Metamizole
Encyclopedia
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
.
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 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
. 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”.
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 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.
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.
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%. 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.
In Argentina it is available as a prescription drug.
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....
and antipyretic
Antipyretic
Antipyretics ; an-tee-pahy-ret-iks; from the Greek anti, against, and pyreticus, are drugs or herbs that reduce fever. Normally, they will not lower body temperature if one does not have a fever. Antipyretics cause the hypothalamus to override an interleukin-induced increase in temperature...
. 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
Hoechst AG
Hoechst AG was a German chemicals then life-sciences company that became Aventis Deutschland after its merger with France's Rhône-Poulenc S.A. in 1999...
(now part of Sanofi-Aventis
Sanofi-Aventis
Sanofi S.A. is a multinational pharmaceutical company headquartered in Paris, France, the world's fourth-largest by prescription sales. Sanofi engages in the research and development, manufacturing and marketing of pharmaceutical products for sale principally in the prescription market, but the...
) 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
Agranulocytosis
Granulopenia, also known as Agranulosis or Agranulocytosis, is an acute condition involving a severe and dangerous leukopenia , most commonly of neutrophils causing a neutropenia in the circulating blood. It represents a severe lack of one major class of infection-fighting white blood cells...
- 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
Over-the-counter drug
Over-the-counter drugs are medicines that may be sold directly to a consumer without a prescription from a healthcare professional, as compared to prescription drugs, which may be sold only to consumers possessing a valid prescription...
.
Risk of agranulocytosis
According to comments by Dr. Anthony Wong of the University of São PauloUniversity of São Paulo
Universidade de São Paulo is a public university in the Brazilian state of São Paulo. It is the largest Brazilian university and one of the country's most prestigious...
in a World Health Organization
World Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...
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
Clozapine
Clozapine is an antipsychotic medication used in the treatment of schizophrenia, and is also used off-label in the treatment of bipolar disorder. Wyatt. R and Chew...
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
Aspirin
Aspirin , also known as acetylsalicylic acid , is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication. It was discovered by Arthur Eichengrun, a chemist with the German company Bayer...
and ibuprofen
Ibuprofen
Ibuprofen is a nonsteroidal anti-inflammatory drug used for relief of symptoms of arthritis, fever, as an analgesic , especially where there is an inflammatory component, and dysmenorrhea....
).
In 1998, Andrade et al. conducted a meta-analysis
Meta-analysis
In statistics, a meta-analysis combines the results of several studies that address a set of related research hypotheses. In its simplest form, this is normally by identification of a common measure of effect size, for which a weighted average might be the output of a meta-analyses. Here the...
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
Anaphylaxis
Anaphylaxis is defined as "a serious allergic reaction that is rapid in onset and may cause death". It typically results in a number of symptoms including throat swelling, an itchy rash, and low blood pressure...
and serious upper gastrointestinal complications was 592 for diclofenac
Diclofenac
Diclofenac is a non-steroidal anti-inflammatory drug taken to reduce inflammation and as an analgesic reducing pain in certain conditions....
, 185 for aspirin, 25 for metamizole, and 20 for paracetamol
Paracetamol
Paracetamol INN , or acetaminophen USAN , is a widely used over-the-counter analgesic and antipyretic . It is commonly used for the relief of headaches and other minor aches and pains and is a major ingredient in numerous cold and flu remedies...
. 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”.
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 important to note that this generic NSAID is very inexpensive when compared to newer COX-2
PTGS2
Prostaglandin-endoperoxide synthase 2, also known as cyclooxygenase-2 or simply COX-2, is an enzyme that in humans is encoded by the PTGS2 gene.- History :...
selective preparations. This has the potential to reduce profits for pharmaceutical companies, theoretically producing financial motivation for its discontinuation.
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.Media attention
Metamizole received a brief period of attention by American media in 2001, when a LatinoHispanic and Latino Americans
Hispanic or Latino Americans are Americans with origins in the Hispanic countries of Latin America or in Spain, and in general all persons in the United States who self-identify as Hispanic or Latino.1990 Census of Population and Housing: A self-designated classification for people whose origins...
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 veterinaryVeterinary medicine
Veterinary Medicine is the branch of science that deals with the prevention, diagnosis and treatment of disease, disorder and injury in non-human animals...
drug. In Germany, Hungary, Italy, Portugal and Spain it is a prescription drug. Some European pharmaceutical companies, notably Hoechst and Merck Serono
Merck Serono
Merck Serono is a pharmaceutical company headquartered in Geneva, Switzerland. In September 2006, Merck KGaA announced its intent to purchase the majority of Serono shares from Ernesto Bertarelli and the Bertarelli family. The Merck-Serono merger was announced on September 21, 2006...
, 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%. 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.
In Argentina it is available as a prescription drug.
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 orphenadrineOrphenadrineOrphenadrine is an anticholinergic drug of the ethanolamine antihistamine class with prominent CNS and peripheral actions used to treat painful muscle spasms, other similar conditions, as well as the treatment...
citrateCitrateA citrate can refer either to the conjugate base of citric acid, , or to the esters of citric acid. An example of the former, a salt is trisodium citrate; an ester is triethyl citrate.-Other citric acid ions:...
and caffeineCaffeineCaffeine is a bitter, white crystalline xanthine alkaloid that acts as a stimulant drug. Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants...
), Neosaldina (combined with isomethepteneIsomethepteneIsometheptene is a sympathomimetic amine sometimes used in the treatment of migraines and tension headaches due to its vasoconstricting properties, that is, it causes constriction of blood vessels...
mucate and caffeineCaffeineCaffeine is a bitter, white crystalline xanthine alkaloid that acts as a stimulant drug. Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants...
), Sedalgina (combined with isomethepteneIsomethepteneIsometheptene is a sympathomimetic amine sometimes used in the treatment of migraines and tension headaches due to its vasoconstricting properties, that is, it causes constriction of blood vessels...
mucate and caffeineCaffeineCaffeine is a bitter, white crystalline xanthine alkaloid that acts as a stimulant drug. Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants...
), Doridina (combined with isomethepteneIsomethepteneIsometheptene is a sympathomimetic amine sometimes used in the treatment of migraines and tension headaches due to its vasoconstricting properties, that is, it causes constriction of blood vessels...
mucate and caffeineCaffeineCaffeine is a bitter, white crystalline xanthine alkaloid that acts as a stimulant drug. Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants...
), Migranette (combined with isomethepteneIsomethepteneIsometheptene is a sympathomimetic amine sometimes used in the treatment of migraines and tension headaches due to its vasoconstricting properties, that is, it causes constriction of blood vessels...
mucate and caffeineCaffeineCaffeine is a bitter, white crystalline xanthine alkaloid that acts as a stimulant drug. Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants...
), Benegrip (combined with chlorphenamineChlorphenamineChlorphenamine or chlorpheniramine , commonly marketed in the form of chlorpheniramine maleate , is a first-generation alkylamine antihistamine used in the prevention of the symptoms of allergic conditions such as rhinitis and urticaria. Its sedative effects are relatively weak compared to other...
maleate and caffeineCaffeineCaffeine is a bitter, white crystalline xanthine alkaloid that acts as a stimulant drug. Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants...
), Anador, Magnopyrol, Conmel, Difebril, Termopirona, Dipifarma, Dorona, Hynalgin, Lisador (combined with adiphenine hydrochloride and promethazinePromethazinePromethazine is a first-generation antihistamine of the phenothiazine family. The drug has anti-motion sickness, antiemetic, and anticholinergic effects, as well as a strong sedative effect and in some countries is prescribed for insomnia when benzodiazepines are contraindicated...
hydrochloride) - Bulgaria: Analgin, Algozone, Proalgin, , Hexalgin, Benalgin (combined with thiamineThiamineThiamine or thiamin or vitamin B1 , named as the "thio-vitamine" is a water-soluble vitamin of the B complex. First named aneurin for the detrimental neurological effects if not present in the diet, it was eventually assigned the generic descriptor name vitamin B1. Its phosphate derivatives are...
and caffeineCaffeineCaffeine is a bitter, white crystalline xanthine alkaloid that acts as a stimulant drug. Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants...
), Spasmalgon (combined with pitofenonePitofenonePitofenone is an antispasmodic....
and fenpiveriniumFenpiveriniumFenpiverinium is an antimuscarinic....
) - Chile: Dipirona, Baralgina, Migranol
- China: An Nai Jin
- Colombia: Novalgina"buscapina"
- Costa Rica: Lisalgil
- Croatia: Analgin
- Czech Republic: AlgifenAlgifenAlgifen is trademark of compositional analgesic drug based on mixture of metamizole, pitofenone and fenpiverinium. It was produced by Zentiva in tablet-form, it was marketed in Central and Eastern Europe....
(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 diazepamDiazepamDiazepam , first marketed as Valium by Hoffmann-La Roche is a benzodiazepine drug. Diazepam is also marketed in Australia as Antenex. It is commonly used for treating anxiety, insomnia, seizures including status epilepticus, muscle spasms , restless legs syndrome, alcohol withdrawal,...
) - 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 (combined with pitofenone and fenpipramide)
- Russia: Analgin, Baralgin, Spazmalgon, Tempalgin (combined with triacetonamine)
- Slovakia: Novalgin, Algifen (combined with pitophenone), Quarelin (In combination with drotaverineDrotaverineDrotaverine is an antispasmodic drug, structurally related to papaverine. Drotaverine is a selective inhibitor of phosphodiesterase 4, and has no anticholinergic effects. Drotaverine has been shown to possess dose-dependant analgesic effects in animal models...
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