWAYTJ-UHFFFAOYSA-M Y
N(what is this?)  (verify)

Metamizole sodium or dipyrone is a powerful analgesic and antipyretic. It is marketed under various trade names, including Algozone, Algocalmin, Analgin, Dipirona, Novalgin, Neo-Melubrina and Optalgin. Metamizole was first synthesized by the German company Hoechst AG (now part of Sanofi-Aventis) in 1920, and its mass production started in 1922. It remained available worldwide until the 1970s, when it was discovered that the drug carries a small risk of causing agranulocytosis - a potentially fatal condition. Controversy remains regarding the level of risk. Several national medical authorities have banned metamizole either totally or have restricted it to be available only on prescription, while others have maintained its availability over the counter.

Risk of agranulocytosis

According to comments by Dr. Anthony Wong of the University of São Paulo in a World Health Organization newsletter,^[1] 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 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).

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.^[2] 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 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”.^[3]

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."^[4]

When considering the data available on the risks and benefits of metamizole, it is important to note that this generic NSAID 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.^[5]

Antipyretic effect

A randomized, double blind, multinational study involving 555 children showed that metamizole and ibuprofen were significantly more effective than paracetamol in achieving normal body temperatures; metamizole produced a significantly greater temperature reduction than ibuprofen and paracetamol, and helped maintain low temperatures for a longer duration.^[6]

Media attention

Metamizole received a brief period of attention by American media in 2001,^[7] 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, 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, Egypt, India, Israel, the Republic of Macedonia, Mexico, Poland, Russia, 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%.^{[citation needed]} 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 500mg/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.

Brand names

• Albania: Analgina
• Argentina: Novalgina
• 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)
• Bulgaria: Analgin, Algozone, Proalgin, , Hexalgin, Benalgin (combined with thiamine and caffeine), Spasmalgon (combined with pitofenone and fenpiverinium)
• Chile: Dipirona, Baralgina
• China: An Nai Jin
• Colombia: Novalgina"buscapina"
• Costa Rica: Lisalgil
• Croatia: Analgin
• Czech Republic: Algifen (combined with pitofenone)
• Dominican Republic: Neo-Melubrina
• Egypt: Novalgin
• Estonia: Analgin
• Finland: Litalgin (combined with pitofenone)
• Germany: Novalgin, Analgin, Berlosin, Metalgin, Metamizol-Puren, Novaminsulfon
• Hungary: Algopyrin, Algozone, Novalgin, Novamid, Panalgorin. In combination with others drugs: Quarelin, Ridol
• India: Novalgin
• Indonesia: Proneuron (combined with diazepam)
• Israel: Optalgin, V-DALGIN
• Italy: Novalgina
• Lithuania: Analginas L, Neoanalginas
• Macedonia: Analgin, Jakagin, Novalgetol, Refalgin
• Mexico: Neo-Melubrina, Prodolina, Conmel
• Nicaragua: Novalgina
• Panama Novalgina
• Paraguay: Dolanet, Novalgina, Difebril.
• Peru: Repriman. Novalgina, Buscapina.
• Poland: Pyralgina, Pyralginum, Pyralgin, Pyrahexal. In combination with others drugs: Scopolan compositum, Spasmalgon, Tolargin
• Portugal: Nolotil
• Romania: Algocalmin, Algozone, Nevralgin, Novocalmin, Piafen
• 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

References

1. ^ Dr. Anthony Wong in WHO Pharmaceuticals Newsletter No. 1, 2002, p.15
2. ^ Andrade SE, Martinez C, Walker AM. Comparative safety evaluation of non-narcotic analgesics. J Clin Epidemiol 1998; 51: 1357-1365.
3. ^ CCIOMS WORKING GROUP IV – Geneva, 1998 – Benefit-Risk Balance of Marketed Drugs: Evaluating Drug Signals.
4. ^ Bäckström, M; Hägg S, Mjörndal T, Dahlqvist R (April–May 2002). "Utilization pattern of metamizole in northern Sweden and risk estimates of agranulocytosis". http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=PubMed&list_uids=12051124&dopt=AbstractPlus. Retrieved 2007-08-21. 
5. ^ The Pharmaceutical Industry — Prices and Progress. F.M. Scherer, Ph.D. N Engl J Med 2004; 351:927-932August 26, 2004
6. ^ 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.
7. ^ Metamizole Use by Latino Immigrants: A Common and Potentially Harmful Home Remedy