{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T18:48:36Z","timestamp":1768848516235,"version":"3.49.0"},"reference-count":32,"publisher":"Springer Science and Business Media LLC","issue":"9","license":[{"start":{"date-parts":[[2022,6,22]],"date-time":"2022-06-22T00:00:00Z","timestamp":1655856000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,6,22]],"date-time":"2022-06-22T00:00:00Z","timestamp":1655856000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100003197","name":"Agenzia Italiana del Farmaco, Ministero della Salute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003197","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004434","name":"Universit\u00e0 degli Studi di Firenze","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004434","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Eur J Clin Pharmacol"],"published-print":{"date-parts":[[2022,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Purpose<\/jats:title>\n                <jats:p>Benzodiazepines (BZD), Z-drugs (ZD), and opioids share a high risk of abuse. This study assessed and characterised adverse events (AEs) related to BDZ, ZD, and opioids leading to emergency department (ED) visits in the Italian setting.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>ED accesses related to BDZ, ZD, and\/or opioids were analysed from the MEREAFaPS database. Information on AEs, suspected and concomitant medications was retrieved. Multivariate logistic regression was used to estimate the reporting odds ratios (RORs) of hospitalisation according to the different treatments.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>A total of 5,970 pharmacovigilance reports involving BZD\/ZD (<jats:italic>n<\/jats:italic>\u2009=\u20093,106), opioids (<jats:italic>n<\/jats:italic>\u2009=\u20092,767), or their combination (<jats:italic>n<\/jats:italic>\u2009=\u200997) were analysed. Compared to opioids, patients with BZD\/ZD-related AEs were often younger (51 vs 64\u00a0years), more frequently presented 2+\u2009suspected medications (13 vs 3%), and often had a history of abuse (4%). Twenty-three percent of BZD\/ZD-related AEs were related to drug abuse (vs 2% of opioid-related ones) and frequently required patient hospitalisation (52% vs 24%), despite the significantly lower clinical complexity of these patients as compared to those on opioids. An increased risk of hospitalisation was found for flurazepam (ROR 1.62; 95% CI, 1.18\u20132.22), prazepam (2.66; 1.05\u20136.70), lorazepam (1.26; 1.07\u20131.49), and morphine (1.76; 1.11\u20132.79).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>These results indicate that, in Italy, the inappropriate use of BZD\/ZD is a relevant heath issue, often leading to serious AEs requiring patients\u2019 ED visits and hospitalisation, especially in young women and patients with a history of substance abuse.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00228-022-03354-7","type":"journal-article","created":{"date-parts":[[2022,6,22]],"date-time":"2022-06-22T22:02:50Z","timestamp":1655935370000},"page":"1511-1519","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Hospitalisations related to benzodiazepine, Z-drug, and opioid treatment in Italy: a claim on the risks associated with inappropriate use"],"prefix":"10.1007","volume":"78","author":[{"given":"Irene","family":"Mattioli","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessandra","family":"Bettiol","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1071-6120","authenticated-orcid":false,"given":"Giada","family":"Crescioli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roberto","family":"Bonaiuti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Domenico","family":"Prisco","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guido","family":"Mannaioni","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Niccol\u00f2","family":"Lombardi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alfredo","family":"Vannacci","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"the MEREAFaPS Study group","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2022,6,22]]},"reference":[{"issue":"3","key":"3354_CR1","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1053\/j.semperi.2019.01.001","volume":"43","author":"J Lyden","year":"2019","unstructured":"Lyden J, Binswanger IA (2019) The United States opioid epidemic. Semin Perinatol 43(3):123\u2013131. https:\/\/doi.org\/10.1053\/j.semperi.2019.01.001","journal-title":"Semin Perinatol"},{"key":"3354_CR2","unstructured":"INCB Narcotic Drugs Stup\u00e9fiants Estupefacientes (2020) Available online at: https:\/\/www.incb.org\/documents\/Narcotic-Drugs\/Technical-Publications\/2020\/Narcotic_Drugs_Technical_publication_2020.pdf. Accessed 2 Mar\u00a02022"},{"key":"3354_CR3","unstructured":"UNODC World Drug Report (2019) Available online at: https:\/\/wdr.unodc.org\/wdr2019\/prelaunch\/pre-launchpresentation_WDR_2019.pdf. Accessed 2 Mar\u00a02022"},{"issue":"15","key":"3354_CR4","doi-asserted-by":"publisher","first-page":"1480","DOI":"10.1056\/NEJMsr1601307","volume":"374","author":"RM Califf","year":"2016","unstructured":"Califf RM, Woodcock J, Ostroff S (2016) A proactive response to prescription opioid abuse. N Engl J Med 374(15):1480\u20131485. https:\/\/doi.org\/10.1056\/NEJMsr1601307","journal-title":"N Engl J Med"},{"issue":"3","key":"3354_CR5","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1080\/14740338.2019.1579796","volume":"18","author":"S Mercadante","year":"2019","unstructured":"Mercadante S (2019) Potential strategies to combat the opioid crisis. Expert Opin Drug Saf 18(3):211\u2013217. https:\/\/doi.org\/10.1080\/14740338.2019.1579796","journal-title":"Expert Opin Drug Saf"},{"issue":"3","key":"3354_CR6","doi-asserted-by":"publisher","first-page":"120","DOI":"10.9740\/mhc.2016.05.120","volume":"6","author":"A Schmitz","year":"2016","unstructured":"Schmitz A (2016) Benzodiazepine use, misuse, and abuse: a review. Ment Health Clin 6(3):120\u2013126. https:\/\/doi.org\/10.9740\/mhc.2016.05.120","journal-title":"Ment Health Clin"},{"issue":"9","key":"3354_CR7","doi-asserted-by":"publisher","first-page":"1006","DOI":"10.1001\/jamapsychiatry.2014.436","volume":"71","author":"LM Hampton","year":"2014","unstructured":"Hampton LM, Daubresse M, Chang HY, Alexander GC, Budnitz DS (2014) Emergency department visits by adults for psychiatric medication adverse events. JAMA Psychiat 71(9):1006\u20131014. https:\/\/doi.org\/10.1001\/jamapsychiatry.2014.436","journal-title":"JAMA Psychiat"},{"issue":"10","key":"3354_CR8","doi-asserted-by":"publisher","first-page":"1414","DOI":"10.1016\/j.ajem.2017.04.023","volume":"35","author":"CN Kaufmann","year":"2017","unstructured":"Kaufmann CN, Spira AP, Alexander GC, Rutkow L, Mojtabai R (2017) Emergency department visits involving benzodiazepines and non-benzodiazepine receptor agonists. Am J Emerg Med 35(10):1414\u20131419. https:\/\/doi.org\/10.1016\/j.ajem.2017.04.023","journal-title":"Am J Emerg Med"},{"issue":"1","key":"3354_CR9","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1007\/s00228-018-2550-1","volume":"75","author":"C Lyphout","year":"2019","unstructured":"Lyphout C, Yates C, Margolin ZR, Dargan PI, Dines AM, Heyerdahl F, Hovda KE, Giraudon I, Bucher-Bartelson B, Green JL, Euro DENRG, Wood DM (2019) Presentations to the emergency department with non-medical use of benzodiazepines and Z-drugs: profiling and relation to sales data. Eur J Clin Pharmacol 75(1):77\u201385. https:\/\/doi.org\/10.1007\/s00228-018-2550-1","journal-title":"Eur J Clin Pharmacol"},{"issue":"7","key":"3354_CR10","doi-asserted-by":"publisher","first-page":"1291","DOI":"10.1007\/s11739-020-02339-7","volume":"15","author":"N Lombardi","year":"2020","unstructured":"Lombardi N, Bettiol A, Crescioli G, Ravaldi C, Bonaiuti R, Venegoni M, Vighi GD, Mugelli A, Mannaioni G, Vannacci A, MES group (2020) Risk of hospitalisation associated with benzodiazepines and z-drugs in Italy: a nationwide multicentre study in emergency departments. Intern Emerg Med 15(7):1291\u20131302. https:\/\/doi.org\/10.1007\/s11739-020-02339-7","journal-title":"Intern Emerg Med"},{"key":"3354_CR11","unstructured":"AIFA OsMed National Reports on Medicines use in Italy. Available online at: https:\/\/www.aifa.gov.it\/rapporti-osmed. Accessed 2 Mar\u00a02022"},{"issue":"1","key":"3354_CR12","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1186\/s40360-018-0207-4","volume":"19","author":"N Lombardi","year":"2018","unstructured":"Lombardi N, Crescioli G, Bettiol A, Marconi E, Vitiello A, Bonaiuti R, Calvani AM, Masi S, Lucenteforte E, Mugelli A, Giovannelli L, Vannacci A (2018) Characterization of serious adverse drug reactions as cause of emergency department visit in children: a 5-years active pharmacovigilance study. BMC Pharmacol Toxicol 19(1):16. https:\/\/doi.org\/10.1186\/s40360-018-0207-4","journal-title":"BMC Pharmacol Toxicol"},{"key":"3354_CR13","doi-asserted-by":"publisher","DOI":"10.3390\/ph14070678","author":"G Crescioli","year":"2021","unstructured":"Crescioli G, Boscia E, Bettiol A, Pagani S, Spada G, Vighi GV, Bonaiuti R, Venegoni M, Vighi GD, Vannacci A, Lombardi N, On Behalf of the MSG (2021) Risk of hospitalization for adverse drug events in women and men: a post hoc analysis of an active pharmacovigilance study in Italian emergency departments. Pharmaceuticals (Basel). https:\/\/doi.org\/10.3390\/ph14070678","journal-title":"Pharmaceuticals (Basel)"},{"key":"3354_CR14","doi-asserted-by":"publisher","first-page":"412","DOI":"10.3389\/fphar.2020.00412","volume":"11","author":"N Lombardi","year":"2020","unstructured":"Lombardi N, Crescioli G, Bettiol A, Tuccori M, Capuano A, Bonaiuti R, Mugelli A, Venegoni M, Vighi GD, Vannacci A, MES group (2020) Italian emergency department visits and hospitalizations for outpatients\u2019 adverse drug events: 12-year active pharmacovigilance surveillance (the MEREAFaPS study). Front Pharmacol 11:412. https:\/\/doi.org\/10.3389\/fphar.2020.00412","journal-title":"Front Pharmacol"},{"issue":"3","key":"3354_CR15","doi-asserted-by":"publisher","first-page":"741","DOI":"10.1007\/s11739-020-02521-x","volume":"16","author":"S Pagani","year":"2021","unstructured":"Pagani S, Lombardi N, Crescioli G, Vighi GV, Spada G, Romoli I, Andreetta P, Capuano A, Marrazzo E, Marra A, Leoni O, Vannacci A, Venegoni M, Vighi GD, MES group (2021) Analysis of fatal adverse drug events recorded in several Italian emergency departments (the MEREAFaPS study). Intern Emerg Med 16(3):741\u2013748. https:\/\/doi.org\/10.1007\/s11739-020-02521-x","journal-title":"Intern Emerg Med"},{"key":"3354_CR16","doi-asserted-by":"publisher","first-page":"611102","DOI":"10.3389\/fphar.2020.611102","volume":"11","author":"G Crescioli","year":"2020","unstructured":"Crescioli G, Bettiol A, Bonaiuti R, Tuccori M, Rossi M, Capuano A, Pagani S, Spada G, Venegoni M, Vighi GD, Mannaioni G, Vannacci A, Lombardi N, MES group (2020) Risk of hospitalization associated with cardiovascular medications in the elderly Italian population: a nationwide multicenter study in emergency departments. Front Pharmacol 11:611102. https:\/\/doi.org\/10.3389\/fphar.2020.611102","journal-title":"Front Pharmacol"},{"key":"3354_CR17","unstructured":"ATC\/DDD Index (2022) Available online at: https:\/\/www.whocc.no\/atc_ddd_index\/. Accessed 2 Mar\u00a02022"},{"key":"3354_CR18","unstructured":"Brunton L, Dandan R (2018) Goodman & Gilman's. The pharmacological basis of therapy, 13th edn. McGraw-Hill Education. ISBN 978-1259584732"},{"key":"3354_CR19","unstructured":"NIH PubChem. Available online at: https:\/\/pubchem.ncbi.nlm.nih.gov. Accessed 2 Mar\u00a02022"},{"issue":"1","key":"3354_CR20","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1111\/j.1365-2125.2012.04317.x","volume":"75","author":"AM Drewes","year":"2013","unstructured":"Drewes AM, Jensen RD, Nielsen LM, Droney J, Christrup LL, Arendt-Nielsen L, Riley J, Dahan A (2013) Differences between opioids: pharmacological, experimental, clinical and economical perspectives. Br J Clin Pharmacol 75(1):60\u201378. https:\/\/doi.org\/10.1111\/j.1365-2125.2012.04317.x","journal-title":"Br J Clin Pharmacol"},{"key":"3354_CR21","unstructured":"European Medicines Agency. Guideline on Good Pharmacovigilance Practices. Available online at: https:\/\/www.ema.europa.eu\/docs\/en_GB\/document_library\/Regulatory_and_procedural_guideline\/2017\/08\/WC500232767.pdf. Accessed 2 Mar\u00a02022"},{"key":"3354_CR22","unstructured":"MedDRA Hierarchy. Available online at: https:\/\/www.meddra.org\/how-to-use\/basics\/hierarchy. Accessed 2 Mar\u00a02022"},{"key":"3354_CR23","doi-asserted-by":"publisher","first-page":"108609","DOI":"10.1016\/j.drugalcdep.2021.108609","volume":"221","author":"GA Bushnell","year":"2021","unstructured":"Bushnell GA, Olfson M, Martins SS (2021) Sex differences in US emergency department non-fatal visits for benzodiazepine poisonings in adolescents and young adults. Drug Alcohol Depend 221:108609. https:\/\/doi.org\/10.1016\/j.drugalcdep.2021.108609","journal-title":"Drug Alcohol Depend"},{"key":"3354_CR24","unstructured":"Rossi F, Cuomo V, Riccardi C (2011) Farmacologia. Principi di base e applicazioni terapeutiche. 2 Edizione. Edizioni Minerva Medica. ISBN 978-8877116994"},{"issue":"1","key":"3354_CR25","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1080\/02791072.2016.1269978","volume":"49","author":"SP Kurtz","year":"2017","unstructured":"Kurtz SP, Buttram ME, Surratt HL (2017) Benzodiazepine dependence among young adult participants in the club scene who use drugs. J Psychoactive Drugs 49(1):39\u201346. https:\/\/doi.org\/10.1080\/02791072.2016.1269978","journal-title":"J Psychoactive Drugs"},{"key":"3354_CR26","doi-asserted-by":"publisher","first-page":"j760","DOI":"10.1136\/bmj.j760","volume":"356","author":"EC Sun","year":"2017","unstructured":"Sun EC, Dixit A, Humphreys K, Darnall BD, Baker LC, Mackey S (2017) Association between concurrent use of prescription opioids and benzodiazepines and overdose: retrospective analysis. BMJ 356:j760. https:\/\/doi.org\/10.1136\/bmj.j760","journal-title":"BMJ"},{"key":"3354_CR27","unstructured":"European Monitoring Centre for Drugs and Drug Addiction, Perspectives on Drugs - The misuse of benzodiazepines among high-risk opioid users in Europe. Available online at: https:\/\/www.emcdda.europa.eu\/system\/files\/publications\/2733\/Misuse%20of%20benzos_POD2015.pdf. Accessed 2 Mar\u00a02022"},{"issue":"9752","key":"3354_CR28","doi-asserted-by":"publisher","first-page":"1558","DOI":"10.1016\/S0140-6736(10)61462-6","volume":"376","author":"DJ Nutt","year":"2010","unstructured":"Nutt DJ, King LA, Phillips LD, Independent Scientific Committee on D (2010) Drug harms in the UK: a multicriteria decision analysis. Lancet 376(9752):1558\u20131565. https:\/\/doi.org\/10.1016\/S0140-6736(10)61462-6","journal-title":"Lancet"},{"issue":"4","key":"3354_CR29","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1007\/s40268-017-0207-7","volume":"17","author":"J Brandt","year":"2017","unstructured":"Brandt J, Leong C (2017) Benzodiazepines and Z-drugs: an updated review of major adverse outcomes reported on in epidemiologic research. Drugs R D 17(4):493\u2013507. https:\/\/doi.org\/10.1007\/s40268-017-0207-7","journal-title":"Drugs R D"},{"issue":"8","key":"3354_CR30","doi-asserted-by":"publisher","first-page":"1271","DOI":"10.1007\/s11739-019-02101-8","volume":"14","author":"M Faccini","year":"2019","unstructured":"Faccini M, Tamburin S, Casari R, Morbioli L, Lugoboni F (2019) High-dose lormetazepam dependence: strange case of Dr. Jekyll and Mr. Hyde. Intern Emerg Med 14(8):1271\u20131278. https:\/\/doi.org\/10.1007\/s11739-019-02101-8","journal-title":"Intern Emerg Med"},{"key":"3354_CR31","unstructured":"NIH National Istitute of Drug Abuse, Overdose Death Rates. Available online at: https:\/\/www.drugabuse.gov\/drug-topics\/trends-statistics\/overdose-death-rates. Accessed 2 Mar\u00a02022"},{"key":"3354_CR32","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s11739-022-02976-0","volume":"12","author":"S Sartori","year":"2022","unstructured":"Sartori S, Crescioli G, Brilli V, Traversoni S, Lanzi C, Vannacci A, Mannaioni G (2022) Lombardi N (2022) Phenobarbital use in benzodiazepine and z-drug detoxification: a single-centre 15-year observational retrospective study in clinical practice. Intern Emerg Med 12:1\u201310. https:\/\/doi.org\/10.1007\/s11739-022-02976-0","journal-title":"Intern Emerg Med"}],"container-title":["European Journal of Clinical Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00228-022-03354-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00228-022-03354-7\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00228-022-03354-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,8,10]],"date-time":"2022-08-10T07:07:18Z","timestamp":1660115238000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00228-022-03354-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,22]]},"references-count":32,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2022,9]]}},"alternative-id":["3354"],"URL":"https:\/\/doi.org\/10.1007\/s00228-022-03354-7","relation":{},"ISSN":["0031-6970","1432-1041"],"issn-type":[{"value":"0031-6970","type":"print"},{"value":"1432-1041","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,22]]},"assertion":[{"value":"4 March 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 June 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 June 2022","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":"Conflict of interest"}}]}}