Metamizole, or dipyrone, is a painkiller, spasm reliever, and fever reliever that also has anti-inflammatory effects. It is most commonly given by mouth or by injection. Although it is available over-the-counter in some countries, it is prescription or banned in other countries, due to its potential for adverse events, including agranulocytosis. It is in the ampyronesulfonate family of medicines. It was patented in 1922 and was first used medically in Germany under the brandname "Novalgin". For many years, it was available over-the-counter in most countries, until its toxicities became apparent. Metamizole is marketed under various trade names.
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 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. Its use during lactation is advised against, as it is excreted in breast milk.
Adverse effects
Metamizole has a potential of blood-related toxicity, but causes less kidney, cardiovascular, and gastrointestinal toxicity than non-steroidal anti-inflammatory drugs. Like NSAIDs, it can trigger bronchospasm or anaphylaxis, especially in those with asthma. Serious side effects include agranulocytosis, aplastic anaemia, hypersensitivity reactions, 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. According to a systematic review from 2016 Metamizole significantly increased the risk of upper gastrointestinal bleeding by a factor ranging from 1.4 to 2.7.
Contraindications
Previous hypersensitivity to metamizole or any of the excipients in the preparation used, acute porphyria, impaired haematopoiesis, third trimester of pregnancy, lactation, children with a body weight below 16 kg, history of aspirin-induced asthma and other hypersensitivity reactions to analgesics. Oral anticoagulants, lithium, captopril, triamterene and antihypertensives may also interact with metamizole, as other pyrazolones are known to interact adversely with these substances.
Overdose
It is considered fairly safe on overdose, but in these cases supportive measures are usually advised as well as measures to limit absorption and accelerate excretion.
Physicochemistry
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
Pharmacology
Its precise mechanism of action is unknown, although it is believed that inhibiting brain and spinal cordprostaglandin 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 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 and 4-Aminoantipyrine.
History
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." Sales of that drug exploded, and in the 1890s chemists at Teerfarbenfabrik Meister, Lucius & Co., 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. Yet later, chemists at Hoechst made a derivative, melubrine, 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. Metamizole was first marketed in Germany as "Novalgin" in 1922.
Society and culture
Legal status
Metamizole is banned in several countries, available by prescription in others, and available over the counter in yet others. For example, approval was withdrawn in Sweden, the USA, and India. In 2018 an investigation in Spain looked into Nolotil after the death of several British people in Spain a possible cause could be a side effect that can cause agranulocytosis.
Brand names
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" brand name. The medicine "Analgin" is produced in Bulgaria.
