Metamizole: Indications and Risks

Background: Metamizole is the most commonly prescribed analgesic drug in Germany, with 280 million daily doses prescribed per year. It is generally considered safe, yet it is controversial and not approved for use in many countries because of the very rare, but potentially lethal risk of agranulocytosis.

Methods: This narrative review is based on pertinent publications retrieved by a search in PubMed and other databases on the topics of metamizole/dipyrone, its adverse effects (especially agranulocytosis), mechanisms of action, and its interactions with other drugs.

Results: There are some 44 reported cases of agranulocytosis in Germany per year. Predicting the individual risk on the basis of genetic factors is not currently possible. Registry studies and data from pharmacovigilance databases yield country-specific incidences of agranulocytosis (per quantity of drug prescribed) that vary from 0.65 to 1400 per million in countries across Europe. In addition to pharmacovigilance data, this article also provides an overview of mechanisms of action, additional adverse effects, and the drug interactions of metamizole, e.g., the induction of CYP3A4.

Conclusion: Metamizole is a powerful analgesic drug whose varying regulatory status from country to country reflects its mixed benefit–risk profile. Patients must be instructed about the risk of agranulocytosis and the symptoms by which it can be recognized early.

Cite this as: Cascorbi I, Baron R: Metamizole: Indications and risks. Dtsch Arztebl Int 2026; 123: 27–34. DOI: 10.3238/arztebl.m2025.0214

Metamizole (also known as dipyrone) is a powerful analgesic and antipyretic drug and is one of the most commonly prescribed medications in Germany. In many hospitals it is considered almost indispensable for postoperative pain relief. Due to its alleged analgesic and antipyretic effect but also its spasmolytic potency, metamizole is indicated for the management of severe acute pain following injury or surgery, in colic, and in tumor pain or other acute or severe pain syndromes when other treatments are not appropriate, as well as in high fever if other measures are unsuccessful. There is no lower or upper age limit, but the dose must be adjusted. From the age of 15 years upward, the daily maximum dose is 4000 mg. Although the high analgesic efficacy of metamizole is often described, systematic studies allowing quantitative comparison with other pain-relieving drugs are rare. In one study on postoperative pain after hip joint replacement, for example, metamizole lowered the pain rating on a 100-point analog visual scale to 17.9, while the score for acetaminophen was 30.6 (1). A significant difference has also been found between metamizole and diclofenac (2). Moreover, a combination of metamizole and ibuprofen proved more effective against pain than either agent alone (3). A systematic review of tumor pain alleviation showed that metamizole 3 × 2 g/d was equivalent to morphine 60 mg p.o., and in cases of less intense pain metamizole was equipotent to other non-opioids (4).

Metamizole is included in the WHO list of essential medicines. Due to serious concerns regarding drug safety, in particular the known risk of agranulocytosis, metamizole has never been approved for use in some countries, or its approval has been revoked. In Germany, the Drug Commission of the German Medical Association and the Federal Institute for Drugs and Medical Devices (BfArM) have regularly (most recently in December 2024) published Dear Healthcare Provider Letters (DHCP) referring to the risk of agranulocytosis and giving treatment recommendations accordingly (5). For this article we conducted a survey of the literature in PubMed, web-based data banks, and product information sheets on metamizole to produce an overview of its known mechanisms of action, the prevalence of adverse drug reactions, and the pharmacokinetic and pharmacodynamic interactions with other drugs. Our aim was to evaluate the benefits and risks of treatment with metamizole.

Learning objectives

After reading this article, the reader should:

• Be familiar with the spectrum of indications for metamizole and its role in relation to other analgesics.
• Be able to recognize the major adverse effects of metamizole—particularly the rarely occurring serious complications—explain them in clear terms, and take adequate account of them in clinical routine.
• Be in a position to incorporate drug interactions and benefit/risk analysis of metamizole in their treatment decisions and modify their management strategies accordingly.

Metamizole’s mechanisms of action

The pyrazolone derivative metamizole, a member of the group of non-acidic non-opioid analgesic drugs, became commercially available in 1922, one of the first purely synthetic analgesics on the market. The mechanism of action of metamizole has still not been completely elucidated; however, the principal pain-relieving effect of the drug is attributed to inhibition of prostaglandin E2 (PGE2) formation by its metabolite 4-methyl-amino-antipyrine (MAA). This is not due to competitive inhibition of arachidonic acid metabolism as is the case with conventional cyclo-oxygenase (COX) inhibitors such as ibuprofen and diclofenac; rather, it is surmised that the effect arises from a reduction in the higher oxidation levels of COX1 and COX2 or sequestration of activating peroxides (6) with direct consequences on the excitability of primary afferent neurons. In addition to interactions with other signaling pathways (7), animal experiments indicate that metabolites of metamizole bring about stimulation of the cannabinoid type 2 (CB2) receptor and trigger activation of the kappa opioid receptor (8). Moreover, the heat receptor TRPV1 is desensitized (9). In summary, metamizole possesses analgesic properties that are independent of COX inhibition and contribute to our understanding of the drug’s pain-relieving potency.

Epidemiology

In the initial period after approval, metamizole was available over the counter. It was only when rare but serious adverse effects became known that prescription requirements were introduced in Germany (in 1987) and other countries. In some European nations such as the UK and in other countries, e.g., the USA, Canada, and Australia, preparations including metamizole are no longer licensed due to serious safety concerns regarding the risk of agranulocytosis. In the European Union, metamizole is approved in Austria, Belgium, Bulgaria, Croatia, the Czech Republic, Hungary, Italy, Latvia, Lithuania, Luxembourg, the Netherlands, Poland, Portugal, Romania, Slovakia, Slovenia, and Spain, in addition to Germany.

In Germany, metamizole remains one of the most commonly prescribed drugs of all. Between 1991 and 2022 the number of defined daily doses (DDD) of metamizole climbed from 15 million to 280 million (10). In a cross-sectional study on adults living in residential care homes (mean age 74.5 years), half of those with severe or disabling pain were found to be consuming analgesic drugs. Of these, 16.1% were taking metamizole. Statutory health insurance data on prescription rates in Germany showed that 8.1% of the 68.4 million insured persons had metamizole prescribed at least once annually (11). According to the BARMER Drug Report 2023, 14.1% of insured persons were prescribed metamizole at least once in the year 2021. Strikingly, especially patients over the age of 80 years were prescribed metamizole at a higher rate (37.9%) (12).

This means that metamizole ranked second only to occasionally consumed COX inhibitors as the most frequently used analgesic drug (13).

Comparative efficacy studies

In Germany, metamizole is not only the non-opioid analgesic most commonly used for perioperative pain relief, but also represents a major pillar of treatment in the management of chronic pain (14), particularly back pain. Metamizole often makes it possible to reduce or even completely discontinue opioid therapy, a crucial goal in view of the opioid crisis in the USA (15, 16). Only a small number of systematic studies with sufficiently large samples have compared metamizole with other non-opioid drugs or examined the additional opioid requirements. A small randomized clinical trial (RCT) of metamizole versus morphine in acute pancreatitis found that lower pain scores were achieved more swiftly with metamizole than with morphine, although the difference was not statistically significant (17). In an RCT on the treatment of pain after outpatient surgery, the combination of metamizole and acetaminophen was not inferior to that of ibuprofen and acetaminophen, but the additional opioid consumption was lower on postoperative day 2 (18). In a pediatric RCT on postoperative pain following tonsillectomy, 10 mg/kg body weight acetaminophen i.v. and 10 mg/kg body weight metamizole i.v. showed no difference in pain reduction or the need for additional pethidine (19). An RCT on the use of metamizole and acetaminophen for the treatment of postoperative pain following breast surgery found a tendency towards less severe pain with acetaminophen, although about the same proportion of patients taking acetaminophen as of those taking metamizole or placebo needed additional morphine. An interesting explanation for the lower pain-relieving potency of metamizole i.v. than metamizole p.o. observed in this trial postulates that without the first-pass effect, less of the active metabolite MAA is formed in the liver and renal excretion of metamizole is faster (20).

Metamizole is not recommended in the guidelines for the treatment of neuropathic pain (21). It should be noted, however, that no controlled trials of metamizole itself are available; rather, the low efficacy of other COX inhibitors was extrapolated to metamizole. In light of the new insights into the mechanism of action of metamizole, this gap in our knowledge should be closed by future research.

Adverse drug reactions

According to the product information (22), metamizole can cause minor adverse reactions in the skin and mucosa, such as itching, burning, reddening, urticaria, and swelling, and may also give rise to dyspnea and, more rarely (0.01%–0.1%), gastrointestinal symptoms (e.g., nausea, dyspepsia, vomiting). Occasionally (0.1%–1%), particularly with parenteral administration, hypotensive reactions may occur, possibly extending as far as a major reduction in blood pressure. Drug-related exanthema may also occasionally be found.

The European pharmacovigilance database EudraVigilance lists a total of 15 770 suspected cases of adverse drug reactions to metamizole (23). Of these, 77.6% were reported by medical professionals, 21.7% by non-medical personnel. The majority of the reports come from Germany (eTable). Women are over-represented (59.8%), while 3.2% of cases could not be assigned. Large numbers of reports concerned the age groups 18–64 years (46.4%) and 65–85 years (24.3%). In 18.1% of cases, no patient age could be stated. The most commonly specified reaction group was “Skin and subcutaneous tissue disorders,” followed by “General disorders and administration site conditions” and “blood and lymphatic system disorders.” “Agranulocytosis” was not included as a category in itself, but subsumed in the reaction groups listed in Table 1. Multiple entries were possible.

Table 1

The number of suspected cases of adverse drug reactions to metamizole, by reaction group and age, reported to the European Union portal EudraVigilance in the period 2012–2025 (23). The portal does not list “Agranulocytosis” as a separate reaction group.

eTable

The number of suspected cases of adverse drug reactions to metamizole from European Union countries and the UK reported to the EU portal EudraVigilance in the period 2012–2025 (23)

Agranulocytosis is not the only life-threatening reaction to metamizole. Equally dangerous is anaphylaxis, which occurs rarely or very rarely and may also arise after previously uncomplicated administration of metamizole. The incidence of anaphylaxis is estimated at 8.1 (95% confidence interval [3.5; 19]) per 10 000 persons exposed, much higher than that of agranulocytosis, but similar to the risk of anaphylaxis after administration of diclofenac, where the incidence is 7.2 [2.6–20] per 10 000 patients treated (6).

Liver toxicity

The risk of drug-induced liver injury (DILI) is thought to be low compared with analgesics such as acetaminophen and some COX inhibitors. A retrospective analysis of 126 cases of DILI in Barcelona, Spain in 2007 showed a non-significant relative risk of 3.1 [0.4–11.4] for metamizole, lower than for acetaminophen, diclofenac, and also ASA (24). A review of the hepatic effects of metamizole published in 2019 lists other cases, some of them historical. The author stated that liver injury seems possible, but the current state of knowledge does not yet allow for definitive conclusions (25). In light of the increasing reports of metamizole-induced liver damage, in 2019 the European Medicines Agency initiated an evaluation process based on the data from a German registry covering the years 2009–2018 and including only cases with no history of liver disease before the first prescription and that were observed over 270 days. The study came to the opposite conclusion: the risk of liver injury was 1.7 times higher for metamizole than for acetaminophen (26). The BfArM drew attention to the risk in a DHCP issued in 2020 (27). Indirect confirmation of the potential risk was provided by a retrospective study of 154 cases of DILI at University Hospital Hamburg-Eppendorf in 2020, in which metamizole was thought to be the cause in 14.9% of cases, second only to the anticoagulant drug phenprocoumon (28).

Patients should be informed accordingly. In particular, metamizole should not be used again in those in whom liver injury of otherwise unexplained origin has occurred during metamizole treatment.

The risk of agranulocytosis

Following the initial global use of metamizole, substantial safety concerns led a number of regulatory authorities to decide to withdraw approval for metamizole due to the very rare but life-threatening occurrence of agranulocytosis. Agranulocytosis is present when the neutrophil count is under 500 cells/μL, and the risk of severe infections is elevated especially if the neutrophil count in peripheral blood falls below 100/μL. Metamizole may also cause a very rare additional decrease in platelet count or, in isolated cases, pancytopenia or aplastic anemia as possible side effects (22). A report from the EudraVigilance database identified 1478 cases of agranulocytosis in the period 1985–2017, most of them in Germany and Switzerland (29). Agranulocytosis events were not dose-dependent: the median dose was 1500 mg/d, within the recommended range, and the events occurred at a median latency of 13 days after starting consumption. Some 43% of the cases were reported as life-threatening and 16.2% (n = 222) as fatal. The proportion of fatal cases reported before 1998 was 20.9% and decreased to 15% after 2007.

The true incidence rate of this very rare event is difficult to estimate. The figures of some 44 reported cases of agranulocytosis per year from 2015 to 2017 and at least 5.54 million prescriptions annually in Germany (11) indicate an incidence rate of 7.9 per million prescriptions. Note that these data do not include how many times metamizole was taken or over what period of time, which could be additionally informative. Other data from various European studies on incidence rates within 7–10 days after exposure, summarized by Andrade et al. (30), vary from 0.6 to 1.4 per million. In contrast, Swedish data from the year 2002, based on 10 spontaneous reports and pharmacy sales data, estimate one case per 1400 outpatients (31), which would correspond to an incidence of 714 per million. Similar incidences were found by a 3-year cohort study of members of a German statutory health insurance fund (Techniker-Krankenkasse). Among the 630 000 outpatients who were prescribed metamizole, 587 cases of agranulocytosis (ICD10 code D70.3) or neutropenia (D70.7) were identified. In a matched control group of 391 000 persons, there were 120 cases. The risk relative to the control group, including neutropenia, was therefore 1:1602 [1:1926; 1:1371] (13). No figures were available for agranulocytosis alone. More recent data from Spain, based not on spontaneous reports but on public healthcare data, indicate a far lower incidence rate (32). In a study on the risk of agranulocytosis and neutropenia in 444 972 patients receiving metamizole for the first time compared with patients treated with COX inhibitors (referred to in the article as NSAID) or with opioids and/or acetaminophen, a total of 21 cases of agranulocytosis occurred. The agranulocytosis incidence rate per 1 million person-weeks was 0.85 for metamizole, 0.44 for COX inhibitors, and 0.24 for opioids/acetaminophen (Table 2).

Table 2

Incidence rates and hazard ratio of agranulocytosis and neutropenia during treatment with metamizole versus COX inhibitors and opioids/acetaminophen. The data come from a registry study using public healthcare data in Spain and incorporate the assumption that illness began 7 days before hospitalization (23).

In light of the ongoing debate on the risk of potentially life-threatening agranulocytosis, in September 2024 the European coordination group CHMP (Committee for Medicinal Products for Human Use) confirmed the recommendation for revision of the product information for metamizole due to the danger of agranulocytosis. The aim is to facilitate early detection. It is explicitly pointed out that metamizole is contraindicated in patients with a history of agranulocytosis caused by metamizole (or other pyrazolones or pyrazolidines) and in persons with impaired bone marrow function or diseases of the hematopoietic system. One should also note that the antimetabolite methotrexate can cause bone marrow depression and should therefore not be used in combination with metamizole. An elevated risk for patients who have had neutropenia or agranulocytosis while taking, for example, the antipsychotic clozapine or thyrostatics such as thiamazole is theoretically possible but has not been attested and has therefore not been incorporated as a warning. Despite all this, the benefit–risk assessment remained positive (33).

Research into the cause

Currently the discussion centers around immunologically mediated processes in the form of a T-cell response directed against neutrophilic granulocytes. Nevertheless, the pathophysiology remains unclear. Since the agranulocytosis triggered by the antipsychotic clozapine is associated with the presence of specific HLA alleles (34), the question arises of whether there could be a genetic basis for the occurrence of agranulocytosis with metamizole. However, small studies on the association of metamizole-induced agranulocytosis in three European populations have not yielded any convincing findings. The most promising genetic variants, attaining marginal significance in a pooled meta-analysis, were rs55898176 and rs4427239, the latter localized in SVEP1 (Sushi, von Willebrand factor type A, EGF and pentraxin domain-containing protein 1), a gene assigned to hematopoiesis (35). Prediction of the individual risk of agranulocytosis through genotyping is, however, not feasible on the basis of our current state of knowledge. The precise reason for the occurrence of agranulocytosis thus remains unknown.

Drug interactions

Given the frequency with which metamizole is prescribed in Germany, drug interactions are likely. For example, three 500-mg tablets of metamizole taken on the same day suffice to bring about CYP3A4 induction-related reduction in bioavailability of the immunosuppressant cyclosporin (36). Apart from CYP3A4, metamizole is a moderate inducer of CYP2B6 and CYP2C19, as well as a weak inducer of CYP2C9 and a weak inhibitor of CYP1A2 (37). The intake of 3 × 1 g metamizole daily for 7 consecutive days led to a decrease in the AUC for efavirenz of 79%, for midazolam of 68%, and for omeprazole of 66%. In addition, the bioavailability of the antipsychotic quetiapine is decreased by more than 50% in the presence of metamizole (38). According to the FDA criteria, this means that metamizole must be classified as a moderate to strong inducer (39). What are the consequences? If metamizole is prescribed for more than just a few days, it could lead to a considerable decrease in the efficacy of other simultaneously administered drugs that are metabolized by P450 enzymes. This is particularly important for drugs with a small therapeutic index. Interestingly, many interaction tables do not feature metamizole, possibly because a large number of countries have not licensed it for use.

Apart from the pharmacokinetic interactions, metamizole—like ibuprofen—impairs the thrombocyte aggregation-inhibiting effect of simultaneously administered ASA (6). The product information has already been amended accordingly, with the recommendation that ASA be taken 30 minutes before metamizole or the metamizole dose reduced to avoid such pharmacodynamic interactions (40).

Risk assessment

Can metamizole still be classified as safe? Although this potent analgesic for acute and chronic pain is no longer approved in many countries due to concerns about the risk of agranulocytosis, a survey of anesthetists in the German-speaking countries shows that metamizole remains the preferred non-opioid analgesic drug for the treatment of acute pain, particularly before the end of surgery and in the recovery room, but also for the management of chronic pain of diverse origin (14). According to the recommendations for the treatment of cancer pain, metamizole, alone or in combination with opioids, is more effective than COX inhibitors, is tolerated well, and has no contraindications such as cardiovascular or gastrointestinal comorbidity. The benefit is therefore considered to outweigh the risks (4). A similar conclusion was reached by the authors of a systematic review of the side effect potential of metamizole, ASA, ibuprofen, and acetaminophen in 1804 patients. None of them led to severe adverse events (SAE); mild and moderate side effects occurred less frequently with metamizole than with ASA and acetaminophen (e1). However, the limited number of patients included in the study permitted no conclusions as to the risk of agranulocytosis. The German registry study mentioned above (13) was able to provide data on incidence based on a cohort of several hundred thousand metamizole patients, as was a Spanish registry study published in 2024 (32). In contrast to the German survey, which calculated a much higher risk than indicated by pharmacovigilance data, the Spanish study revealed a far lower occurrence of agranulocytosis. The two studies agree, however, that the risk is much higher than for treatment with other analgesic drugs.

Metamizole can thus be viewed as basically effective and safe if used as indicated, but the risk of a very rare SAE exists.

Careful clinical monitoring and patient information regarding the potential early clinical signs of granulocytopenia are therefore indispensable whenever metamizole is prescribed (Box).

Box

Recommendations of the DHCP issued on 9 February 2024 (5)

The following are considered as risk factors: previous agranulocytosis, simultaneous use of bone marrow-suppressing drugs such as methotrexate, and bone marrow diseases. There are no biomarkers to predict the risk of agranulocytosis. It must be borne in mind that agranulocytosis—though very rare—is not only a threat to life but may also cause long-lasting health impairments.

In view of the recent data on the risk of liver injury and on the previously less clearly recognized risk of drug interactions, additional caution is warranted, and long-term use of metamizole should be considered carefully. Given the variation in prescription patterns in different countries and the ongoing discussions about safety concerns, metamizole will remain a drug with ambivalent properties in terms of its potential benefits and risks.

Conflict of interest statement
RB has received financial support from Pfizer Pharma GmbH, Grünenthal GmbH, Mundipharma Research GmbH, Alnylam Pharmaceuticals Inc, Zambon GmbH, Sanofi Aventis GmbH, and Viatris. He has received lecture honoraria from Pfizer Pharma GmbH, Sanofi Aventis GmbH, Grünenthal GmbH, Mundipharma, Lilly GmbH, Desitin Arzneimittel GmbH, Teva GmbH, Bayer AG, MSD GmbH, Seqirus Australia Pty. Ltd, Novartis Pharma GmbH, TAD Pharma GmbH, Grünenthal SA Portugal, Grünenthal Pharma AG Switzerland, Grünenthal B.V. Niederlande, Evapharma, Takeda Pharmaceuticals International AG Switzerland, Ology Medical Education Netherlands, Ever Pharma GmbH, Amicus Therapeutics GmbH, Novo Nordisk Pharma GmbH, Chiesi GmbH, Stada Mena DWC LLC Dubai, Hexal AG, Viatris, AstraZeneca GmbH, Sandoz, Aristo, Esanum, and Docflix GmbH. He has received consultancy fees from Pfizer Pharma GmbH, Sanofi Aventis GmbH, Grünenthal GmbH, Lilly, Novartis Pharma GmbH, Bristol-Myers Squibb, Biogenidec, AstraZeneca GmbH, Daiichi Sankyo, Glenmark Pharmaceuticals S.A., Seqirus Australia Pty. Ltd, Teva Pharmaceuticals Europe Netherlands, Teva GmbH, Genentech, Mundipharma International Ltd. UK, Galapagos NV, Kyowa Kirin GmbH, Vertex Pharmaceuticals Inc., Biotest AG, Celgene GmbH, Desitin Arzneimittel GmbH, Regeneron Pharmaceuticals Inc. USA, Theranexus DSV CEA France, Abbott Products Operations AG Switzerland, Bayer AG, Grünenthal Pharma AG Switzerland, Akcea Therapeutics Germany GmbH, Asahi Kasei Pharma Corporation, AbbVie Germany GmbH & Co. KG, Air Liquide Sante International France, Alnylam Germany GmbH, Lateral Pharma Pty Ltd, Hexal AG, Angelini, Janssen, SIMR Biotech Pty Ltd Australia, Confo Therapeutics N. V. Belgium, Merz Pharmaceuticals GmbH, Neumentum Inc., F. Hoffmann-La Roche Ltd. Switzerland, AlgoTherapeutix SAS France, Nanobiotix SA France, AmacaThera Inc. Canada, Hoba Therapeutics, Heat2Move, Resano GmbH, Esteve Pharmaceuticals SA, Aristo, Viatris, Vertanical GmbH.

IC declares that no conflict of interest exists.

Manuscript submitted on 9 July 2025, revised version accepted on
17 November 2025

Translated from the original German by David Roseveare

Corresponding author
Prof. Dr. med. Dr. rer. nat. Ingolf Cascorbi

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