A probable case of metamizole-induced neutropaenia presenting 10 days after drug discontinuation

Abstract

Metamizole (dipyrone) is a non-opioid analgesic and antipyretic agent belonging to the pyrazolone class. While it is widely used in many countries due to its favourable safety profile compared to non-steroidal anti-inflammatory drugs and opioids, its use has been associated with rare but potentially life-threatening haematologic adverse effects, including neutropaenia and agranulocytosis. These complications typically occur within 6–14 days of treatment initiation but may also arise earlier or significantly later, even after discontinuation of the drug. Given that late-onset neutropaenia after metamizole discontinuation may be underdiagnosed, we present the case of a 92-year-old woman who developed transient, likely drug-induced neutropaenia 10 days later, with spontaneous haematologic recovery. The patient remained asymptomatic, with no signs of infection or evidence of inflammatory or neoplastic systemic disease.

Learning Points

• High suspicion of metamizole-induced neutropaenia should be maintained, even after cessation of metamizole therapy.

• Although rare, serious complications from metamizole warrant close monitoring, particularly in elderly patients or those with a history of haematologic disorders.

• When haematologic abnormalities are present, metamizole should be discontinued immediately, and analgesic therapy should be switched to alternative regimens such as opioids.

Introduction

Metamizole (dipyrone) is a member of the pyrazolone group with analgesic and antipyretic properties, which, despite significant safety concerns, particularly the risk of neutropaenia and agranulocytosis, ¹ remains widely used in many countries.^2,3 Metamizole-related neutropaenia, defined as an absolute neutrophil count <1500/µL, is observed in ~1 in 1602 patients receiving the drug.^1,4 However, its pathogenetic mechanisms remain incompletely understood, with genetic, toxic, and autoimmune factors likely playing a significant role in its development.^2,5,6 Clinical research indicates a median latency period of 6–14 days between the initiation of metamizole and the onset of agranulocytosis. However, cases can occur immediately after treatment begins or after significantly longer periods.^3,7,8 Although it has been reported that the risk of neutropaenia and agranulocytosis decreases significantly 10 days after therapy termination, ² rare cases of late-onset neutropaenia after discontinuation have also been described. ⁹ Here, we describe a rare case of neutropaenia in a 92-year-old patient that occurred 10 days after the last dose of metamizole.

Case description

A 92-year-old female patient was referred to our clinic for geriatric rehabilitation by the Internal Medicine Department following transfusion-dependent anaemia due to lower gastrointestinal bleeding, Campylobacter jejuni enteritis treated with azithromycin, and left-sided heart failure. Moreover, her medical history included gastroesophageal reflux disease, atrial fibrillation, multiple transient ischaemic attacks, chronic renal failure, anxiety symptoms treated with escitalopram, and an unclear abdominal tumour resection performed ~55 years ago.

On admission, the patient was alert, fully oriented, haemodynamically stable (arterial blood pressure 118/64 mmHg, heart rate 65 beats/min) and afebrile (temperature 36.7 °C). She reported recurrent dull right lower abdominal pain. While these episodes had previously occurred more frequently, they had recently decreased to approximately once daily. The pain was not clearly related to meals, and no specific triggering factors were identified. Physical examination revealed a soft abdomen with tenderness localized to the right lower quadrant. Bilateral lower extremity oedema was noted. The remainder of the examination was unremarkable. The abdominal pain resolved over the course of her stay.

On admission, her medications included apixaban (for atrial fibrillation), psyllium husk (for stool regulation), pantoprazole (due to a history of gastrointestinal bleeding), escitalopram and torsemide (for left-sided heart failure).

Blood tests on hospital day (HD) 19 (counted from admission to the Department of Internal Medicine) revealed anaemia and leukopaenia, with a preserved neutrophil count. A follow-up blood test on HD 22 demonstrated bicytopaenia, now including neutropaenia, with an absolute neutrophil count of 0.9 × 109/L (Table 1).

Table 1.

Laboratory data.

Laboratory parameter	Reference values	Admission	HD 16	HD 19	HD 22	HD 25	HD 28	HD 36	HD 39	HD 42
Leucocytes	3.6–10.5 × 109/L	8.1	3.7	2.7	2.6	2.2	2.0	5.6	3.0	2.7
Neutrophils	1.5–7.7 × 109/L	6.4	-	1.7	1.3	-	0.9	3.7	-	1.3
Hb	118–158 g/L	119	92	91	94	99	112	102	121	122
PLTs	150–370 × 109/L	221	214	227	234	237	226	336	192	188

Hb: haemoglobin; PLTs: platelets; HD: hospital day.

Given the development of leukopaenia followed by neutropaenia, the patient’s recent medication history was thoroughly reviewed to identify potential iatrogenic causes. It was noted that she had received metamizole at a dose of 500 mg three times daily for 5 days (HD 4–HD 8) to manage recurrent abdominal pain, ~10 days prior to admission to the rehabilitation clinic.

To reduce the risk of worsening neutropaenia, escitalopram, and pantoprazole were temporarily discontinued; however, given the chronic administration of escitalopram, it appears unlikely to be the cause of leukopaenia, and the therapy was therefore restarted. Furthermore, azithromycin has been reported as a potential cause of leukopaenia and neutropaenia. Nevertheless, these adverse effects are rare, occurring predominantly in the paediatric population. ¹⁰ In our patient, leukopaenia was observed 37 days after the last azithromycin dose, which makes it unlikely to represent the underlying aetiology.

The patient remained asymptomatic, with no signs of infection or evidence of inflammatory or neoplastic systemic disease. Another cause explaining the development of leukopaenia and neutropaenia could not be identified. We discussed the case with the in-house haematologists, who recommended continued observation prior to considering a bone marrow biopsy, given the patient’s advanced age and asymptomatic presentation. Laboratory follow-up on HD 36 demonstrated normalization of haematologic parameters; however, on HD 39, a recurrent episode of mild leukopaenia and neutropaenia was diagnosed (Table 1). The patient was discharged home, and a follow-up with her general practitioner had been suggested, but the patient did not attend. A follow-up ~8 weeks after the initial episode of leukopaenia—performed in our hospital for an unrelated reason—revealed a normal leukocyte count (8.6 × 10⁹/L).

Discussion

Metamizole, also known as dipyrone, belongs to the pyrazolone family and is characterized by its analgesic, antipyretic, and spasmolytic properties. It is widely used in many countries due to its favourable safety profile compared to non-steroidal anti-inflammatory drugs and opioids, with fewer renal, gastrointestinal, cardiovascular, and neurological side effects.^2,3 Despite the exact mechanism of action of metamizole remaining uncertain, it is assumed to involve inhibitory effects on cyclooxygenase-1 (COX-1) and COX-2, as well as inhibition of spinal prostaglandin production. Moreover, it has been recently reported that two bioproducts of metamizole metabolism may have the ability to bind to cannabinoid receptors, exhibiting analgesic properties similar to paracetamol. ² Nevertheless, its use has also been associated with severe adverse reactions, such as leukopaenia, neutropaenia, and agranulocytosis, which have led many countries, including Denmark, Sweden, Finland, Australia, the USA, Canada, and Japan, to restrict or withhold its licensure.^1,2

Metamizole-induced neutropaenia, defined as an absolute neutrophil count <1500/µL, has been reported to occur in ~1 in 1602 patients receiving the drug.^1,11 The pathophysiology of metamizole-induced neutropaenia and agranulocytosis is complex. It involves, among other factors, genetically defined variations, such as polymorphisms in the N-acetyltransferase 2 (NAT2), cytochrome P450 (CYP) 2C9, and CYP2C19 genes, ⁴ as well as toxic mechanisms (Figure 1). Indeed, in vitro studies have shown that N-methyl-4-aminoantipyrine, the main metabolite of metamizole, can enhance the cytotoxicity of haemin via a mechanism involving the formation of an electrophilic metabolite, ultimately leading to bone marrow suppression and neutropaenia.^5,6 Thus, the delayed onset of leukopaenia could theoretically be explained by deficiencies in the genes CYP2C9, CYP2C19, and NAT2, which may, particularly in cases of haemolysis, induce bone marrow cytotoxicity and inhibit granulocyte maturation.^4,6 Furthermore, it has been suggested that drug interactions, such as with strong CYP1A2 inhibitors, and impaired hepatic metabolism may increase plasma concentrations of 4-methylaminoantipyrine, thereby enhancing the risk of myelotoxicity. These factors could also contribute to the pathophysiology of late-onset and recurrent cases. ¹² Moreover, as in a variety of drug-related neutropaenias, immune reactions appear to play a fundamental role in the pathogenesis of metamizole-induced neutropaenia and agranulocytosis. It is hypothesized that, similar to the pathophysiology of aminopyrine-induced neutropaenia, another pyrazolone family member, a hapten mechanism, could also be involved in metamizole-induced neutropaenia. This hypothesis is further supported by research showing that the active metabolite of metamizole, through its hapten function, can stimulate T-cell reactions against granulocytes. ² Indeed, drug-dependent antibodies against glycoprotein structures on the granulocyte membrane seem to contribute to the pathogenesis of neutropaenia by leading to immune-mediated lysis of neutrophils (Figure 1). ⁸ In our patient, a possible explanation for the delayed metamizole toxicity could theoretically be associated with an underlying impairment of the patient’s drug metabolism capacity.

Figure 1.

Simplified schematic overview of the pathophysiology of metamizole-induced neutropaenia.

Earlier research has identified a variety of risk factors potentially contributing to the development of neutropaenia in patients receiving metamizole, including prior drug hypersensitivity reactions and allergic episodes, a history of leukopaenia, the presence of autoimmune diseases, a history of hepatitis, and concurrent therapies with potentially leukopaenia-inducing drugs, particularly methotrexate. ¹ A retrospective, observational, matched case–control study assessing risk factors for the development of metamizole-induced leukopaenia found that a history of leukopaenic values was significantly more common in patients with metamizole-induced neutropaenia compared to controls. ¹

The median latency period between starting metamizole and the diagnosis of agranulocytosis ranges from 6 to 14 days in different studies. However, cases occurring after just the first or second dose, as well as after significantly longer periods of more than 6 weeks after the start of therapy, have also been reported.^3,7,8 Data regarding the development of neutropaenia after discontinuation of metamizole are scarce. However, it is generally assumed that no further risk of agranulocytosis is to be expected more than 10 days after the last dose. ² In a retrospective study investigating metamizole-induced agranulocytosis, the majority of patients developed agranulocytosis during metamizole therapy (62%), while in 35% of cases, agranulocytosis was observed up to 5 days after discontinuation of the drug. However, the authors also reported cases where agranulocytosis developed as late as 15 days after the last dose. ⁹ Our patient developed leukopaenia and neutropaenia 10 days after the last administration of metamizole, and no additional aetiologic factors could be identified, raising the question of whether such cases might remain undiagnosed.

The clinical manifestations of agranulocytosis may vary; however, the typical constellation includes a combination of fever, fatigue, muscle pain, sore throat, and inflammatory mucosal ulcerations, such as ulcerative tonsillitis and aphthous stomatitis. Nonetheless, severe septic complications with potentially fatal outcomes may also occur, with reported mortality rates ranging from 5% to 23.6%.^2,8

In patients with suspected metamizole-induced neutropaenia, metamizole should be discontinued immediately, as should any concomitantly administered drugs known to cause neutropaenia. Analgesic therapy should be modified to regimens that do not cause haematologic abnormalities, such as opioids. If the patient develops an infectious complication, appropriate diagnostic measures should be undertaken, and empirical antibiotic therapy should be initiated based on the suspected infection, local antibiotic resistance patterns, antibiotic spectrum and the patient’s history of antibiotic use. Despite the limited available data, the administration of recombinant human growth factors, such as granulocyte colony-stimulating factor, should be considered in severe cases to support the re-establishment of myelopoiesis.^2,8,13

Conclusion

This probable rare case of metamizole-induced neutropaenia, occurring 10 days after discontinuation, highlights the importance of maintaining a high index of suspicion for this condition in patients presenting with signs of infection, even after cessation of metamizole therapy. A deeper understanding of the pathophysiology underlying metamizole-associated neutropaenia and agranulocytosis is essential for improving patient management and outcomes. The infrequent documentation of late-onset neutropaenia raises the critical question of whether such reactions are truly rare or simply underdiagnosed. Further research is needed to clarify the exact pathophysiologic mechanisms involved and to guide more effective monitoring and intervention strategies.