Metamizole

Metamizole, or dipyrone, is a painkiller, spasm reliever, and fever reliever. It is most commonly given by mouth or by intravenous infusion.[12][13][14] It belongs to the ampyrone sulfonate family of medicines and was patented in 1922. Metamizole is marketed under various trade names.[15][16] It was first used medically in Germany under the brandname "Novalgin".[17]

Not to be confused with methimazole or methazolamide.
Metamizole
Clinical data
Trade namesNovalgin, Algocalmin,[1] Analgin, others[2]
Other namesDipyrone (BAN UK, USAN US, Sulpyrine (JAN JP)
AHFS/Drugs.comInternational 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.[3][4]
Routes of
administration		Oral, IM, IV, rectal
ATC code
Legal status
Legal status
  • AU: Withdrawn
  • BR: OTC (Over the counter)
  • CA: Veterinary only[5]
  • DE: § 48 AMG/§ 1 MPAV (Prescription only)[6]
  • NZ: Prescription only[7][8]
  • UK: Withdrawn
  • US: Veterinary only (horses)[9]
  • EU: Legally available[10]
Pharmacokinetic data
Bioavailability100% (active metabolites)[11]
Protein binding48–58% (active metabolites)[11]
MetabolismLiver[11]
Elimination half-life14 minutes (parent compound; parenteral);[4] metabolites: 2–4 hours[11]
ExcretionUrine (96%, IV; 85%, oral), faeces (4%, IV).[4]
Identifiers
  • [(2,3-Dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazol-4-yl)methylamino] methanesulfonic acid
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.000.631
Chemical and physical data
FormulaC13H17N3O4S
Molar mass311.36 g·mol−1
3D model (JSmol)
  • c1ccccc1N2N(C)C(C)=C(C2=O)N(C)CS(=O)(=O)O
  • 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) ☒N
  • Key:LVWZTYCIRDMTEY-UHFFFAOYSA-N ☒N
 ☒NcheckY (what is this?)  (verify)

Though it is available over-the-counter in almost all countries, beginning in the 1970s it was withdrawn in some countries due to studies linking it to severe adverse effects, including agranulocytosis.[18] Other studies deny this and claim it is a safer drug than other painkillers.[19][20] Metamizole is highly popular elsewhere in the world.

Medical uses

It is primarily used for perioperative pain, acute injury, colic, cancer pain, other acute/chronic forms of pain and high fever unresponsive to other agents.[4]

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 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.[4]

Adverse effects

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).[11] Like NSAIDs, it can trigger bronchospasm or anaphylaxis, especially in those with asthma.[21]

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.[3][11][21] 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.[3][22][23] Genetics may play a significant role in metamizole sensitivity.[24] 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.[25]

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 (relative risk).[26] A study by one of the manufacturers of the drug found the risk of agranulocytosis within the first week of treatment to be a 1.1 in a million, versus 5.9 in a million for diclofenac.

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.[4]

In 2018, the European Medicines Agency reviewed the safety of metamizole and concluded it to be generally safe for the general population. However, they advised against its use in the third trimester of pregnancy or while breastfeeding due to risks of renal impairment or ductus arteriosus to the fetus or infant.[10]

Known interactions
Drug(s)Interaction/reason for theoretical potential for interaction
CiclosporinDecreased serum levels of ciclosporin.[4]
ChlorpromazineAdditive hypothermia (low body temperature) may result.[4]
Hydroxyethyl starchAcute renal insufficiency. Low evidence, but discouraged simultaneous administration.[27]
MethotrexateAdditive risk for haematologic (blood) toxicity.[4] More specifically, bone marrow aplasia.[27]

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).[4]

Physicochemistry

It is a sulfonic acid and comes in calcium, sodium and magnesium salt forms.[3] 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.[28]

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.[21] In the 2000s, researchers uncovered another mechanism involving metamizole being a prodrug. 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, specifically Arachidonoyl-4-methylaminoantipyrine (ARA-4-MAA) and Arachidonoyl-4-aminoantipyrine (ARA-4-AA).[29][30] This mechanism of action has been compared to Paracetamol and its active arachidonic acid metabolite AM404. The CB1 receptor inverse agonist AM-251 was able to reduce the cataleptic response and thermal analgesia of Dipyrone.[31] Another study found its antihyperalgesic effect reversed by the CB2 inverse agonist AM-630[32] Although it seems to inhibit fevers caused by prostaglandins, especially prostaglandin E2,[33] metamizole appears to produce its therapeutic effects by means of its metabolites, especially N-methyl-4-aminoantipyrine (MAA) and 4-Aminoantipyrine (AA) which form through the FAAH enzyme to create Arachidonoyl-4-methylaminoantipyrine (ARA-4-MAA) and Arachidonoyl-4-aminoantipyrine (ARA-4-AA).[4]

Pharmacokinetics of metamizole's major metabolites[4]
MetaboliteAcronymBiologically active?Pharmacokinetic properties

N-methyl-4-aminoantipyrine
MAAYesBioavailability≈90%. Plasma protein binding: 58%. Excreted in the urine as 3±1% of the initial (oral) dose

4-aminoantipyrine
AAYesBioavailability≈22.5%. Plasma protein binding: 48%. Excreted in the urine as 6±3% of the initial (oral) dose

N-formyl-4-aminoantipyrine
FAANoPlasma protein binding: 18%. Excretion in the urine as 23±4% of the initial oral dose

N-acetyl-4-aminoantipyrine
AAANoPlasma 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.[1][34] 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."[1][35]: 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.[1]

In 1893, a derivative of antipyrine, aminopyrine, was made by Friedrich Stolz at Hoechst.[35]: 26–27  Yet later, chemists at Hoechst made a derivative, melubrine (sodium antipyrine aminomethanesulfonate), which was introduced in 1913;[36] finally in 1920, metamizole was synthesized.[20] Metamizole is a methyl derivative of melubrine and is also a more soluble prodrug of pyramidon.[1][35]: 26–27  Metamizole was first marketed in Germany as "Novalgin" in 1922.[1][20]

Society and culture
World map of availability of Metamizole
World map of availability of Metamizole (Dipyrone)
   Over-the-counter with limited restrictions.
   Available, but no data on the requirement of prescriptions.
   Prescription-only, with fairly limited restrictions on its use.
   Prescription-only, with extensive restrictions on its use.
   Banned for human use. It may still be used by veterinary cases.
   No data.

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.[37][38][39] For example, approval was withdrawn in Sweden (1974), the USA (1977),[40] and India (2013, ban lifted in 2014).[41][42][43]

Although metamizole is banned in the US, it was reported by small surveys that 28% of Hispanics in Miami have possession of it,[44] and 38% of Hispanics in San Diego, CA reported some usage.[45]

There were unauthorized sales and use of dipyrone in horses in the US. After reviewing trial data on its safety, the FDA approved it for treating fever in equines.[9]

Amid the opioid crisis, a study pointed out that the legal status of metamizole has a relation to the consumption of oxycodone, showing the use of those drugs were inversely correlated. Its use could be beneficial when adjusted for the addictive risk of opioids, especially on limited and controlled use of metamizole.[46] A 2019 Israeli conference also justified the approved status as a preventive to opioid dependence, and metamizole being safer than most analgesics for renal impaired patients.[47]

Metamizole is the most sold medication in São Paulo, Brazil, accounting for 488 tons in 2016.[48] Given this contrasting consumption compared to other countries, the Brazilian Health Regulatory Agency (ANVISA) convened an international panel for evaluating its safety in 2001, and the conclusion was that the benefits substantially outweighed the risks, and imposing restrictions would lead to significant negative consequences to the population.[49][23] It is also highly popular in Latin America overall. In 2022 in Brazil alone over 215 million doses were administered.[50]

The Bulgarian pharmaceutical Sopharma produces it under the brand Analgin, which as of 2014, has been the top-selling analgesic in Bulgaria for over a decade.[51]

In Germany, the drug is the most commonly-prescribed painreliever.[46]

In 2012, headache accounts for 70% of its use in Indonesia.[52]

In 2018, investigators in Spain looked into Nolotil (as metamizole is known in Spain) after the death of several British people in Spain. A possible factor in these deaths might have been a side effect of metamizole that can cause agranulocytosis (a lowering of white blood cell count).[53]

Brand names

Metamizole is the international nonproprietary name, and in countries where it is marketed, it is available under many brand names.[2]

In Romania metamizole is available as the original marketed pharmaceutical product by Zentiva as Algocalmin, as 500 mg immediate release tablets. It's also available as an injection with 1 g of metamizole sodium dissolved in 2 ml of solvent.

In Israel it is sold under the brand name "Optalgin" (Hebrew: אופטלגין), manufactured by Teva.

It is known as Sulpyrin and Sulpyrine in South Korea (설피린) and Japan. (スルピリン)[54][55]

Analgin

Analgin (Russian: Анальгин) is a generic name used in the former USSR pharmacopeia.[56] It remains as a popular term in Slavic nations, but there was a firm in Russia that tried unsuccessfully to claim it as their own private trademark.[57][58] However, in Bulgaria, Sopharma succeeded in registering Analgin as a trademark.[59]

Analgin is also the common term used in the Indian pharmacopeia.[60]

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