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Metamizole monohydrate 3D ball-and-stick.png
Clinical data
Trade namesNovalgin,[1] others[2]
Other namesDipyrone (BAN UK, USAN US)
AHFS/Drugs.comInternational Drug Names
  • 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
Oral, IM, IV, rectal
ATC code
Legal status
Legal status
  • Over-the-counter (some countries, see text); prescription-only (others); withdrawn (others)
Pharmacokinetic data
Bioavailability100% (active metabolites)[5]
Protein binding48–58% (active metabolites)[5]
Elimination half-life14 minutes (parent compound; parenteral);[4] metabolites: 2–4 hours[5]
ExcretionUrine (96%, IV; 85%, oral), faeces (4%, IV).[4]
  • [(2,3-Dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazol-4-yl)methylamino] methanesulfonic acid
CAS Number
PubChem CID
CompTox Dashboard (EPA)
ECHA InfoCard100.000.631 Edit this at Wikidata
Chemical and physical data
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
 ☒NcheckY (what is this?)  (verify)

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.[4][5]

Although it is available over-the-counter in some countries, it is banned in others, due to its potential for adverse events, including agranulocytosis.[6][7] A study by one of the manufacturers of the drug found the risk of agranulocytosis within the first week of treatment to be a mere 1.1 in a million, versus 5.92 in a million for diclofenac.[8] It is in the ampyrone sulfonate family of medicines.

It was patented in 1922[9] and was first used medically in Germany under the brandname "Novalgin". For many years, it was available over-the-counter in most countries, before its withdrawal due to severe adverse effects.[10] Metamizole is marketed under various trade names.[2][3]

Medical uses[edit]

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[edit]

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[edit]

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).[5] Like NSAIDs, it can trigger bronchospasm or anaphylaxis, especially in those with asthma.[7]

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][5][7] 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][11] Genetics may play a significant role in metamizole sensitivity.[12] 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.[13]

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).[14]


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]

Known interactions[4]
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).[4]


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[15]


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.[7] 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.[16] Despite this, studies in animals have found that the CB1 cannabinoid receptor is not involved in the analgesia induced by metamizole.[17] Although it seems to inhibit fevers caused by prostaglandins, especially prostaglandin E2,[18] metamizole appears to produce its therapeutic effects by means of its metabolites, especially N-methyl-4-aminoantipyrine (MAA) and 4-Aminoantipyrine (AA).[4]

Pharmacokinetics of metamizole's major metabolites[4]
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


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][19] 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][20]: 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.[20]: 26–27 Yet later, chemists at Hoechst made a derivative, melubrine (sodium antipyrine aminomethanesulfonate), which was introduced in 1913;[21] finally,[when?] metamizole was synthesized. Metamizole is a methyl derivative of melubrine and is also a more soluble prodrug of pyramidon.[1][20]: 26–27 Metamizole was first marketed in Germany as "Novalgin" in 1922.[1]

Society and culture[edit]

Legal status[edit]

Metamizole's legal status by country as of April 2014 Grey: No data; likely over-the-counter if the country is not developed, it is Rx, so prescription only, with the prescription cannot be refilled, and it is withheld by the pharmacist. 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.[10]

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.[10][22][23] For example, approval was withdrawn in Sweden (1974), the USA (1977), and India (2013, ban lifted in 2014).[24][25]

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).[26]

Brand names[edit]

Metamizole is generic, and in countries where it is marketed, it is available under many brand names.[2] In Russia, it is commonly sold under the "Analgin" (Russian: Анальгин) trade name.[27][28]

In Romania it's 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.


  1. ^ a b c d e f Brune, K (1997). "The early history of non-opioid analgesics". Acute Pain. 1: 33–40. doi:10.1016/S1366-0071(97)80033-2.
  2. ^ a b c international listings for Metamizole Page accessed June 21, 2015
  3. ^ a b c d e Brayfield A, ed. (13 December 2013). "Dipyrone". Martindale: The Complete Drug Reference. Pharmaceutical Press. Retrieved 19 April 2014.
  4. ^ a b c d e f g h i j k "Fachinformation (Zusammenfassung der Merkmale des Arzneimittels) Novaminsulfon injekt 1000 mg Lichtenstein Novaminsulfon injekt 2500 mg Lichtenstein" (PDF). Winthrop Arzneimittel GmbH (in German). Zinteva Pharm GmbH. February 2013. Retrieved 19 April 2014.
  5. ^ a b c d e f g Jage J, Laufenberg-Feldmann R, Heid F (April 2008). "[Drugs for postoperative analgesia: routine and new aspects. Part 1: non-opioids]" [Drugs for postoperative analgesia: routine and new aspects. Part 1: non-opioids]. Der Anaesthesist (in German). 57 (4): 382–90. doi:10.1007/s00101-008-1326-x. PMID 18351305. S2CID 32814418.
  6. ^ Lutz, Mathias (November 2019). "Metamizole (Dipyrone) and the Liver: A Review of the Literature". The Journal of Clinical Pharmacology. 59 (11): 1433–1442. doi:10.1002/jcph.1512. PMID 31433499.
  7. ^ a b c d Brack A, Rittner HL, Schäfer M (March 2004). "Nichtopioidanalgetika zur perioperativen Schmerztherapie" [Non-opioid analgesics for perioperative pain therapy. Risks and rational basis for use]. Der Anaesthesist (in German). 53 (3): 263–80. doi:10.1007/s00101-003-0641-5. PMID 15021958. S2CID 8829564.
  8. ^ Nikolova, Irina; Tencheva, Jasmina; Voinikov, Julian; Petkova, Valentina; Benbasat, Niko; Danchev, Nikolai (2014). "Metamizole: A Review Profile of a Well-Known "Forgotten" Drug. Part I: Pharmaceutical and Nonclinical Profile". Biotechnology & Biotechnological Equipment. 26 (6): 3329–3337. doi:10.5504/BBEQ.2012.0089. ISSN 1310-2818.
  9. ^ Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 530. ISBN 9783527607495.
  10. ^ a b c United Nations Department of Economic and Social Affairs (2005). Consolidated List of Products Whose Consumption and/or Sale Have Been Banned, Withdrawn, Severely Restricted of Not Approved by Governments (PDF) (12th ed.). New York: United Nations. pp. 171–5. Retrieved 3 April 2013.
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  12. ^ García-Martín E, Esguevillas G, Blanca-López N, García-Menaya J, Blanca M, Amo G, Canto G, Martínez C, Cordobés C, Agúndez JA (September 2015). "Genetic determinants of metamizole metabolism modify the risk of developing anaphylaxis". Pharmacogenetics and Genomics. 25 (9): 462–4. doi:10.1097/FPC.0000000000000157. PMID 26111152.
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  14. ^ Andrade S, Bartels DB, Lange R, Sandford L, Gurwitz J (2016). "Safety of metamizole: a systematic review of the literature". J Clin Pharm Ther. 41 (5): 459–77. doi:10.1111/jcpt.12422. PMID 27422768.CS1 maint: multiple names: authors list (link)
  15. ^ Council of Europe; Council of Europe. European Directorate for the Quality of Medicines & HealthCare (EDQM); Rada Europy; European Pharmacopoeia Commission; European Directorate for the Quality of Medicines & Healthcare (2013). European Pharmacopoeia: Published in Accordance with the Convention on the Elaboration of a European Pharmacopoeia (European Treaty Series No. 50). Council of Europe. ISBN 978-92-871-7527-4.
  16. ^ Jasiecka A, Maślanka T, Jaroszewski JJ (2014). "Pharmacological characteristics of metamizole". Polish Journal of Veterinary Sciences. 17 (1): 207–14. doi:10.2478/pjvs-2014-0030. PMID 24724493.
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  18. ^ Malvar D, Aguiar FA, Vaz A, Assis DC, de Melo MC, Jabor VA, Kalapothakis E, Ferreira SH, Clososki GC, de Souza GE (August 2014). "Dipyrone metabolite 4-MAA induces hypothermia and inhibits PGE2 -dependent and -independent fever while 4-AA only blocks PGE2 -dependent fever". British Journal of Pharmacology. 171 (15): 3666–79. doi:10.1111/bph.12717. PMC 4128064. PMID 24712707.
  19. ^ Nobel Committee Emil Fischer – Biographical
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  22. ^ Department of Economic and Social Affairs of the United Nations Secretariat Consolidated List of Products Whose Consumption and/or Sale Have Been Banned, Withdrawn, Severely Restricted or not Approved by Governments Fourteenth Issue (New data only) (January 2005 – October 2008): Pharmaceuticals United Nations – New York, 2009
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  24. ^ Bhaumik S (July 2013). "India's health ministry bans pioglitazone, metamizole, and flupentixol-melitracen". BMJ. 347: f4366. doi:10.1136/bmj.f4366. PMID 23833116. S2CID 45107003.
  25. ^ "Govt lifts ban on painkiller Analgin". Business Standard India. 19 March 2014.
  26. ^ "Exclusive: southern spain hospitals in british expat hotspot issue warning for 'lethal' painkiller nolotil". Retrieved 27 April 2018.
  27. ^ "Анальгин Авексима - официальная инструкция по применению, аналоги". (in Russian). Retrieved 2019-01-08.
  28. ^ "Анальгин". (in Russian). Retrieved 2019-01-08.