International Journal of Environmental Research and Public Health Article Regional Differences in Prescribing Patterns of Metamizole in Germany Based on Data from 70 Million Persons Falk Hoffmann 1 , Carsten Bantel 2, Frederik Tilmann von Rosen 1 and Kathrin Jobski 1,* 1 Department of Health Services Research, Carl von Ossietzky University Oldenburg, 26129 Oldenburg, Germany; falk.hoff[email protected] (F.H.); [email protected] (F.T.v.R.) 2 University Department of Anesthesiology, Critical Care, Emergency and Pain Medicine, Klinikum Oldenburg, 26133 Oldenburg, Germany; [email protected] * Correspondence: [email protected]; Tel.: +49-(0)441-798-2330 Received: 8 May 2020; Accepted: 28 May 2020; Published: 30 May 2020 Abstract: The non-opioid analgesic metamizole (dipyrone) is commonly used in Germany despite its narrow indications and market withdrawal from several countries. In this study we analyzed prescribing patterns of metamizole focusing on regional differences. The source of data was the “Information system for health care data” which includes data from the statutory health insurance funds for about 70 million Germans. We received aggregated data of individuals with at least one metamizole prescription in 2010 as well as the number of prescribed packages by age, sex, state and district along with the number of insured persons in each stratum. We calculated prescription prevalence stratified by age, sex, state and district. Among 68.4 million insured persons (mean age: 43.6 years; 53.0% female) 5.5 million received at least one metamizole prescription (8.1%, overall 12.2 million packages). Prevalence increased with age, and women received metamizole more often than men. In adults (total prevalence: 9.4%), levels varied between 7.0% (Saxony) and 11.1% (Schleswig-Holstein), whereas on a district level use ranged from 4.3% to 14.3%. In 2010, one of 12 individuals received metamizole at least once. Noticeable were the large regional variations which certainly cannot be explained by patient-related factors. Keywords: metamizole; dipyrone; prescribing patterns; prevalence; regional variations; Germany 1. Introduction Metamizole is a non-opioid analgesic. It has been available for nearly a century, and can be placed in the first step on the World Health Organization (WHO) analgesic ladder. It shows good analgesic, antipyretic and spasmolytic efficacy, although studies have been largely confined to the acute setting [1–3]. Compared to nonsteroidal anti-inflammatory drugs (NSAIDs) or opioids, metamizole seems to display a favorable profile of renal and gastrointestinal risks [3,4]. Yet, the safety of metamizole has been the topic of a lengthy and controversial debate due to the possibility of agranulocytosis as a grave and potentially fatal adverse effect [3,5–7]. Although the true incidence of metamizole-induced agranulocytosis is unclear and varies widely between studies [8–12], many countries including the UK, France, Norway, Sweden, the USA, Canada and Australia have decided to withhold or withdraw market authorization, while it is available over-the-counter (OTC) in others [5]. Germany subjected metamizole to prescription-only status in 1987, and actively narrowed its indications [13]. Nonetheless, metamizole remains a widely used medication in Germany, both in inpatient and outpatient settings [14–16]. According to the annual German Drug Prescription Report, prescription volume among outpatients increased fifteen-fold between 1991 and 2018 (Figure1), from 15 to 225 million defined daily doses (DDD) [17–19]. The DDD describes the assumed average maintenance Int. J. Environ. Res. Public Health 2020, 17, 3892; doi:10.3390/ijerph17113892 www.mdpi.com/journal/ijerph Int. J. Environ. Res. Public Health 2020, 17, 3892 2 of 10 doseInt. J. per Environ. day Res. for Public a drug Health used2020 for, 17 ,its 3892 main indication in adults [20]. For metamizole, the DDD is 3 2 ofg. 9 Correspondingly, a total of 675 tons of metamizole were prescribed to members of statutory health funds in Germany in 2018, which would translate to 18.5 tablets of 500 mg for each insured individual (Figuredose per 1). day However, for a drug the usedyearly for prescription its main indication volume by in adultsitself lacks [20]. the For information metamizole, necessary the DDD to is evaluate3 g. 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To prescriptions our knowledge, in outpatientno study has care, been with performed a particular with focus greater on geographicregional differences resolution on than the atdistrict the state (Landkreis) level, although level. it can be assumed that marked differences exist even within states. Figure 1. Prescriptions of metamizole in Germany from 1991 to 2018 (according to the Annual Drug Figure 1. Prescriptions of metamizole in Germany from 1991 to 2018 (according to the Annual Prescription Reports [17–19]), displayed as defined daily doses (DDD); 1 DDD = 3 g (lower caption) as Drug Prescription Reports [17–19]), displayed as defined daily doses (DDD); 1 DDD = 3 g (lower well as the calculated number of 500 mg tablets per insured person (upper italic caption). caption) as well as the calculated number of 500 mg tablets per insured person (upper italic caption). The aim of this study is to provide an insight into the number of metamizole prescriptions in 2.outpatient Materials care, and withMethods a particular focus on regional differences on the district (Landkreis) level. We obtained data from the “Information System for Health Care Data” located at the German 2. Materials and Methods Institute of Medical Documentation and Information (DIMDI) [21]. It is based on data from some 70 millionWe individuals obtained data covered from by the all “Information statutory health System insurance for Health funds Care in Germany Data” located which at are the supplied German toInstitute the Federal of Medical Office Documentation of Social Security and Information to implement (DIMDI) the [morbidity-oriented21]. 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Eligible institutions can applyA formal for permissionapplication to for analyze data usage parts of and the a dataset, data analysis and after script thorough were scrutiny submitted receive on 29 anonymized February 2016.aggregate At the data time [22 of]. the application, the most recent data available with information on the district level wasA formal from application2010. After adaption for data usageand a andnarrowing a data of analysis our data script request were (e.g., submitted removal on of 29 our February initial request2016. At for the high-resolution time of the application, stratification the by most age), recent our application data available was thoroughly with information screened on by the DIMDI. district Welevel received was from the 2010.final dataset After adaption on 19 December and a narrowing 2018. of our data request (e.g., removal of our initial Int. J. Environ. Res. Public Health 2020, 17, 3892 3 of 9 request for high-resolution stratification by age), our application was thoroughly screened by DIMDI. We received the final dataset on 19 December 2018. We received strongly aggregated data of individuals with at least one prescription for metamizole, and the number of packs (of any size) prescribed. Data was also provided on age (five age brackets), sex, state (Bundesland), and on the number of persons in each stratum.