Metamizole
Clinical data | |
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Trade names | Novalgin, Algocalmin,[1] Analgin, others[2] |
Other names | Dipyrone (BAN UK, USAN US, Sulpyrine (JAN JP) |
AHFS/Drugs.com | International Drug Names |
Pregnancy category |
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Routes of administration | Oral, IM, IV, rectal |
ATC code | |
Legal status | |
Legal status | |
Pharmacokinetic data | |
Bioavailability | 100% (active metabolites)[11] |
Protein binding | 48–58% (active metabolites)[11] |
Metabolism | Liver[11] |
Elimination half-life | 14 minutes (parent compound; parenteral);[4] metabolites: 2–4 h[11] |
Duration of action | 4–6 h[12] |
Excretion | Urine (96%, IV; 85%, oral), faeces (4%, IV).[4] |
Identifiers | |
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Metamizole or dipyrone is a painkiller, spasm reliever, and fever reliever drug. It is most commonly given by mouth or by intravenous infusion.[13][11][14] It belongs to the ampyrone sulfonate family of medicines and was patented in 1922. Metamizole is marketed under various trade names.[2][3] It was first used medically in Germany under the brandname "Novalgin".[15]
Metamizole is available over-the-counter in many countries, but from in the 1970s it was banned in some countries due to studies linking it to severe adverse effects, including agranulocytosis.[16] Other studies find that it is a safer drug than other painkillers.[17][18] Metamizole is popular in many countries where it is available.[19]
Medical uses
Metamizole, with its potent
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] Metamizole also effectively manages biliary and intestinal colic-like pain, and reduces the spasm of the smooth muscle of the sphincter of Oddi.[21]
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
While metamizole is a relatively safe medication,[22] it is not entirely devoid of adverse effects.[22]
Metamizole has a potential of blood-related toxicity (blood
Serious side effects include
A 2015 meta-analysis concluded that on the evidence available "for short-term use in the hospital setting, metamizole seems to be a safe choice when compared to other widely used analgesics", but that the "results were limited by the mediocre overall quality of the reports" analysed.[28]
A systematic review from 2016 found that metamizole significantly increased the relative risk of upper gastrointestinal bleeding, by a factor of 1.4–2.7 times.[29] 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.[medical citation needed] Therapeutic effect of metamizole on intestinal colic is attributed to its analgesic properties, with no evidence of interference in small bowel or colon motility.[21]
Metamizole has potential for hepatotoxicity.[30]
Contraindications
Previous hypersensitivity (such as
In 2018, the
Interactions
A clinically severe interaction has been identified between aspirin and metamizole for patients who regularly take aspirin to manage vascular disease: this interaction occurs due to steric hindrance at the active aspirin binding site of COX-1 by metamizole; to manage this interaction, it is recommended to make a delay between the intake of each of these drugs, with aspirin being taken at least 30 minutes before metamizole.[31]
Drug(s) | Interaction/reason for theoretical potential for interaction |
---|---|
Aspirin | Platelet aggregation inhibition (PAI) by aspirin; metamizole prevents aspirin from inhibiting COX-1.[31] |
Ciclosporin | Decreased serum levels of ciclosporin.[4] |
Chlorpromazine | Additive hypothermia (low body temperature) may result.[4] |
Hydroxyethyl starch | Acute renal insufficiency. Low evidence, but discouraged simultaneous administration.[32] |
Methotrexate | Additive risk for haematologic (blood) toxicity.[4] More specifically, bone marrow aplasia.[32] |
Oral
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
Physicochemistry
Metamizole is a sulfonic acid and comes in
Pharmacology
Its precise mechanism of action of metamizole is unknown, although it is believed that metamizole generally exerts its action by inhibiting the COX-3 enzyme which is responsible for the biosynthesis of prostaglandins in the central nervous system (CNS)—in the brain and spinal cord. Prostaglandins are lipid compounds that play a role in inflammation, pain, and fever. By inhibiting the COX-3 enzyme in the CNS, metamizole reduces the production of prostaglandins, thereby alleviating pain, reducing fever, and potentially lessening inflammation.[14][34] Metamizole is classified as an atypical nonsteroidal anti-inflammatory drug (NSAID). Unlike typical NSAIDs, metamizole exhibits weak or no anti-inflammatory properties (at least in therapeutic doses),[20][34] but possesses potent analgesic effects via its action in the CNS: this central action distinguishes it from other NSAIDs, which generally exert their effects peripherally.[34] The inhibition by metamizole of COX-1 and COX-2 is less potent than the inhibition of these enzymes by traditional NSAIDs.[12]
Metamizole is metabolized in the liver, where it is converted into active metabolites through the process of N-demethylation.[35] The mechanism of action of metamizole is believed to be exerted via its active metabolites, specifically, arachidonoyl-4-methylaminoantipyrine (ARA-4-MAA) and arachidonoyl-4-aminoantipyrine (ARA-4-AA).[36][17][22] 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.[37] Another study found its antihyperalgesic effect reversed by the CB2 inverse agonist AM-630[38] Although it seems to inhibit fevers caused by prostaglandins, especially prostaglandin E2,[39] 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]
Metamizole likely induces the CYP2B6 and CYP3A4 enzymes.[20]
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 |
History
In 1893, a derivative of antipyrine,
Society and culture
Legal status
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 in some countries. No data. |
Metamizole is banned in several countries, available by prescription in others (sometimes with strong warnings, sometimes without), and available
Although metamizole is banned in the US because of its risk of agranulocytosis,[49] it was reported by small surveys that 28% of Hispanics in Miami have possession of it,[50] and 38% of Hispanics in San Diego reported some usage.[51]
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.[8]
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.[52] 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.[53]
Metamizole is the most sold medication in São Paulo, Brazil, accounting for 488 tons in 2016.[54] 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.[55][24] It is also highly popular in Latin America overall. In 2022 in Brazil alone over 215 million doses were administered.[56]
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.[57]
In Germany, the drug is the most commonly prescribed painreliever.[52]
In 2012, headache accounts for 70% of its use in Indonesia.[58]
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).[59]
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)[60][61]
Analgin
Analgin (Russian: Анальгин) is a
Analgin is also the common term used in the Indian pharmacopeia.[66]
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