(2002; 22 pages)
METAMIZOLE - Analysis of Swedish adverse reaction reports
In one of the earlier issues of the WHO Pharmaceuticals Newsletter (Issue No. 1, 2002) we published a discussion paper entitled ‘A reappraisal of antipyretic and analgesic drugs’ by Dr Anthony Wong, University of Sao Paulo, Brazil. The author discussed the continued presence of metamizole sodium (dipyrone) in the Brazilian market despite reports of metamizole-induced agranulocytosis in other countries. As anticipated, the article generated a volley of opinions and counter arguments on the merits and demerits of metamizole, an analgesic drug. In presenting the ‘other side of the story on metamizole’ we refer our readers to a recent article published by Dr Karin Hedenmalm and Dr Olav Spigset in the Pharmacoepidemiology and Prescription section of the European Journal of Clinical Pharmacology (Hedenmalm K, Spigset O (2002): Agranulo-cytosis and other blood dyscrasias associated with metamizole (dipyrone), Eur J Clin Pharmacol 58: 265-274). This is abstracted below:
Metamizole (dipyrone) is an analgesic compound structurally related to amidopyrine from the phenylpyrazolone group. In the early 1930s, amidopyrine was identified as a cause of agranulocytosis. Soon after metamizole was also associated with agranulocytosis and the risk was suggested to be about 1 in 120 treated patients. This estimate however appeared to be based on potentially biased information from published and unpublished patient series. Because of the risk of agranulocytosis, metamizole has been banned or withdrawn from the market in most industrialised countries but is still available in some countries in Europe including Germany, France and Spain, the far East, Africa and Latin and South America. Of particular intrigue are the Swedish regulatory measures for metamizole. In Sweden all metamizole containing products were first withdrawn in March 1974 due to an estimated incidence of agranulocytosis of 1 in 3000 patients. However, later, data from the International Agranulocytosis and Aplastic Anaemia (IAAA) study put down the risk for agranulocytosis as low as 1.1 cases per million users. Therefore, in September 1995, metamizole was re-approved based on the results from the IAAA study and then later, again suspended in April 1999 based on Swedish adverse drug reactions data, which have now been published. Dr Karin Hedenmalm from the Swedish Medical Products Agency and Dr Olav Spigset from Norway’s St. Olav’s University Hospital have reviewed all reports of metamizole-related blood dyscrasias that were submitted to the Swedish Adverse Drug Reactions Advisory Committee (SADRAC). Based on pharmacy sales data and spontaneous reporting of blood dyscrasias in Sweden, they estimate that the risk of agranulocytosis related to metamizole (dipyrone) appears to be at least 1:1439 (95% confidence interval 1:850, 1:4684) prescriptions, a much higher figure than previously estimated. Ninety two percent of the cases of blood dyscrasias occurred during the first 2 months of treatment. Additional risk factors were identified in 36% of the patients. In addition, they report that agranulocytosis was not the only manifestation of metamizole-induced blood dys-crasias; in some of the cases all three haematopoiesis were affected according to bone marrow sample findings. In these cases, the outcome was significantly poorer. Thus the risks of agranulocytosis from the present report seem to be considerably higher than the previously estimated risks from the IAAA study. The authors identify several possible reasons for this difference. For example, in countries where metamizole has been available for several years, the number of susceptibles will decrease because individuals who develop agranulocytosis will discontinue the offending drug. In contrast, countries such as Sweden have a greater population of treatment-naïve individuals. The criteria of fever as a measure of agranulocytosis in the IAAA study also might have affected the choice of cases. Anybody taking metamizole for fever (and not just pain) would therefore not be included as cases in that study. Besides, an unknown proportion of agranulocytosis cases was not included in the IAAA study because the patients either recovered or died before hospital admission. Thus, the differences may be more representative of methodological gaps and do not necessarily represent different results.
The present publication provides evidence for the claims of a high risk of agranulocytosis with metamizole in Swedish patients. The study does not, however, clarify whether Scandinavians are genetically at a greater risk for such reactions. Comparative studies in various countries with more diverse population could help resolve this issue further and until this data is available, other drugs should be considered as first-line analgesics.