Metamizole

Not to be confused with methimazole or methazolamide.

Metamizole

Systematic (IUPAC) name
[(2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazol-4-yl)methylamino] methanesulfonic acid
Clinical data
Trade names	Originally Novalgin, now generic
AHFS/Drugs.com	International Drug Names
Pregnancy category	None assigned; no evidence of teratogenicity in animal studies, but use in the third trimester may cause adverse effects in the newborn or ductus arteriosus (a heart defect) due to its weak NSAID activity.
Legal status	Over-the-counter (some countries, see text); prescription-only (others); withdrawn (others)
Routes of administration	Oral, IM, IV, rectal
Pharmacokinetic data
Bioavailability	100% (active metabolites)
Protein binding	48%-58% (active metabolites)
Metabolism	Liver
Biological half-life	14 minutes (parent compound; parenteral); metabolites: 2–4 hours
Excretion	Urine (96%, IV; 85%, oral), faeces (4%, IV).
Identifiers
CAS Number	68-89-3 (sodium salt)
ATC code	N02BB02 (WHO)
PubChem	CID: 80254
DrugBank	DB04817 Y
ChemSpider	3000
UNII	VSU62Z74ON Y
ChEBI	CHEBI:59033 Y
ChEMBL	CHEMBL487894 Y
Chemical data
Formula	C13H17N3O4S
Molecular mass	311.357 g/mol
SMILES Cc1c(c(=O)n(n1C)c2ccccc2)N(C)CS(=O)(=O)O
InChI InChI=1S/C13H17N3O4S/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) Key:LVWZTYCIRDMTEY-UHFFFAOYSA-N
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Metamizole (INN), or dipyrone (BAN, USAN), is an ampyrone sulfonate analgesic (pain reliever), antispasmodic (spasm reliever) and antipyretic (fever reducer) similar to paracetamol in that it has minimal anti-inflammatory effects and which is most commonly given orally or parenterally (by injection) to prevent and treat pain related to surgery or for the treatment of acute pain. It was first introduced into clinical use in Germany in 1922 under the brandname "Novalgin" and for many years it was available over-the-counter in most countries, until its toxicities became apparent, although in some countries it is available over-the-counter, its use is usually restricted in developed countries, due to its potential for causing toxic reactions.

Metamizole is marketed under various trade names.

Despite its potential haematologic (blood-related) toxicity (that is potential for causing blood dyscrasias) it produces no clinically relevant effects in the way of kidney toxicity, cardiovascular toxicity and GI toxicity when compared to non-steroidal anti-inflammatory drugs (NSAIDs). Unlike paracetamol and similarly to the NSAIDs it can trigger bronchospasm or anaphylaxis, especially in those with asthma.

Medical uses

It is primarily used for perioperative pain, although the clinical trial data to support this use is limited at best. It is also used for acute injury, colic, cancer pain, other acute/chronic forms of pain and high fever unresponsive to other agents.

Special populations

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 or those with liver/kidney impairment is advised against, but if these groups of people must be treated a lower dose and caution is usually advised; its use in lactation is advised against as it is excreted in breast milk.

Adverse effects

It is known to cause minimal side effects in most people given it; 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 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.

Contraindications

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.

Known interactions

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.

Overdose

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).

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 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 couple of cannabinoid and NSAID arachidonic acid conjugates (although not in the strict chemical meaning of the word) of metamizole's breakdown products. Despite this studies in animals have found that the first cannabinoid receptor is not involved in the analgesia induced by metamizole. Although it seems to inhibit fevers caused by prostaglandins, especially prostaglandin E2. It appears to produce its therapeutic effects by means of its metabolites, especially N-methyl-4-aminoantipyrine (MAA) and 4-aminoantipyrine (AA).

Pharmacology of metamizole's major metabolites

Metabolite	Acronym	Biologically active?	Pharmacokinetic properties
N-methyl-4-aminoantipyrine	MAA	Yes	Bioavailability≈90%. Plasma protein binding: 58%. Excreted in the urine as 3±1% of the initial (oral) dose
4-aminoantipyrine	AA	Yes	Bioavailability≈22.5%. Plasma protein binding: 48%. Excreted in the urine as 6±3% of the initial (oral) dose
N-formyl-4-aminoantipyrine	FAA	No	Plasma protein binding: 18%. Excretion in the urine as 23±4% of the initial oral dose
N-acetyl-4-aminoantipyrine	AAA	No	Plasma protein binding: 14%. Excretion in the urine as 26±8% of the initial oral dose

History

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 quinolone 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. (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. Yet later, chemists at Hoechst made a derivative, melubrine (sodium antipyrine aminomethanesulfonate), which was introduced in 1913, and yet later metamizole was synthesized; metamilzole is a methyl derivative of melubrine and is also a more soluble prodrug of pyramidon. Metamizole was first marketed as "Novalgin" in 1922.

Metamizole had strong worldwide sales up until the 1970s, but there had been reports of agranulocytosis in the literature since the 1930s. In the 1970s AMA Drug Evaluations and other formularies called attention to these events and warned physicians against liberal use of metamizole, and the drug was banned in several countries. International controversy became heated in the 1970s and 1980s, especially with regard to marketing of the drug in the developing world, where agranulocytosis was difficult to manage and usually led to death, unlike in the developed world, where patients could generally be saved.

One difficulty in determining the risk of agranulocytosis was the lack of consistent epidemiological data; estimates ranged from 9 cases per 1000 uses to 2 cases per 10 million uses, and there was no known mechanism of toxicity. Hoechst commissioned a study of the drug to get better data, which published in JAMA in 1986. The study reported wildly inconsistent country-to-country variation in agranulocytosis and only intensified the controversy with supporters of the drug finding vindication and critics now additionally angry over the conduct of the study. As of 2014 the safety of the drug remained controversial.

Society and culture

Legal status

Metamizole's legal status by country as of April 2014 Grey: No data; likely over-the-counter if the country is not developed, otherwise likely banned. Light blue: over-the-counter with limited restrictions. Blue: Prescription-only, with fairly limited restrictions on its use. Orange: Prescription-only, with extensive restrictions on its use. Red: complete ban.

Metamizole is banned completely in several countries, available by prescription in others (sometimes with strong warnings, sometimes without them), and available over the counter in yet others, based on the judgement of regulators of the risk of drug-induced agranulocytosis and the level of development of the regulatory system. For example, it is not available in the US, but is recommended and used as a first line treatment for postoperative pain in Germany.

Brand names

Metamizole is generic, and in countries where it is marketed, it is available under many brand names.