|Trade names||Novalgin, others|
|Other names||Dipyrone (BAN UK, USAN US)|
|By mouth, IM, IV, rectal|
|AHFS/Drugs.com||International Drug Names|
|Bioavailability||100% (active metabolites)|
|Protein binding||48–58% (active metabolites)|
|Elimination half-life||14 minutes (parent compound; parenteral); metabolites: 2–4 hours|
|Excretion||Urine (96%, IV; 85%, oral), faeces (4%, IV).|
|Chemical and physical data|
|Molar mass||311.36 g·mol−1|
|3D model (JSmol)|
|(what is this?)|
Metamizole, also known as dipyrone, is a pain medication, spasm reliever, and fever reducer. It may be used when other medications are not effective. Onset is rapid and effects last up to 8 hours. It is may be given by mouth, rectally, or by injection.
Common side effects include sleepiness, abdominal discomfort, and nausea. Serious side effects my include allergic reactions, including anaphylaxis, and low white blood cells. While it appears relatively safe in early pregnancy, there are concerns in later pregnancy. Use is not recommended when breastfeeding. It is in the ampyrone family of medicines. It is not an opioid; though sources differ regarding if it is an NSAID.
Metamizole was patented in 1922 and was first used medically in Germany. It is marketed under various trade names. It was withdrawal from market in a number of countries, including the United States and United Kingdom, in the 1960s and 70s due to side effects. Though it remains available in parts of Europe and the developing world as of 2019.
Its use in the elderly and those with liver or kidney impairment is advised against, but if these groups of people must be treated, a lower dose and caution is usually advised.
Metamizole has a potential of blood-related toxicity (blood dyscrasias), but causes less kidney, cardiovascular, and gastrointestinal toxicity than non-steroidal anti-inflammatory drugs (NSAIDs). Like NSAIDs, it can trigger bronchospasm or anaphylaxis, especially in those with asthma.
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 the sulfonamides. The relative risk for agranulocytosis appears to greatly vary according to the country of estimates on said rate and opinion on the risk is strongly divided. Genetics may play a significant role in metamizole sensitivity. It is suggested that some populations are more prone to suffer from metamizole induced agranulocytosis than others. As an example, metamizole-related agranulocytosis seems to be an adverse effect more frequent in British population as opposed to Spaniards.
Pregnancy and breastfeeding
Its use in pregnancy is advised against, although animal studies are reassuring in that they show minimal risk of birth defects. Its use during lactation is advised against, as it is excreted in breast milk.
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).
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 pair 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 CB1 cannabinoid receptor is not involved in the analgesia induced by metamizole. Although it seems to inhibit fevers caused by prostaglandins, especially prostaglandin E2, metamizole 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|
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
Ludwig Knorr was a student of Emil Fischer who won the Nobel Prize for his work on purines and sugars, which included the discovery of phenylhydrazine. In the 1880s, Knorr was trying to make quinine derivatives from phenylhydrazine, and instead made a pyrazole derivative, which after a methylation, he made into phenazone, also called antipyrine, which has been called "the 'mother' of all modern antipyretic analgesics.": 26–27 Sales of that drug exploded, and in the 1890s chemists at Teerfarbenfabrik Meister, Lucius & Co. (a precursor of Hoechst AG which is now Sanofi), made another derivative called pyramidon which was three times more active than antipyrine.
In 1893, a derivative of antipyrine, aminopyrine, was made by Friedrich Stolz at Hoechst.: 26–27 Yet later, chemists at Hoechst made a derivative, melubrine (sodium antipyrine aminomethanesulfonate), which was introduced in 1913, and yet later metamizole was synthesized; metamizole is a methyl derivative of melubrine and is also a more soluble prodrug of pyramidon.: 26–27 Metamizole was first marketed in Germany as "Novalgin" in 1922.
Society and culture
Metamizole is banned in several countries, available by prescription in others (sometimes with strong warnings, sometimes without), and available over the counter in yet others. For example, approval was withdrawn in Sweden (1974), the USA (1977), and India (2013, ban lifted in 2014).
In 2018 an investigation in Spain looked into Nolotil (as metamizole is known in Spain) after the death of several British people in Spain a possible cause could be a side effect that can cause agranulocytosis (a lowering of white blood cell count).
Metamizole is generic, and in countries where it is marketed, it is available under many brand names. In Russia, it is commonly sold under the "Analgin" (Russian: Анальгин) brand name (the drugs are typically issued in the form of sodium metamizole). The medicine "Analgin" is produced in Bulgaria. 
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