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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Metamizole [Dipyrone]

Last Update: June 2, 2024.

OVERVIEW

Introduction

Metamizole, also known as dipyrone, is an oral analgesic that is not available in the United States but is available over-the-counter in many countries of the world. Therapy with metamizole has been associated with rare severe bone marrow and liver adverse events including agranulocytosis, acute hepatitis, and acute liver failure.

Background

Metamizole (me tam’ i zole), also known as dipyrone (dye’ pir on), is a widely used oral agent for moderate-to-severe pain, fever, and spasm that is banned and not available in the United States but is widely used and available over-the-counter in other selected countries and areas of the world, including Germany, Russia, Mexico, South America, and China. First patented in 1922 and marketed under the names Novalgin and Analgin, metamizole was a popular and widely prescribed analgesic. However, because of reports of agranulocytosis, it was withdrawn from the market in the United States and subsequently in the United Kingdom, France, Canada, India, Japan, and Australia. Nevertheless, it remained available by prescription as well as over-the-counter in many other countries. Metamizole is a well tolerated drug and has fewer common side effects than aspirin and nonsteroid antiinflammatory agents (NSAIDS) such as ibuprofen and naproxen. Metamizole also has antipyretic and spasmolytic activities and was frequently used for postoperative pain and fever. The European Medicines Agency conducted an extensive review of its efficacy, safety, and benefit-to-risk ratio, concluding that metamizole was generally safe and that agranulocytosis and liver injury occurred with its use, but rarely and not much more commonly than with other over the counter analgesics. In selected countries, metamizole is available in tablets for oral use, suppositories for rectal administration, and in solution for intramuscular or intravenous use. The recommended oral dosage is 500 to 1,000 mg orally 1 to 4 times a day as needed. Dipyrone in solution is also available for intramuscular or intravenous use. Common adverse events include nausea, vomiting, headache, weakness, fever, abdominal pain, somnolence, vertigo, spams, neutropenia, renal dysfunction, and rash. Rare but potentially serious adverse events include hypersensitivity reactions, urticaria, angioedema, anaphylaxis, Stevens-Johnson syndrome, toxic epidermal necrolysis, interstitial nephritis, tachycardia, hypotension, shock, and agranulocytosis (estimated incidence ranging from 1:10,000 to 1:1,000,000 exposed persons).

Hepatotoxicity

Cases of liver injury from metamizole were rarely reported before 2019 when two case series of liver injury from its use including fatalities were reported from Germany. Reassessments were conducted by the European Medicines Agency based upon accumulation of more than 40 cases. Within a year or two, reviews of more than 50 cases of clinically apparent liver injury due to metamizole were described. The clinical features of metamizole-associated liver injury have varied greatly, some being hyper-acute with rapid onset of fever, rash, and jaundice after the initial or first several doses. These cases may represent hypersensitivity reactions such as hepatic involvement in DRESS syndrome, toxic epidermal necrolysis, or Stevens-Johnson syndrome.

In other instances, metamizole induced liver injury arises during more prolonged therapy after a latency of 2 to 16 weeks, manifested by the gradual onset of fatigue, nausea, anorexia, and right upper quadrant discomfort followed by dark urine and jaundice. The enzyme elevations are typically hepatocellular, but mixed and even cholestatic patterns have been described. The disease is usually self-limited with rapid improvement once metamizole is stopped. Rash, fever, and eosinophilia arise in some cases but are generally transient and mild. Autoantibodies including ANA and AMA are frequently detected, but IgG levels are usually normal and liver histology does not resemble autoimmune hepatitis. Recovery is usually rapid once metamizole is stopped and rarely requires immunosuppressive therapy. As might be expected, the fatality rate appears to be at least 10% in cases with hepatocellular injury and jaundice. There have been reports of fatalities and need for liver transplants due to liver injury caused by the drug. Recurrence upon re-exposure is usually abrupt in onset and more severe in course than the initial episode.

Likelihood score: A (well described although rare cause of clinically apparent liver injury).

Mechanism of Injury

The causes of the liver injuries from metamizole are likely to be immune mediated and the two patterns of injury suggest an immediate hypersensitivity reaction and a more delayed adaptive immune mediated injury. Metamizole can cause hypersensitivity reactions without liver injury including urticaria and rash, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Patients who develop agranulocytosis due to metamizole frequently have accompanying liver injury that is generally mild and overshadowed by the hematologic events.

Outcome and Management

Metamizole should be discontinued immediately in any patient presenting with acute liver injury and held until the diagnosis is clear. While metamizole is not available in the United States, immigrants from areas of the world where it is used may bring or order metamizole (frequently called dipyrone) from their countries of origin and may not report its use to physicians because it is considered a common, safe, over-the-counter medication. There is little evidence that immunosuppressive therapy is beneficial, although it is often used when improvement does not occur rapidly upon withdrawal of metamizole. The drug should not be restarted in anyone with suspected metamizole liver injury. Furthermore, patients taking the drug should be encouraged to discontinue it because of its propensity to cause serious side effects.

Drug Class: Nonsteroidal Antiinflammatory Drugs (NSAIDs)

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Metamizole (Dipyrone) – Generic

DRUG CLASS

Nonsteroidal Antiinflammatory Drugs

LABELING INFORMATION

Product labeling at European Medicines Agency

CHEMICAL FORMULA AND STRUCTURE

DRUGCAS REGISTRY NUMBERMOLECULAR FORMULASTRUCTURE
Metamizole 68-89-3 C13-H17-N3-O4-S image 134971374 in the ncbi pubchem database

ANNOTATED BIBLIOGRAPHY

References updated: 02 June 2024

Abbreviations: NSAIDS, nonsteroidal anti-inflammatory drugs, ULN, upper limit of the normal range.

  • Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999.
    (Expert review and compendium of hepatotoxicity published in 1999 does not mention dipyrone or metamizole).
  • Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013.
    (Textbook of hepatotoxicity published in the United States in 2013, does not mention dipyrone or metamizole).
  • Grosser T, Smyth EM, FitzGerald GA. Pharmacotherapy of inflammation, fever, pain, and gout. In, Brunton LL, Hilal-Dandan R, Knollman BC, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 13th ed. New York: McGraw-Hill, 2018, pp. 685-709.
    (Textbook of pharmacology and therapeutics does not include mention or discussion of dipyrone or metamizole).
  • Federmann G, Becker EW, Tautorat H, Penschuck C, Berg PA. [Demonstration by lymphocyte transformation test of the allergic genesis in a case of acute hepatitis]. Dtsch Med Wochenschr. 1988;113:1676-9. German. [PubMed: 2903041]
    (50 year old man developed jaundice shortly after cholecystectomy and a single oral dose of metamizole for postoperative fever and pain having received this medication several times in the past for arthritis [bilirubin rising rapidly to 43.9 mg/dL, ALT to 222 U/L, and Alk P to 497 U/L], but bilirubin and enzymes then falling promptly over the next 1-2 weeks).
  • Herdeg C, Hilt F, Büchtemann A, Bianchi L, Klein R. Allergic cholestatic hepatitis and exanthema induced by metamizole: verification by lymphocyte transformation test. Liver. 2002;22:507-13. [PubMed: 12445177]
    (66 year old man developed truncal rash 12 hours after taking a single dose of metamizole for fever, which became generalized and associated with eosinophilia and liver test abnormalities [bilirubin rising to 1.6 mg/dL, ALT to 636 U/L, Alk P to 719 U/L], treated with corticosteroids and with subsequent slow recovery).
  • Contreras J, Poniachik J, Planzer M, Lazarte R, Smok G, Oksenberg D, Madrid AM, Brahm J [Drug induced liver disease: clinical and pathological patterns in 33 cases]. Rev Med Chil. 2003;131:1128-34. Spanish. [PubMed: 14692302]
    (Among 33 cases of suspected drug induced liver injury who underwent liver biopsy between 1988 and 2000 at the Clinical Hospital of the University of Chile, two cases were attributed to dipyrone, one was given in combination with piroxicam and one with estradiol and prasterone).
  • Hernández N, Bessone F, Sáhez A, di Pace M, Brahm J, Zapata R, A Chirino R, et al. Profile of idiosyncratic drug induced liver injury in Latin America. An analysis of published reports. Ann Hepatol 2014; 13: 231-9. [PubMed: 24552865]
    (Systematic review of literature of drug induced liver injury in Latin American countries published from 1996 to 2012 identified 176 cases, two of which were attributed to dipyrone, both from Chile [Contreras 2003]).
  • Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52.e7. [PMC free article: PMC4446235] [PubMed: 25754159]
    (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, none of the cases were attributed to metamizole or dipyrone).
  • Douros A, Bronder E, Andersohn F, Klimpel A, Thomae M, Sarganas G, Kreutz R, et al. Drug-induced liver injury: results from the hospital-based Berlin Case-Control Surveillance Study. Br J Clin Pharmacol. 2015;79:988-99. [PMC free article: PMC4456131] [PubMed: 25444550]
    (A prospective case surveillance study conducted at 51 hospitals in Berlin between 2002 and 2011 enrolled 198 cases of idiopathic acute hepatitis, 13 of 122 outpatient cases were taking metamizole [11%] vs 14 outpatient controls [2%], while rates metamizole exposure in inpatient cases was the same as rates in inpatient controls).
  • Huber M, Andersohn F, Sarganas G, Bronder E, Klimpel A, Thomae M, Konzen C, et al. Metamizole-induced agranulocytosis revisited: results from the prospective Berlin Case-Control Surveillance Study. Eur J Clin Pharmacol. 2015;71:219-27. [PubMed: 25378038]
    (A prospective surveillance study for agranulocytosis conducted at 51 hospitals in Berlin between 2002 and 2011 enrolled 88 cases, including 26 [30%] at least possibly attributable to metamizole, mostly in women [73%], ages 19 to 82 years, median duration of therapy 6 days, median dose 2.25 g (range .250 to 4.0 g) daily, estimated frequency 1 per million population).
  • Kötter T, da Costa BR, Fässler M, Blozik E, Linde K, Jüni P, Reichenbach S, et al. Metamizole-associated adverse events: a systematic review and meta-analysis. PLoS One. 2015;10:e0122918. [PMC free article: PMC4405027] [PubMed: 25875821]
    (Systematic review of safety of metamizole in 3,716 patients in 79 randomized controlled trials, mostly short term studies of pain relief, found similar rates of adverse events from metamizole vs placebo [13.2% vs 14.0%], acetaminophen [15.8% vs 13.9%], and NSAIDS [24.8% vs 27.1%], but lower rates in comparison to opioids [32.2% vs 39.7%] and only unrelated and varied serious adverse events; no cases of agranulocytosis and no mention of hepatotoxicity).
  • Krisai P, Rudin D, Grünig D, Scherer K, Pichler W, Terracciano L, Krähenbühl S. Acute liver failure in a patient treated with metamizole. Front Pharmacol. 2019;10:996. [PMC free article: PMC6749849] [PubMed: 31572180]
    (54 year old German woman developed severe hepatitis 2 months after starting metamizole [4 g daily] for postoperative pain [bilirubin 11.4 mg/dL, ALT 3375 U/L, Alk P 586 U/L], which steadily worsened despite stopping the drug with biopsy showing massive necrosis, undergoing liver transplantation 16 days after presentation).
  • Lutz M. Metamizole (Dipyrone) and the liver: a review of the literature. J Clin Pharmacol. 2019;59:1433-1442. [PubMed: 31433499]
    (Review of the literature on metamizole induced liver injury concludes that “…experimental and clinical studies make some hepatotoxic potential of metamizole at least conceivable”).
  • Sebode M, Reike-Kunze M, Weidemann S, Zenouzi R, Hartl J, Peiseler M, Liwinski T, et al. Metamizole: An underrated agent causing severe idiosyncratic drug-induced liver injury. Br J Clin Pharmacol. 2020;86:1406-1415. [PMC free article: PMC7319009] [PubMed: 32080881]
    (Among 151 cases of drug induced liver injury seen at a single German referral center between 2008 and 2017, metamizole was the second most frequently implicated agent with 23 cases, 65% in women, median age 40 years, latency 4 weeks, median ALT at onset 779 U/L, Alk P 131 U/L, bilirubin 1.9 mg/dL [range 0.3-21.1 mg/dL], 2 patients requiring urgent liver transplant, 4 patients had recurrence on reexposure).
  • Björnsson ES. Liver injury associated with the analgetic drug metamizole. Br J Clin Pharmacol. 2020;86:1248-1250. [PMC free article: PMC7319005] [PubMed: 32400058]
    (Short review of the liver injury attributed to metamizole, based upon at least 40 reports in the literature, mostly coming from Germany, the typical case being hepatocellular, with positive rechallenges and fatal cases included).
  • Weber S, Benesic A, Gerbes AL. Further evidence for the hepatotoxic potential of metamizole. Br J Clin Pharmacol. 2021;87:1587-1588. [PubMed: 32696537]
    (Letter in response to Bjornsson [2020] describes 10 cases of liver injury attributed to metamizole captured in a German database [Weber, Drug Safety: 2021]).
  • Weber S, Benesic A, Neumann J, Gerbes AL. Liver injury associated with metamizole exposure: features of an underestimated adverse event. Drug Saf. 2021;44:669-680. [PMC free article: PMC8184550] [PubMed: 33638811]
    (Among 238 cases of suspected drug induced liver injury enrolled in a German registry between 2013 and 2020, 32 were attributed to metamizole, 22 in women [69%], 26 hepatocellular [81%], 5 mixed, and 1 cholestatic, 23 ANA positive [72%], 7 acute liver failure [22%] and 2 had liver transplant [6%], 4 had a positive rechallenge).
  • Liu J, Dai XL, Zhou XJ, Gu BH, Yang ZH, Lai J. Metamizole-induced acute liver failure in a boy. Clin Res Hepatol Gastroenterol. 2021;45:101570. [PubMed: 33303406]
    (15 year old Chinese male developed chills and fatigue and jaundice 24 hours after taking a single dose of metamizole [bilirubin 37.3 mg/dL, ALT 8140 U/L, INR 3.0], with rapid subsequent improvement and normal values 2 months later).
  • Hedenmalm K, Pacurariu A, Slattery J, Kurz X, Candore G, Flynn R. Is there an increased risk of hepatotoxicity with metamizole? A comparative cohort study in incident users. Drug Saf. 2021;44:973-985. [PubMed: 34273099]
    (Analysis of a German healthcare database from 2009-2018 of admissions for liver injury in patients without underlying liver disease prescribed metamizole [n=489,980] or acetaminophen [n=143,871] for the first time and followed for at least a year, found 1723 vs 197 liver injury cases with an increased hazard ratio of 1.69 for metamizole).
  • Preveden N, Liechti ME, Oettl T, Erb S. Metamizole as a rare cause of drug-induced Liver injury. Eur J Case Rep Intern Med. 2022;9:003349. [PMC free article: PMC9239029] [PubMed: 35774740]
    (56 year old man developed fever and fatigue within 12 hours of starting metamizole for osteoarthritis, with history of 3 previous similar episodes after taking the drug [bilirubin 1.0 mg/dL, ALT 1374 U/L, Alk P 51 U/L], biopsy showing steatosis, subacute hepatic necrosis, and eosinophilic infiltrates, and rapid improvement on stopping without worsening or jaundice).
  • Pohl J, Bischoff P, Oellinger R, Schoening W, Lurje G, Pratschke J, Horst D, et al. Liver transplantation for metamizole induced acute liver failure. Transplant Proc. 2022;54:1854-1858. [PubMed: 35933233]
    (Two cases of acute liver failure from a single German referral center presenting in April-May 2021; a 61 year old man and 56 year old woman presented after 3 months and 3 weeks of starting metamizole [2 g daily] for pain [bilirubin 19.5 and 15.2 mg/dL, ALT 446 and 3169 U/L], with rapid worsening and hepatic failure and liver transplant within 6 days; mentions that of 61 cases of metamizole liver injury in the literature, there were 6 reports of death or transplant).
  • Schulte B, Tergast TL, Griemsmann M, Menti D, Deveci N, Kahlhöfer J, Dörge P, et al. Metamizole-associated risks in decompensated hepatic cirrhosis. Dtsch Arztebl Int. 2022;119:687-693. [PMC free article: PMC9830680] [PubMed: 35912424]
    (Among 532 adults with decompensated cirrhosis and ascites in a German retrospective cohort, the 110 who were treated for pain with metamizole had a higher, 28-day incidence of acute kidney injury than those receiving other analgesics [68% vs 40%], as well as severe kidney injury [24% vs 9%] and rate of death or liver transplantation [22% vs 9%], results that were duplicated in a prospective cohort of 110 patients).
  • Lutz M, Grünewald I, Lenze F, Heinzow H, Ullerich H, Kabar I, Schmidt HH, et al. Unmasking of metamizole-induced liver injury by simultaneous development of characteristic agranulocytosis. Curr Drug Saf. 2023;18(3):404-412. [PubMed: 35670337]
    (Abstract only: 22 year old woman developed fever, rash, and jaundice two months after starting over-the-counter metamizole accompanied by low granulocytes and ANA and SMA positivity; the agranulocytosis treated successfully with corticosteroids and granulocyte colony stimulating factor).

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