2) Agranulocitose:
Agranulocytosis is defined as an absolute circulating neutrophil count of less than 500 / µl45. The most common clinical course of agranulocytosis is associated with pharyngotonsillitis, stomatitis and / or pneumonia. The frequency of the disease varies with age, with only 10% of cases being reported in children and young adults, and more than half of the episodes occurring in people over 60 years of age. It is a rare condition and is associated with a fatality rate of 8 to 10%. Association rates with drug use vary in the different studies, but in Brazil, for example, it is around 56%46.
No randomised clinical trials using dipyrone as a postoperative analgesic in children have reported the occurrence of agranulocytosis to date. Studies show that the incidence of agranulocytosis varies between countries. The LATIN46 study was a prospective case-control study carried out in cities in Brazil, Argentina and Mexico. The overall incidence rate was estimated at 0.38 per million inhabitants/year. Methimazole was the only drug significantly associated with agranulocytosis (p <0.001), and there was no significant association with dipyrone. A rare incidence of agranulocytosis associated with drugs has been reported in a retrospective study in the city of São Paulo / Brazil (0.44 to 0.82 cases per million inhabitants / year)47 and in the collaborative study of Brazil, Argentina and Mexico mentioned above, similar to the finding in Thailand - 0.8:1 million inhabitants/year48. This contrasts with the higher incidence reported in the United States of America, from 2.4 to 15.4 per million inhabitants / year49, and in European countries, such as that of the collaborative study in Germany, Italy, Spain, Hungary, Bulgaria and Sweden, in addition to Israel, which found 1.1 to 6.2 cases / million / year and a mortality rate of 0.5 cases / million / year. However, this study noted a great regional variability in the presentation of blood dyscrasias50. The risk was significantly associated with the use of ticlopidine, sulphonamides, non-steroidal anti-inflammatory drugs, calcium dobesilate, antithyroid drugs, spironolactone and dipyrone. There was a subsequent study, in the city of Barcelona, ​​which found an incidence of agranulocytosis associated with medications in the order of 3.46 cases per million inhabitants / year20. In France, the corresponding number was 6 cases per million inhabitants / year51. The specific incidence of agranulocytosis associated with dipyrone varied from one for every 1,439 prescriptions in Sweden³⁶, to 0.56 cases per million inhabitants / year in Barcelona20, reaching up to 0.96 cases per million / year in Berlin19. A cohort of hospitalised patients in Bogotá, Colombia, involving 2,743 patients, showed no cases of agranulocytosis52. In the LATIN study47, the odds ratio (OR) for drug-associated agranulocytosis was 2.4 (95% CI 0.8–6.7). The corresponding figures in Barcelona were 25.8 (95% CI 8.8-79.1)20. In a study published in 2020, the OR for agranulocytosis and drug-induced neutropenia was 3.03 (95% CI 2.49 to 3.69). The risk of developing agranulocytosis and neutropenia after a dipyrone prescription was 1:1,602 (95% CI 1:1,926 to 1:1,371)53. There are several possible explanations for the differences found in incidence between the various studies, ranging from the use of different methodologies to the genetic heterogeneity of populations, with probable gene polymorphisms of their own, which have not yet been studied specifically for dipyrone.
Even though the risk of agranulocytosis with dipyrone is undeniable, its real incidence in the population is not known, but it is assumed to be low. For this reason, the German consensus that brought together several representative entities concluded that dipyrone has a positive risk-benefit rate compared to other non-opioid analgesics, recommending its use54.