Dipyrone (metamizol) is a drug with analgesic effects used for the treatment of acute post-operative pain, oncologic pain, cramp-like pain, and migraine.^1-3 It was widely used before the 1970s, until an association was started to be found between its use and serious adverse reactions such as agranulocytosis,^4,5 defined as a drop in granulocyte count to less than 0.5 x 10⁹/L; although infrequent, the associated mortality was 10%, due to the predisposition to develop pneumonia, sepsis, toxic epidermal necrolysis, and necrotizing fasciitis,^6-9 prompting the Federal Food and Drug Administration (FDA) to ban it in the United States in 1977.¹⁰ Since then, more than 30 countries to date have banned its general use.

Several factors that could contribute to the onset of agranulocytosis, have been proposed, but no direct relationship has been established for any of them so far. The most important include extended use (>14 days), female gender, age (over 60 years), concomitant use of methotrexate, and immune and metabolic susceptibility.¹¹ The following is a case description that illustrates this effect.

Dipyrone is a pyrazolone derivative with analgesic, antipyretic, and antispasmodic effects, but with little anti-inflammatory effect.^1,7 It is used in the management of postoperative pain, cramp-like pain, cancer pain, and migraine; although its use is very controversial in many countries because of the risk of agranulocytosis, it is still sold over the counter in other countries.¹²

Its antipyretic effect is believed to be due to a reduction in blood levels of prostaglandin E₂ followed by an antipyretic effect on the EP3 located on anterior hypothalamic thermoregulatory neurons.

Associated adverse effects include nausea, vomiting,¹hypotension, cardiogenic shock,^13,14 exanthemata, urticaria,⁵ interstitial nephritis, acute renal failure,¹⁵ anaphylaxis,¹⁶ and Stevens-Johnson syndrome,¹⁷ pancytopenia, and agranulocytosis,^1,6,18 these latter 2 being the conditions that have limited its widespread use. Regarding agranulocytosis, several explanations have been proposed: one of the theories suggests a toxic effect on peripheral blood caused by aminopyrine where drug-dependent anti-neutrophil antibodies are formed which then induce the formation of immune complexes with the drug, leading to neutrophil cell lysis.¹⁹ However, lysis of these leukocytes may also occur in the bone marrow given that one of the metabolites of dipyrone is capable of interacting with lysine chains in the cell, and triggering an immune response. Another theory proposes that neutrophils produce reactive oxygen species capable of oxidizing some drugs into reactive products which act as haptens, inducing antibody formation.^7,20 Another immune mechanism suggests a reduced in vitro growth of myeloid progenitor cells, multipotent primitive progenitor cells and erythroid progenitor caused by dipyrone in an in vitro culture of bone marrow and CD34+ cells.²¹

On the other hand, several factors have been proposed as contributors to the onset of agranulocytosis, including exposure to high doses, prolonged treatment (>14 days), female gender, age over 65 years, drug interactions, and genetic predisposition.^1,11 However, no direct relationship has been established with dipyrone-induced agranulocytosis for any of them.^11,22

We present the case of a 59-year-old female in a multiple-trauma context, managed with dipyrone for 23 days, and who developed granulocytopenia from no other apparent cause. No temporal association could be found between the other medications she received and this same type of adverse event. When the drug was discontinued, the follow-up complete blood count showed evidence of increased leukocytes. The patient did not have an underlying infectious process and was discharged with no additional complication. In accordance with the protocols and recommendations required in these types of events, the algorithm by Naranjo et al²³ was applied in an attempt to establish a causality association. The result was a score of 7, consistent with a probable adverse drug reaction.

Although this reaction is infrequent in our setting, physicians and staff caring for patients with pain for prolonged periods should bear in mind the risk of using dipyrone for more than 14 days, as well as its associations with a drop in white blood cell counts and, consequently, immunosuppression and increased probability of infection.

Protection of human and animal subjects. The case report was prepared with the informed consent of the family, in accordance with Resolution No. 8430 of 1993 of the Colombian Ministry of Health, guaranteeing patient information confidentiality pursuant to the principles of the Declaration of Helsinki.

Confidentiality of data. The authors declare that they have followed the protocols of their work center on the publication of patient data.

Right to privacy and informed consent. The authors have obtained the informed consent of the and 2 witnesses. This document work in the power of the correspondence author.