{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T11:13:28Z","timestamp":1791976408290,"version":"4.4.0"},"reference-count":31,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T00:00:00Z","timestamp":1764288000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T00:00:00Z","timestamp":1764288000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"DOI":"10.1038\/s41598-025-27009-6","type":"journal-article","created":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T10:57:28Z","timestamp":1764327448000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A systematic review and pharmacovigilance analysis of the risk of agranulocytosis associated with metamizole use"],"prefix":"10.1038","volume":"15","author":[{"given":"Alessia","family":"Zinzi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Gaio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donatella","family":"Ruggiero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Consiglia","family":"Riccardi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilia","family":"Cagnotta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ciro","family":"Pentella","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annalisa","family":"Capuano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Concetta","family":"Rafaniello","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,28]]},"reference":[{"key":"27009_CR1","unstructured":"European Medicines Agency (EMA). Measures to Minimise Serious Outcomes of Known Side Effect with Painkiller Metamizole (2024)."},{"key":"27009_CR2","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1186\/s40348-023-00160-8","volume":"10","author":"MK Tomidis Chatzimanouil","year":"2023","unstructured":"Tomidis Chatzimanouil, M. K., Goppelt, I., Zeissig, Y., Sachs, U. J. & Laass, M. W. Metamizole-Induced agranulocytosis (MIA): A mini review. Mol. Cell. Pediatr. 10, 6. https:\/\/doi.org\/10.1186\/s40348-023-00160-8 (2023).","journal-title":"Mol. Cell. Pediatr."},{"key":"27009_CR3","first-page":"1012","volume":"34","author":"T Stammschulte","year":"2011","unstructured":"Stammschulte, T. & Gundert Remy, U. Metamizole (Dipyrone) and agranulocytosis in germany: Long-Term consequences of a regulatory measure in 1986. Drug Saf. 34, 1012 (2011).","journal-title":"Drug Saf."},{"key":"27009_CR4","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1186\/s12913-017-2086-6","volume":"17","author":"MM Wertli","year":"2017","unstructured":"Wertli, M. M. et al. Changes over time in prescription practices of pain medications in Switzerland between 2006 and 2013: an analysis of insurance claims. BMC Health Serv. Res. 17, 167. https:\/\/doi.org\/10.1186\/s12913-017-2086-6 (2017).","journal-title":"BMC Health Serv. Res."},{"key":"27009_CR5","doi-asserted-by":"publisher","first-page":"58","DOI":"10.2174\/1874473711666180911091846","volume":"11","author":"S Preissner","year":"2019","unstructured":"Preissner, S. et al. Pain-Prescription Differences - An analysis of 500,000 discharge summaries. Curr. Drug Res. Rev. 11, 58\u201366. https:\/\/doi.org\/10.2174\/1874473711666180911091846 (2019).","journal-title":"Curr. Drug Res. Rev."},{"key":"27009_CR6","doi-asserted-by":"publisher","first-page":"347","DOI":"10.2174\/1874210601812010347","volume":"12","author":"GP Pastore","year":"2018","unstructured":"Pastore, G. P., Goulart, D. R., Pastore, P. R., Prati, A. J. & de Moraes, M. Self-Medication among myofascial pain patients: A preliminary study. Open. Dent. J. 12, 347\u2013353. https:\/\/doi.org\/10.2174\/1874210601812010347 (2018).","journal-title":"Open. Dent. J."},{"key":"27009_CR7","unstructured":"Meeting Highlights from the Pharmacovigilance Risk Assessment Committee (PRAC. ) 10\u201313 June 2024 | European Medicines Agency (EMA) Available online: October (accessed on 29 October 2024). https:\/\/www.ema.europa.eu\/en\/news\/meeting-highlights-pharmacovigilance-risk-assessment-committee-prac-10-13-june-2024 (2024)."},{"key":"27009_CR8","doi-asserted-by":"publisher","first-page":"b2535","DOI":"10.1136\/bmj.b2535","volume":"339","author":"D Moher","year":"2009","unstructured":"Moher, D., Liberati, A., Tetzlaff, J. & Altman, D. G. PRISMA group preferred reporting items for systematic reviews and Meta-Analyses: the PRISMA statement. BMJ 339, b2535. https:\/\/doi.org\/10.1136\/bmj.b2535 (2009).","journal-title":"BMJ"},{"key":"27009_CR9","unstructured":"EudraVigilance | European Medicines Agency. (accessed on 7 February 2024). https:\/\/www.ema.europa.eu\/en\/human-regulatory-overview\/research-and-development\/pharmacovigilance-research-and-development\/eudravigilance."},{"key":"27009_CR10","unstructured":"Help to Shape the MedDRA Terminology | MedDRA. (accessed on 12 April 2023). https:\/\/www.meddra.org\/."},{"key":"27009_CR11","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1097\/CJ9.0000000000000023","volume":"46","author":"VH Gonz\u00e1lez-C\u00e1rdenas","year":"2018","unstructured":"Gonz\u00e1lez-C\u00e1rdenas, V. H. et al. Analysis of the incidence of adverse events related to the administration of dipyrone. Colomb J. Anesthesiol. 46, 119\u2013125. https:\/\/doi.org\/10.1097\/CJ9.0000000000000023 (2018).","journal-title":"Colomb J. Anesthesiol"},{"key":"27009_CR12","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1007\/s00228-013-1618-1","volume":"70","author":"M Huber","year":"2014","unstructured":"Huber, M. et al. Drug-Induced agranulocytosis in the Berlin Case-Control surveillance study. Eur. J. Clin. Pharmacol. 70, 339\u2013345. https:\/\/doi.org\/10.1007\/s00228-013-1618-1 (2014).","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"27009_CR13","doi-asserted-by":"publisher","first-page":"244","DOI":"10.1177\/0960327115580603","volume":"35","author":"R Navarro-Mart\u00ednez","year":"2016","unstructured":"Navarro-Mart\u00ednez, R., Chover-Sierra, E. & Cauli, O. Non-Chemotherapy Drug-Induced agranulocytosis in a tertiary hospital. Hum. Exp. Toxicol. 35, 244\u2013250. https:\/\/doi.org\/10.1177\/0960327115580603 (2016).","journal-title":"Hum. Exp. Toxicol."},{"key":"27009_CR14","doi-asserted-by":"publisher","first-page":"1143","DOI":"10.1007\/s11096-019-00873-9","volume":"41","author":"JL Revuelta-Herrero","year":"2019","unstructured":"Revuelta-Herrero, J. L. et al. Drug safety surveillance within a strategy for the management of Non-Chemotherapy Drug-Induced neutropenia. Int. J. Clin. Pharm. 41, 1143\u20131147. https:\/\/doi.org\/10.1007\/s11096-019-00873-9 (2019).","journal-title":"Int. J. Clin. Pharm."},{"key":"27009_CR15","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1001\/archinte.159.4.369","volume":"159","author":"MM Van Der Klauw","year":"1999","unstructured":"Van Der Klauw, M. M. et al. A Population-Based Case-Cohort study of Drug-Associated agranulocytosis. Arch. Intern. Med. 159, 369\u2013374. https:\/\/doi.org\/10.1001\/archinte.159.4.369 (1999).","journal-title":"Arch. Intern. Med."},{"key":"27009_CR16","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1111\/bcpt.12014","volume":"111","author":"R Puig Treserra","year":"2012","unstructured":"Puig Treserra, R., Vendrell Bosch, L., Ib\u00e1\u00f1ez Mora, L., Sancho Ponce, E. & Laporte Rosell\u00f3, J. R. Epidemiology of In-Hospital agranulocytosis in Barcelona (1981\u20132011). Basic. Clin. Pharmacol. Toxicol. 111, 17\u201318. https:\/\/doi.org\/10.1111\/bcpt.12014 (2012).","journal-title":"Basic. Clin. Pharmacol. Toxicol."},{"key":"27009_CR17","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1111\/j.0954-6820.1982.tb03216.x","volume":"212","author":"P Arneborn","year":"1982","unstructured":"Arneborn, P. & Palmblad, J. Drug-Induced Neutropenia: A survey for Stockholm 1973\u20131978. Acta Med. Scand. 212, 289\u2013292 (1982).","journal-title":"Acta Med. Scand."},{"key":"27009_CR18","doi-asserted-by":"publisher","first-page":"488","DOI":"10.1177\/147323000203000504","volume":"30","author":"S Maj","year":"2002","unstructured":"Maj, S. & Lis, Y. The incidence of metamizole Sodium-Induced agranulocytosis in Poland. J. Int. Med. Res. 30, 488\u2013495. https:\/\/doi.org\/10.1177\/147323000203000504 (2002).","journal-title":"J. Int. Med. Res."},{"key":"27009_CR19","first-page":"PI93","volume":"10","author":"S Maj","year":"2004","unstructured":"Maj, S. & Centkowski, P. A. Prospective study of the incidence of agranulocytosis and aplastic anemia associated with the oral use of metamizole sodium in Poland. Med. Sci. Monit. Int. Med. J. Exp. Clin. Res. 10, PI93\u201395 (2004).","journal-title":"Med. Sci. Monit. Int. Med. J. Exp. Clin. Res."},{"key":"27009_CR20","doi-asserted-by":"publisher","first-page":"681","DOI":"10.1007\/s00210-019-01774-4","volume":"393","author":"S Klose","year":"2020","unstructured":"Klose, S., Pflock, R., K\u00f6nig, I. R., Linder, R. & Schwaninger, M. Metamizole and the risk of Drug-Induced agranulocytosis and neutropenia in statutory health insurance data. Naunyn Schmiedebergs Arch. Pharmacol. 393, 681\u2013690. https:\/\/doi.org\/10.1007\/s00210-019-01774-4 (2020).","journal-title":"Naunyn Schmiedebergs Arch. Pharmacol."},{"key":"27009_CR21","doi-asserted-by":"publisher","first-page":"1503","DOI":"10.1007\/s00228-024-03706-5","volume":"80","author":"M\u00c1 Maci\u00e1-Mart\u00ednez","year":"2024","unstructured":"Maci\u00e1-Mart\u00ednez, M. \u00c1., Castillo-Cano, B., Garc\u00eda-Poza, P. & Mart\u00edn-Merino, E. Risk of agranulocytosis with metamizole in comparison with alternative medications based on health records in Spain. Eur. J. Clin. Pharmacol. 80, 1503\u20131514. https:\/\/doi.org\/10.1007\/s00228-024-03706-5 (2024).","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"27009_CR22","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1007\/s00228-014-1781-z","volume":"71","author":"LS Blaser","year":"2015","unstructured":"Blaser, L. S. et al. Hematological safety of metamizole: retrospective analysis of WHO and Swiss spontaneous safety reports. Eur. J. Clin. Pharmacol. 71, 209\u2013217. https:\/\/doi.org\/10.1007\/s00228-014-1781-z (2015).","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"27009_CR23","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1007\/s40272-021-00481-z","volume":"24","author":"J Zahn","year":"2022","unstructured":"Zahn, J. et al. Metamizole use in children: analysis of drug utilisation and adverse drug reactions at a German university hospital between 2015 and 2020. Pediatr. Drugs. 24, 45\u201356. https:\/\/doi.org\/10.1007\/s40272-021-00481-z (2022).","journal-title":"Pediatr. Drugs"},{"key":"27009_CR24","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1002\/(SICI)1096-8652(199803)57:3<206::AID-AJH4>3.0.CO;2-Z","volume":"57","author":"MM Van Der Klauw","year":"1998","unstructured":"Van Der Klauw, M. M., Wilson, J. H. P. & Stricker, B. H. Ch. Drug-Associated agranulocytosis: 20 years of reporting in the Netherlands (1974\u20131994). Am. J. Hematol. 57, 206\u2013211. https:\/\/doi.org\/10.1002\/(SICI)1096-8652(199803)57:3%3C206::AID-AJH4%3E3.0.CO;2-Z (1998).","journal-title":"Am. J. Hematol."},{"key":"27009_CR25","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1111\/jcpt.12422","volume":"41","author":"S Andrade","year":"2016","unstructured":"Andrade, S., Bartels, D. B., Lange, R., Sandford, L. & Gurwitz, J. Safety of metamizole: A systematic review of the literature. J. Clin. Pharm. Ther. 41, 459\u2013477. https:\/\/doi.org\/10.1111\/jcpt.12422 (2016).","journal-title":"J. Clin. Pharm. Ther."},{"key":"27009_CR26","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1111\/jcpt.12768","volume":"44","author":"RR Shah","year":"2019","unstructured":"Shah, R. R. & Metamizole Dipyrone)-Induced agranulocytosis: does the risk vary according to ethnicity? J. Clin. Pharm. Ther. 44, 129\u2013133. https:\/\/doi.org\/10.1111\/jcpt.12768 (2019).","journal-title":"J. Clin. Pharm. Ther."},{"key":"27009_CR27","unstructured":"Ungoed-Thomas, J. & Jones, S. \u2018Like a bad dream\u2019: briton\u2019s death in Spain heightens fears about painkiller Nolotil. The Observer (2024)."},{"key":"27009_CR28","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1046\/j.1365-2125.1998.00817.x","volume":"46","author":"RM Martin","year":"1998","unstructured":"Martin, R. M., Biswas, P. N., Freemantle, S. N., Pearce, G. L. & Mann, R. D. Age and sex distribution of suspected adverse drug reactions to newly marketed drugs in general practice in england: analysis of 48 cohort studies. Br. J. Clin. Pharmacol. 46, 505\u2013511. https:\/\/doi.org\/10.1046\/j.1365-2125.1998.00817.x (1998).","journal-title":"Br. J. Clin. Pharmacol."},{"key":"27009_CR29","doi-asserted-by":"publisher","first-page":"952","DOI":"10.1002\/pds.5220","volume":"30","author":"LC Hendriksen","year":"2021","unstructured":"Hendriksen, L. C., Verhamme, K. M. C., Van der Linden, P. D., Stricker, B. H. & Visser, L. E. Women are started on a lower daily dose of Metoprolol than men irrespective of dose recommendations: A potential source of confounding by contraindication in pharmacoepidemiology. Pharmacoepidemiol Drug Saf. 30, 952\u2013959. https:\/\/doi.org\/10.1002\/pds.5220 (2021).","journal-title":"Pharmacoepidemiol Drug Saf."},{"key":"27009_CR30","doi-asserted-by":"publisher","first-page":"904","DOI":"10.3390\/ph17070904","volume":"17","author":"M Gaio","year":"2024","unstructured":"Gaio, M. et al. Pregnancy recommendations solely based on preclinical evidence should be integrated with Real-World evidence: A disproportionality analysis of certolizumab and other TNF-Alpha inhibitors used in pregnant patients with psoriasis. Pharm. Basel Switz. 17, 904. https:\/\/doi.org\/10.3390\/ph17070904 (2024).","journal-title":"Pharm. Basel Switz."},{"key":"27009_CR31","first-page":"114","volume":"5","author":"G Mauro","year":"2019","unstructured":"Mauro, G. et al. di Adverse drug reactions and gender differences: what changes in drug safety? J. Sex- Gend. -Specif Med. 5, 114\u2013122 (2019).","journal-title":"J. Sex- Gend. -Specif Med."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-27009-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-27009-6","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-27009-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T10:57:30Z","timestamp":1764327450000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-27009-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,28]]},"references-count":31,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["27009"],"URL":"https:\/\/doi.org\/10.1038\/s41598-025-27009-6","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,28]]},"assertion":[{"value":"31 March 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"31 October 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 November 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"42796"}}