Dipyrone (metamizole) use in the United States: a lethal tango?

The nonsteroidal agent dipyrone (metamizole) was banned by the United States Federal Drug Administration (FDA) in the late 1970s after it was associated with myelotoxicity. This toxicity and, specifically, the development of agranulocytosis remain a topic of discussion within the medical literature. Less debatable, but perhaps more surprising, is the fact that this drug is still commonly seen in the United States despite the FDA ban. As described by Garcia et al, (1) dipyrone was found in 28% of surveyed Latino households in Miami. The drug is generally obtained over the counter in Latin America and is being used by Latinos for treatment of pain and/or fever.

A survey of the medical literature reveals multiple case reports of agranulocytosis attributed to dipyrone, but the actual incidence of this potentially fatal side effect is still the subject of debate. A recent, population-based survey in hematology units in Spain documented 177 cases of drug-induced agranulocytosis for a follow-up of over 78 million person-years. (2) While agranulocytosis was a rare event, the medications most associated with this toxicity included ticlopidine, calcium dobesilate, antithyroid drugs, spironolactone, and dipyrone. A Swedish study looking at spontaneous reports of blood dyscrasias with dipyrone estimated the reported incidence of agranulocytosis to be approximately 1:1,400, considerably higher than previous studies. (3) The International Agranulocytosis and Aplastic Anemia Study (IAAAS) also reported on dipyrone-induced myelotoxicity, finding an incidence of approximately 1:20,000. (4)

But uncertainty as to this association remains. Edwards et al have noted that these studies have strikingly different findings in terms of magnitude of risk, and the absolute risk of agranulocytosis may be quite small. (5) Confounding issues such as consumption, frequency of use, geography, and genetic factors might also affect the ultimate risk of toxicity with this drug. (6,7) Similarly, Bensenor has noted that the relative risk of toxicity with this inexpensive and effective nonsteroidal medication--when compared with other commonly used analgesics such as acetaminophen--is likely quite low. (8)

The ongoing LATIN study (incidence of aplastic anemia and agranulocytosis in Latin America) may answer these questions for us. (6,9) This multicenter, international, case-control study is collecting data on the incidence of agranulocytosis and aplastic anemia in Latin America and offers hope that the longstanding debate surrounding the use of dipyrone will be settled. The countries involved in the study have decided not to withdraw this drug from their markets.

In the meantime, the ban in the US will rightly remain. Clinicians must be cognizant, however, that dipyrone is readily available in Latino communities and likely possesses at least some risk to patients. Garcia et al note that the drug is available alone and in multiple combination forms. (1) As such, a detailed history of prescription and nonprescription medication use must be obtained--particularly in the setting of blood dyscrasias.

References

1. Garcia S, Canoniero M, Lopez G, et al. Metamizole use among Hispanics living in the United States: report of a survey conducted in a primary care setting in Miami. Southern Med J 2006;99:924-926.

2. Ibanez L, Vidal X, Ballarin E, et al. Population-based drug-induced agranulocytosis. Arch Intern Med 2005;165:869-874.

3. Hedenmalm K, Spigset O. Agranulocytosis and other blood dyscrasias associated with dipyrone (metamizole). Eur J Clin Pharmacol 2002;58:265-274.

4. 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. JAMA 1986;256:1749-1757.

5. Edwards JE, McQuay HJ. Dipyrone and agranulocytosis: what is the risk? Lancet 2002;360:1438.

6. Hamerschlak N, Maluf E, Pasquini R, et al. Incidence of aplastic anemia and agranulocytosis in Latin America-the LATIN study. Sao Paulo Med J 2005;123:101-104.

7. Vlahov V, Bacracheva N, Tontcheva D, et al. Genetic factors and risk of agranulocytosis from metamizol. Pharmacogenetics 1996;6:67-72.

8. Bensenor IM. Dipyrone and blood dyscrasia revisited: "non-evidence based medicine." Sao Paulo Med J 2005;123:99-100.

9. Hamerschlak N, Cavalcanti AB. Neutropenia, agranulocytosis and dipyrone. Sao Paulo Med J 2005;123:247-249.

Jonathan Moorman, MD, PhD

From the Department of Internal Medicine, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN.

Reprint requests to Jonathan Moorman, MD, PhD, Associate Professor, Department of Internal Medicine, James H. Quillen College of Medicine, East Tennessee State University, Box 70622, Johnson City, TN 37614. Email: [e-mail]

Accepted April 21, 2006.