Metamizole, also known as dipyrone, was introduced to the market nearly a century ago. Due to its excellent analgesic, antipyretic, and spasmolytic properties combined with its mostly favorable gastrointestinal tolerability, the drug was extensively applied worldwide during the first decades after its market introduction. Although rare, agranulocytosis is a well-known adverse event of metamizole and led to its withdrawal from the market in a number of countries beginning in the 1960s. Nevertheless, metamizole is still a frequently used drug worldwide either legally (by prescription in some countries, over the counter in other countries) or without official approval (especially by immigrants knowing the drug from their home countries) or even illegally (due to its growing application as an adulterant in illicit drugs). Metamizole undergoes extensive metabolism in the liver and cases of potential metamizole-associated hepatotoxicity have been described. Here, the literature is extensively reviewed for the first time regarding hepatic effects associated with the use of metamizole.

Based on spontaneous reports from Spain, it is claimed that the British, Irish and Scandinavians are at a greater risk of dipyrone‐induced agranulocytosis. This report examines the evidence.

<h4>Background</h4>Dipyrone (metamizole) is a non-steroidal anti-inflammatory drug used in some countries to treat pain (postoperative, colic, cancer, and migraine); it is banned in others because of an association with life-threatening blood agranulocytosis. This review updates a 2001 Cochrane review, and no relevant new studies were identified, but additional outcomes were sought.<h4>Objectives</h4>To assess the efficacy and adverse events of single dose dipyrone in acute postoperative pain.<h4>Search strategy</h4>The earlier review searched CENTRAL, MEDLINE, EMBASE, LILACS and the Oxford Pain Relief Database to December 1999. For the update we searched CENTRAL, MEDLINE,EMBASE and LILACS to February 2010.<h4>Selection criteria</h4>Single dose, randomised, double-blind, placebo or active controlled trials of dipyrone for relief of established moderate to severe postoperative pain in adults. We included oral, rectal, intramuscular or intravenous administration of study drugs.<h4>Data collection and analysis</h4>Studies were assessed for methodological quality and data extracted by two review authors independently. Summed total pain relief over six hours (TOTPAR) was used to calculate the number of participants achieving at least 50% pain relief. Derived results were used to calculate, with 95% confidence intervals, relative benefit compared to placebo, and the number needed to treat (NNT) for one participant to experience at least 50% pain relief over six hours. Use and time to use of rescue medication were additional measures of efficacy. Information on adverse events and withdrawals was collected.<h4>Main results</h4>Fifteen studies tested mainly 500 mg oral dipyrone (173 participants), 2.5 g intravenous dipyrone (101), 2.5 g intramuscular dipyrone (99); fewer than 60 participants received any other dose. All studies used active controls (ibuprofen, paracetamol, aspirin, flurbiprofen, ketoprofen, dexketoprofen, ketorolac, pethidine, tramadol, suprofen); eight used placebo controls.Over 70% of participants experienced at least 50% pain relief over 4 to 6 hours with oral dipyrone 500 mg compared to 30% with placebo in five studies (288 participants; NNT 2.4 (1.9 to 3.2)). Fewer participants needed rescue medication with dipyrone (7%) than with placebo (34%; four studies, 248 participants). There was no difference in participants experiencing at least 50% pain relief with 2.5 g intravenous dipyrone and 100 mg intravenous tramadol (70% vs 65%; two studies, 200 participants). No serious adverse events were reported.<h4>Authors' conclusions</h4>Based on very limited information, single dose dipyrone 500 mg provides good pain relief to 70% of patients. For every five individuals given dipyrone 500 mg, two would experience this level of pain relief who would not have done with placebo, and fewer would need rescue medication, over 4 to 6 hours.

INTRODUCTION: The therapeutic role of metamizole (dipyrone) remains controversial because of the risk of metamizole-induced agranulocytosis, a very rare, idiosyncratic, life-threatening adverse reaction. We described utilisation, spontaneous reporting and recent regulatory actions in Switzerland. METHODS: We estimated national metamizole utilisation as defined daily doses (DDD; WHO DDD 3 g/day) for 2014–2023, derived from aggregated national sales data; individual case safety reports (ICSR) of metamizole-induced agranulocytosis were retrieved from VigiBase (the WHO global safety database) for 2014–2024. Outputs included annual counts, fatal proportion and utilisation-normalised reporting (metamizole-induced agranulocytosis per million DDD); analyses were primarily descriptive. RESULTS: Utilisation increased by ~79% during the analysed period with a formulation mix of 95.7% oral, 4.2% ampoules, 0.1% suppositories. Metamizole-induced agranulocytosis reports rose from 13 (2014) to 57 (2024), with year-to-year variability; the fatal proportion declined from 13.5% (2014–2018; 17/126) to 5.8% (2019–2023; 13/224) and 1.8% in 2024 (1/57). Utilisation-normalised reporting increased from 1.42 to 3.29 per million DDD (total), while fatal reports remained low and trended downward (mean 0.249 per million DDD, 2014–2023). Among Swiss fatal cases, methotrexate was co-reported as a concomitant drug in 39.5% (15/38) (extended fatal set 2011–2025; fatal ICSRs irrespective of onset year). Switzerland contributes a disproportionately high absolute number of cumulative metamizole-induced agranulocytosis reports. REGULATORY ACTIONS: EMA and Swissmedic implemented strengthened warnings; Swissmedic additionally required a red-framed outer carton statement, clarified indications (second-line severe pain; refractory high fever) and advised avoiding concomitant methotrexate; a Direct Healthcare Professional Communication was issued. CONCLUSION: Regulatory assessments by EMA and Swissmedic concluded that the benefits of metamizole continue to outweigh the risks, provided the drug is used appropriately, action is taken promptly at first symptoms and concomitant methotrexate is avoided. However, the number of reported cases of agranulocytosis underscores the known risk in the context of widespread use. Spontaneous reports reflect reporting intensity, not incidence; ongoing monitoring of risk-minimisation effectiveness is warranted.

Risks of agranulocytosis and aplastic anemia. A first report of their relation to drug use with special reference to analgesics. The International Agranulocytosis and Aplastic Anemia Study. The risks of agranulocytosis and aplastic anemia in relation to analgesic drug use were evaluated in a population-based case-control study conducted in Europe and Israel. Analgesic use in the week before the onset of illness was compared between 221 cases of agranulocytosis and 1425 hospital controls. Analgesics significantly associated with agranulocytosis were dipyrone (metamizol sodium), indomethacin, and butazones (phenylbutazone and oxyphenbutazone). For dipyrone, the rate ratio estimate was 23.7 in Ulm, West Germany, West Berlin, and Barcelona, Spain, and the estimated excess risk for any exposure in a one-week period was 1.1 per million. In Israel and Budapest, Hungary, where the rate ratio estimate was 0.8, there was no evidence of excess risk. In all of the regions combined, the rate ratio estimates were 8.9 for indomethacin and 3.8 for butazones, with excess risk estimates of 0.6 and 0.2 per million, respectively.

Metamizole is a pyrazole that is antiipyrine substituted at C-4 by a methyl(sulfomethyl)amino group, the sodium salt of which, metamizole sodium, was widely used as a powerful analgesic and antipyretic, but withdrawn from many markets from the 1970s due to a risk of causing risk of causing agranulocytosis. It has a role as a non-narcotic analgesic, an antipyretic, an antirheumatic drug, a peripheral nervous system drug, a prodrug, an anti-inflammatory agent and a cyclooxygenase 3 inhibitor. It is a member of pyrazoles and an amino sulfonic acid. It is functionally related to an antipyrine. It

Intravenous indomethacin in biliary pain. A clinical investigation with metamizole as the control. The efficacy of single doses of intravenously administered indomethacin (50 mg) and metamizole (2.5 g) in the relief of biliary pain were compared in 60 consecutive patients attending the emergency ward of university central hospital. There were no statistically significant differences between the two treatment groups. There was no response in 13.3% in both groups and additional analgecics were required by 20% of the patients in both groups. Intravenous indomethacin is a recommendable alternative for intravenous metamizole in the treatment of biliary pain and the risks for agranulocytosis appear to be lesser than those associated with metamizole. Published in Annales chirurgiae et gynaecologiae (1984)