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.