Should We Still Prescribe Metamizole (Analgin)?

Metamizole (also known as dipyrone) is an analgesic, antipyretic, and spasmolytic that has been used in various countries since 1922. It is well known for its effectiveness in treating moderate to severe pain, including postoperative pain, cancer-related pain, and migraines, and offers certain advantages compared with nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids. Specifically, it is associated with lower gastrointestinal, cardiovascular, and renal toxicity. However, despite these benefits, metamizole has been linked to a rare but serious adverse reaction: agranulocytosis, a condition that can lead to life-threatening infections due to a sudden and significant reduction in granulocytes.

Availability of Metamizole

The availability and use of metamizole vary greatly worldwide. It is banned in several countries, including the United Kingdom, the United States, Canada, and parts of Scandinavia (Norway, Denmark, Sweden), primarily due to concerns about agranulocytosis. On the other hand, metamizole is widely available in many European and non-European countries, including Spain, Germany, Brazil, Russia, and Mexico. These differences largely reflect long-standing debates regarding the drug’s safety profile.

In Croatia, metamizole is available by prescription.

What is the risk of agranulocytosis with metamizole?

Agranulocytosis is a rare but potentially fatal adverse reaction to metamizole, defined as a drop in neutrophil count (a type of white blood cell) below 500 cells per mm³ of blood. This condition severely compromises the immune system, making patients highly vulnerable to severe infections. Agranulocytosis may occur at any time during treatment or shortly after discontinuation, and it can develop rapidly, especially in patients with prior exposure to the drug.

The risk increases with longer treatment duration, though it is not dose-dependent. Certain groups, including women and older adults, appear to be at greater risk.

Reports on the incidence of metamizole-induced agranulocytosis vary significantly across studies and regions. The International Agranulocytosis and Aplastic Anemia Study (IAAAS), conducted in the 1980s, was one of the first large-scale investigations. It reported an incidence of 1 case per 1.1 million user-weeks, or approximately 6.2 cases per million users per year, suggesting a very low risk.

Subsequent European studies generally confirmed a low incidence, between 0.6 and 1.4 cases per million within 7–10 days of exposure. However, some studies reported higher rates: a widely cited Swedish study found 1 case per 1,431 prescriptions, while a German study estimated 1 case per 1,602 prescriptions. These discrepancies may reflect methodological differences or population-based genetic factors, making risk assessment challenging.

EMA safety measures

Due to these concerns, the European Medicines Agency (EMA) has periodically reviewed metamizole’s safety. In September 2024, the EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) recommended new measures to reduce the risk of serious consequences of metamizole-induced agranulocytosis. This review was triggered by Finland’s national medicines agency after continued reports of agranulocytosis despite earlier risk minimization measures.

The review of available data, including post-marketing surveillance and spontaneous reports from healthcare professionals, confirmed that agranulocytosis remains a serious and unpredictable adverse event of metamizole. PRAC concluded that, although the benefits of metamizole in treating pain and fever outweigh the risks, stricter safety measures are necessary. These include:

• Updating product information: EMA recommended updates for all metamizole-containing products in the EU to better inform healthcare professionals and patients about the risk of agranulocytosis and to facilitate early recognition and treatment.

• Patient warnings: Healthcare providers are now required to advise patients to stop taking metamizole immediately and seek medical attention if they develop symptoms such as fever, sore throat, chills, or mucosal ulcerations. Since agranulocytosis can progress rapidly and cause severe infections, early recognition is critical.

• Restrictions for at-risk groups: PRAC advised against prescribing metamizole in patients at increased risk, including those with a history of metamizole-induced agranulocytosis or reactions to similar pyrazolone derivatives, and patients with bone marrow disorders or coagulation abnormalities. ⚠️ Note: The pyrazolone derivative propyphenazone is present in certain combination analgesics on the Croatian market (e.g., Caffetin, Saridon, Plivadon).

Mechanism of agranulocytosis

The exact mechanism by which metamizole causes agranulocytosis is not fully understood. Evidence suggests an immune-mediated mechanism, where metamizole or its metabolites may trigger an abnormal immune response leading to granulocyte destruction. Another theory proposes a direct toxic effect on bone marrow precursors. Genetic studies have not identified consistent risk markers, complicating definitive conclusions.

Efficacy and safety compared with other analgesics

In terms of analgesic efficacy, metamizole has shown pain relief comparable to paracetamol, NSAIDs, and opioids.

One of its main advantages over NSAIDs is the lower risk of gastrointestinal, cardiovascular, and renal adverse effects, making it particularly useful for patients intolerant to these complications. However, the risk of agranulocytosis remains the key concern, requiring careful risk-benefit assessment, especially with longer treatment durations.

Conclusion

Metamizole remains available as an analgesic and antipyretic in many countries, including Croatia (by prescription), particularly for patients needing alternatives to NSAIDs or opioids. Its long history of use underscores its efficacy in treating pain and fever. However, although the incidence of metamizole-induced agranulocytosis is low, it is a serious and unpredictable adverse event that requires close monitoring and implementation of risk reduction measures.

Therefore, metamizole should be considered a second-line option for pain or fever management, reserved for patients where other therapies are unsuitable.

References:

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3. Summary of product characteristic, Alkagin 500 mg, April 21, 2022. Available at: https://halmed.hr/upl/lijekovi/SPC/Analgin-SPC.pdf

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