Metamizole, also sold as dipyrone, is banned in the United States, United Kingdom, Japan, Sweden, and several other countries because it can trigger a rare but potentially fatal blood disorder called agranulocytosis. The FDA pulled it from the U.S. market in 1979, and other nations followed in the early 1980s. The drug remains widely available by prescription across much of Europe and Latin America, creating one of the most striking regulatory divides in modern medicine.
What Agranulocytosis Actually Does
Agranulocytosis is a sudden, sharp drop in a type of white blood cell called granulocytes. These cells are the immune system’s first responders against bacterial and fungal infections. When their numbers collapse, even a minor infection can become life-threatening within days. Patients typically develop high fever, mouth ulcers, and sore throat as early signs, but without prompt treatment, the condition can progress to sepsis and death.
The exact way metamizole causes this isn’t fully settled. One proposed mechanism involves the drug triggering the formation of antibodies that attack the body’s own neutrophils (a key type of granulocyte) after they bind to metamizole or its breakdown products. Another line of evidence suggests that a primary metabolite of the drug may directly poison the precursor cells in bone marrow that produce granulocytes. Either way, the result is the same: the body temporarily loses its ability to fight infection.
How Rare the Risk Actually Is
This is where the controversy gets interesting. The risk of metamizole-induced agranulocytosis is genuinely small. A study using Spanish health data reported roughly 1 to 14 cases per 10 million person-weeks of continuous treatment. Most estimates place the overall incidence somewhere between 1 in 1,500 and 1 in several million users, depending on the population studied and how cases are counted. The wide range itself is part of the problem: regulators in different countries looked at the same uncertain data and reached opposite conclusions.
Researchers have tried to identify genetic markers that would predict who is vulnerable. A European study examined eight genes in the HLA system (the part of the genome that governs immune responses) across Swiss, German, and Spanish patients. One variant, HLA-C*04:01, showed a statistical link in the Swiss group, but no candidate gene held up consistently across all three populations. The conclusion was blunt: there is no reliable genetic test to screen out high-risk patients before prescribing the drug. That unpredictability is a core reason regulators in banning countries considered the risk unacceptable.
Why Some Countries Ban It and Others Don’t
The FDA’s 1979 decision was straightforward. Agranulocytosis is unpredictable, potentially fatal, and there are alternative painkillers available. Countries like the UK, Sweden, Denmark, and Japan applied the same logic. If a drug carries even a small chance of killing someone through a side effect that no screening can prevent, and if other options exist, the calculus tips toward removal.
Countries that kept metamizole on the market weighed the equation differently. Metamizole is a genuinely effective painkiller. It works against postoperative pain, cancer pain, kidney colic, and migraine. It also reduces fever and relaxes smooth muscle spasms, a combination that few single drugs can match. In many European and Latin American health systems, it fills a practical gap: it’s a strong non-opioid option for patients who can’t tolerate standard anti-inflammatory drugs due to stomach problems, kidney disease, or cardiovascular risk.
As of 2024, metamizole remains authorized in at least 18 EU member states, including Germany, Spain, Italy, Poland, Austria, and the Netherlands. In several Latin American countries, particularly Brazil, it is available over the counter and ranks among the most commonly used painkillers.
The Safety Comparison That Complicates the Story
One large comparative safety analysis estimated the excess deaths per 100 million users from serious side effects of common painkillers: agranulocytosis, aplastic anemia, anaphylaxis, and serious upper gastrointestinal bleeding combined. Metamizole came in at an estimated 25 excess deaths per 100 million users. Acetaminophen (paracetamol) was similar at 20. Aspirin was estimated at 185, and diclofenac at 592.
The dramatically higher numbers for aspirin and diclofenac were driven almost entirely by gastrointestinal bleeding, a well-documented risk of anti-inflammatory drugs. The authors calculated that the risk of agranulocytosis from metamizole would need to be more than 300 times higher than observed to push its overall mortality rate up to the level of aspirin. In other words, the drug that got banned appears, by this measure, to be safer overall than painkillers that remain freely available in every pharmacy.
This paradox fuels ongoing debate. Critics of the ban argue the decision was based on fear of a dramatic but exceedingly rare side effect, while ignoring the slower, less visible toll of gastrointestinal bleeding from drugs that stayed on the market. Defenders of the ban counter that agranulocytosis is sudden, difficult to catch early, and disproportionately fatal when it occurs, making it qualitatively different from risks that can be managed with dose adjustments or co-prescribed stomach protectors.
Europe’s 2024 Safety Review
In June 2024, the European Medicines Agency launched a formal review of metamizole, specifically examining whether existing safety measures were doing enough to minimize agranulocytosis outcomes. By September 2024, the EMA’s safety committee recommended updating product information to raise awareness of the risk and improve early detection. The committee did not recommend pulling the drug from the market.
The updated guidance focuses on making sure prescribers and patients recognize the early warning signs of agranulocytosis, particularly unexplained fever, sore throat, and mouth sores, so that treatment can be stopped and blood counts checked before the condition becomes dangerous. This reflects the European regulatory philosophy: keep the drug available, but tighten the safety net around it.
What Metamizole Actually Does in the Body
Metamizole is a prodrug, meaning it’s inactive until the body breaks it down into active compounds. Its pain-relieving effects come from blocking the same enzymes (COX-1 and COX-2) that aspirin and ibuprofen target, reducing the production of chemicals that sensitize nerve endings to pain. But it also appears to work through at least two additional pathways: it activates the body’s internal opioid system and interacts with the cannabinoid system, the same network that cannabis acts on. This multi-pathway action likely explains why it’s effective for types of pain that standard anti-inflammatory drugs handle poorly, particularly visceral pain from internal organs.
Its fever-reducing effect works centrally, by blocking the production of inflammatory signaling molecules in the brain. The combination of strong pain relief, fever reduction, and muscle-spasm relaxation in a single non-opioid drug is unusual, which is why countries that allow it consider it difficult to replace.