Metamizole‐induced reactions as a paradigm of drug hypersensitivity: Non‐allergic reactions, anaphylaxis, and delayed‐type allergy

Metamizole belongs to the group of non-opioid analgesics and, as for other non-steroidal anti-inflammatory drugs (NSAID) such as acetylsalicylic acid, diclofenac or ibuprofen, both isoforms of cyclooxygenase are inhibited. Metamizole is an important trigger of non-allergic and allergic hypersensitivity reactions and has been withdrawn from the US, Australian, and UK market due to the risk of agranulocytosis, but is still available and broadly used in many countries of Europe, Central and South America, and Asia.


Metamizole-induced reactions as a paradigm of drug hypersensitivity: Non-allergic reactions, anaphylaxis, and delayed-type allergy
To the Editor Metamizole belongs to the group of non-opioid analgesics, and as for other non-steroidal anti-inflammatory drugs (NSAID) such as acetylsalicylic acid, diclofenac, or ibuprofen, both isoforms of cyclooxygenase are inhibited. Metamizole is an important trigger of non-allergic and allergic hypersensitivity reactions and has been withdrawn from the United States, Australian, and UK market due to the risk of agranulocytosis, but is still available and broadly used in many countries of Europe, Central and South America, and Asia.
We retrospectively evaluated clinical and diagnostic data from 239 consecutive patients with metamizole hypersensitivity over a period of 19 years; Table S1 shows baseline clinical parameters.
Metamizole anaphylaxis was diagnosed in 75 patients (31.4%), non-allergic immediate hypersensitivity in 95 (39.7%), and delayed reactions in 69 (28.9%). (Table 1, Figure 1). The number of diagnoses per year steadily increased from 2000 to 2019 along with the prescription numbers of metamizole in Germany, which almost doubled between 2008 and 2017 1 ( Figure S1A,B). The unbroken and even growing popularity of metamizole possibly reflects its otherwise favourable safety profile including a comparatively low renal, gastrointestinal, and hepatic toxicity. Indications for metamizole include severe pain following surgery or serious trauma, colic, tumour pain, and high fever. Beyond these clear-cut indications, metamizole is also used for mild and moderate pain, though alternatives with a better safety profile are available. This is in accordance with our observation of an uncritical use of metamizole for the treatment of back and joint pain (20.5%) or headache (20.5%) (Table S1).
Sixty-five out of 75 patients with metamizole anaphylaxis had a history of moderate to severe symptoms (86.7%) ( Table 1; the classification of anaphylaxis is detailed in Table S2). In a mild reaction found in 10 of our 75 anaphylaxis patients (13.3%), urticaria was the most prominent feature. In more than half of the anaphylaxis cases (n = 43), the reaction occurred within 5 minutes after administration of metamizole, 66 reactions (88.0%) set in within 30 minutes, and all occurred within the first hour (Table 1). Positive results in prick and intradermal testing and in basophil activation tests suggest that anaphylactic reactions to metamizole are mediated by specific IgE antibodies. 2,3 Unmetabolized metamizole in the circulating blood is measurable for a maximum of 15 minutes following intravenous administration and cannot be detected upon oral intake due to immediate hydrolysis into the active moiety 4-methylaminoantipyrine. 4 The latter may bind to cellular or serum proteins, resulting in a complex capable to activate the immune system. The antigenic determinant is to date unknown; however, certain metamizole metabolites increase the sensitivity of basophil activation testing. 5 Of the 69 patients with delayed reactions, 37 suffered from measles-like exanthem (53.6%), and 15 developed a fixed drug eruption (FDE) (21.7%) ( Table 1) Several of our patients reported initial signs of the delayed reaction already within 12 hours after first intake of metamizole (Table 1).
Data from medical history, however, are to a certain extent subjective, which may explain the contrast to the statement that delayed reactions regularly occur after 24-48 hours. 8 Skin testing was performed according to international guidelines and included reading at 15 minutes in immediate reactions and additional readings on days two, three, and four in delayed reactions. The original concentration of an intravenous metamizole solution (500 mg/mL) was used for patch and prick testing, a dilution of 1:100 (5 mg/mL) for intradermal testing. A wheal of at least 3 mm in diameter with surrounding erythema was considered a positive prick test result, and a wheal of at least 6 mm was considered positive in intradermal testing. An erythematous and infiltrated plaque or eczematous lesion clearly visible and palpable on days two, three, and four was assessed as a positive delayed-type skin test reaction. Test results of the 239 patients with metamizole hypersensitivity are depicted in Table S3. Thirty-one patients with a delayed reaction showed a positive intradermal test result. In  (Table S3). Intradermal testing of metamizole permits an accurate diagnosis of metamizole allergy in the majority of cases. The sensitivity of skin testing for delayed reactions can be further increased by simultaneous patch testing as a combination of prick and intradermal testing occasionally reveals a (false) negative result. 6 In our group of patients, skin testing of metamizole revealed an overall sensitivity of 78.0% for delayed exanthem, and 97.3% for anaphylaxis. In a comparable study of 139 patients (132 immediate and five delayed reactions), combined skin testing, that is prick, intradermal, and patch, was positive in 62.0% of cases. 9 Focus of our data evaluation was the diagnosis of allergic metamizole hypersensitivity which has to be differentiated from non-allergic reactions appearing either as urticaria or as an obstructive reaction of the airways. 8