{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T04:27:29Z","timestamp":1780633649983,"version":"3.54.1"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,4,14]],"date-time":"2022-04-14T00:00:00Z","timestamp":1649894400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007658","name":"Crohn's and Colitis Canada","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007658","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008794","name":"Research Manitoba","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008794","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Use of benzodiazepines and Z-drugs (non-benzodiazepine sedative hypnotics) is controversial due to adverse health outcomes in the general population. However, little is known about their use in people with multiple sclerosis (MS). We estimated the incidence and prevalence of benzodiazepine and Z-drug use (jointly BZD) in the MS population as compared to an age-, sex- and geographically-matched population without MS, and examined the association of mood\/anxiety disorders with the use of BZD over a twenty-year period.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Using administrative data from Manitoba, Canada, we identified 2,985 persons with incident MS and 14,891 persons without MS matched 5:1 on sex, birth year and region. We applied validated case definitions to identify persons with any mood\/anxiety disorder. Dispensations of BZD were identified. To assess the association between MS, mood\/anxiety disorders and BZD use we constructed generalized linear models adjusting for age, sex, index year, socioeconomic status, urban\/rural residence, physical comorbidities, and health care use. We also examined patterns of BZD use.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In 2016, the crude incidence of benzodiazepine use in the MS cohort was 2.10% (95%CI: 1.43\u20132.98%), 1.49-fold higher than in the non-MS cohort (1.41%; 95%CI: 1.18\u20131.67%). The crude incidence of Z-drug use in the MS cohort was 1.77% (95%CI: 1.20\u20132.51%), 1.78-fold higher than in the non-MS cohort (0.99%; 95%CI: 0.81\u20131.21%). After adjusting for covariates, among individuals without an active mood\/anxiety disorder, the MS cohort had a 39% increased incidence rate of benzodiazepine use and a 72% increased incidence rate of Z-drug use as compared to the non-MS cohort. Among individuals with an active mood\/anxiety disorder, the incidence of BZD use did not differ between the MS and non-MS cohorts. A higher proportion of people with MS used BZD for \u22656 months than people without MS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Use of BZD is more common in people with MS than in general population controls, and use of these agents is in persons with MS is often chronic.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fneur.2022.874724","type":"journal-article","created":{"date-parts":[[2022,4,14]],"date-time":"2022-04-14T10:26:06Z","timestamp":1649931966000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Use of Benzodiazepines and Z-Drugs in Multiple Sclerosis"],"prefix":"10.3389","volume":"13","author":[{"given":"Ruth Ann","family":"Marrie","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John D.","family":"Fisk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Randy","family":"Walld","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James M.","family":"Bolton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jitender","family":"Sareen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott B.","family":"Patten","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Singer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa M.","family":"Lix","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol A.","family":"Hitchon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ren\u00e9e","family":"El-Gabalawy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan","family":"Katz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James J.","family":"Marriott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles N.","family":"Bernstein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"the CIHR Team in Defining the Burden Managing the Effects of Psychiatric Comorbidity in Chronic Immunoinflammatory Disease","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,4,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1972","DOI":"10.1212\/WNL.0000000000002174","article-title":"Differences in the burden of psychiatric comorbidity in MS vs the general population","volume":"85","author":"Marrie","year":"2015","journal-title":"Neurology."},{"key":"B2","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1016\/j.msard.2015.07.010","article-title":"InMS: Chronic insomnia disorder in multiple sclerosis \u2013 a Portuguese multicentre study on prevalence, subtypes, associated factors and impact on quality of life","volume":"4","author":"Viana","year":"2015","journal-title":"Mult Scler Relat Disord."},{"key":"B3","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1007\/s40268-017-0207-7","article-title":"Benzodiazepines and Z-Drugs: an updated review of major adverse outcomes reported on in epidemiologic research","volume":"17","author":"Brandt","year":"2017","journal-title":"Drugs R D."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1047","DOI":"10.1007\/s00127-016-1234-3","article-title":"Prescribed psychiatric medication among multiple sclerosis patients before and after disability pension: a register study with matched controls","volume":"51","author":"Brenner","year":"2016","journal-title":"Soc Psychiatry Psychiatr Epidemiol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"188","DOI":"10.1017\/cjn.2017.274","article-title":"Clinical profile of persons with multiple sclerosis across the continuum of care","volume":"45","author":"Turcotte","year":"2018","journal-title":"Can J Neurol Sci."},{"key":"B6","doi-asserted-by":"publisher","first-page":"E208","DOI":"10.9778\/cmajo.20130076","article-title":"Use of benzodiazepines and related drugs in Manitoba: a population-based study","volume":"2","author":"Alessi-Severini","year":"2014","journal-title":"CMAJ Open."},{"key":"B7","first-page":"e187399","article-title":"Patterns in outpatient benzodiazepine prescribing in the United States","volume-title":"JAMA Netw Open.","author":"Agarwal","year":"2019"},{"key":"B8","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1016\/j.jamda.2017.12.098","article-title":"Fall-risk-increasing drugs: a systematic review and meta-analysis: II. psychotropics","volume":"19","author":"Seppala","year":"2018","journal-title":"J Am Med Direct Assoc."},{"key":"B9","first-page":"9","article-title":"The effects of benzodiazepines on cognition","volume":"66","author":"Stewart","year":"2005","journal-title":"J Clin Psychiatry."},{"key":"B10","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1007\/s40264-020-00992-7","article-title":"Patterns of benzodiazepine use and excess risk of all-cause mortality in the elderly: a nationwide cohort study","volume":"44","author":"Mathieu","year":"2021","journal-title":"Drug Safety."},{"key":"B11","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1212\/WNL.0b013e3181cf6ec0","article-title":"The rising prevalence and changing age distribution of multiple sclerosis in Manitoba","volume":"74","author":"Marrie RA Yu","year":"2010","journal-title":"Neurology."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1169","DOI":"10.1136\/bmj.38623.768588.47","article-title":"Sedative hypnotics in older people with insomnia: meta-analysis of risks and benefits","volume":"331","author":"Glass","year":"2005","journal-title":"BMJ."},{"key":"B13","volume-title":"Standard of practice: prescribing benzodiazepines & Z-drugs (including Zopiclone & other drugs) Section 82","year":"2020"},{"key":"B14","doi-asserted-by":"publisher","first-page":"E256","DOI":"10.9778\/cmajo.20140027","article-title":"Impact of legislation and a prescription monitoring program on the prevalence of potentially inappropriate prescriptions for monitored drugs in Ontario: a time series analysis","volume":"2","author":"Gomes","year":"2014","journal-title":"CMAJ Open."},{"key":"B15","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1111\/j.1365-2710.2011.01245.x","article-title":"The intended and unintended consequences of benzodiazepine monitoring programmes: a review of the literature","volume":"37","author":"Fisher","year":"2012","journal-title":"J Clin Pharm Ther."},{"key":"B16","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1017\/cjn.2017.301","article-title":"Establishing the Incidence and Prevalence of Multiple Sclerosis in Saskatchewan","volume":"45","author":"Al-Sakran","year":"2018","journal-title":"Can J Neurol Sci."},{"key":"B17","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1186\/1471-2377-13-16","article-title":"Mental comorbidity and multiple sclerosis: validating administrative data to support population-based surveillance","volume":"13","author":"Marrie","year":"2013","journal-title":"BMC Neurol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"959","DOI":"10.1016\/j.cpr.2007.02.005","article-title":"Risk for recurrence in depression","volume":"27","author":"Burcusa","year":"2007","journal-title":"Clin Psychol Rev."},{"key":"B19","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1017\/S1092852900025815","article-title":"Defining response and remission in anxiety disorders: toward an integrated approach","volume":"11","author":"Bandelow","year":"2006","journal-title":"CNS Spectr."},{"key":"B20","doi-asserted-by":"publisher","first-page":"j3927","DOI":"10.1136\/bmj.j3927","article-title":"Risk of relapse after antidepressant discontinuation in anxiety disorders, obsessive-compulsive disorder, and post-traumatic stress disorder: systematic review and meta-analysis of relapse prevention trials","volume":"358","author":"Batelaan","year":"2017","journal-title":"BMJ."},{"key":"B21","doi-asserted-by":"publisher","first-page":"619","DOI":"10.1186\/s13104-017-2958-1","article-title":"Estimating annual prevalence of depression and anxiety disorder in multiple sclerosis using administrative data","volume":"10","author":"Marrie","year":"2017","journal-title":"BMC Res Notes."},{"key":"B22","unstructured":"Anatomic Therapeutic Chemical Classification System Oslo: Norwegian Institute of Public Health2011"},{"key":"B23","doi-asserted-by":"publisher","first-page":"e043930","DOI":"10.1136\/bmjopen-2020-043930","article-title":"Medication adherence in multiple sclerosis as a potential model for other chronic diseases: a population-based cohort study","volume":"11","author":"Evans","year":"2021","journal-title":"BMJ Open."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1037","DOI":"10.1016\/j.eurpsy.2015.09.003","article-title":"Long-term use of benzodiazepines: Definitions, prevalence and usage patterns \u2013 a systematic review of register-based studies","volume":"30","author":"Kurko","year":"2015","journal-title":"Eur Psychiatry."},{"key":"B25","doi-asserted-by":"publisher","first-page":"S23","DOI":"10.1007\/BF03403825","article-title":"Learning from the census: the Socio-economic Factor Index (SEFI) and health outcomes in Manitoba","volume":"103","author":"Chateau","year":"2012","journal-title":"Can J Public Health."},{"key":"B26","first-page":"53","article-title":"Ambulatory care groups: a categorization of diagnoses for research and management","volume":"26","author":"Starfield","year":"1991","journal-title":"Health Serv Res."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1345","DOI":"10.1111\/1475-6773.01029","article-title":"Assessing population health care need using a claims-based ACG morbidity measure: a validation analysis in the province of manitoba","volume":"37","author":"Reid","year":"2002","journal-title":"Health Serv Res."},{"key":"B28","doi-asserted-by":"publisher","first-page":"1411","DOI":"10.1177\/1352458520963880","article-title":"Effect of mood and anxiety disorders on health care utilization in multiple sclerosis","volume":"27","author":"Marrie","year":"2021","journal-title":"Mult Scler J."},{"key":"B29","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1016\/j.sleep.2014.09.006","article-title":"Hypnotic use and fatigue in multiple sclerosis","volume":"16","author":"Braley","year":"2015","journal-title":"Sleep Med."},{"key":"B30","doi-asserted-by":"publisher","first-page":"818","DOI":"10.1186\/s12889-020-08984-z","article-title":"Trends in the consumption rates of benzodiazepines and benzodiazepine-related drugs in the health region of Lleida from 2002 to 2015","volume":"20","author":"Torres-Bondia","year":"2020","journal-title":"BMC Public Health."},{"key":"B31","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1002\/pds.4123","article-title":"Trends in incident use of benzodiazepines and Z-drugs in France from 2006 to 2012: a population-based study","volume":"26","author":"B\u00e9nard-Laribi\u00e8re","year":"2017","journal-title":"Pharmacoepidemiol Drug Saf."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1180","DOI":"10.1111\/jgs.15292","article-title":"Benzodiazepine use in older adults in the United States, Ontario, and Australia from 2010 to 2016","volume":"66","author":"Brett","year":"2018","journal-title":"J Am Geriatr Soc."},{"key":"B33","first-page":"e473","article-title":"Choosing wisely Canada recommendations","volume":"63","author":"Klein","year":"2017","journal-title":"Can Fam Physician."},{"key":"B34","volume-title":"Benzodiazepines for the Treatment of Adults with Mental Health Conditions or Sleep Disorders: Guidelines.","year":"2019"},{"key":"B35","volume-title":"Canadian Guidelines on Benzodiazepine Receptor Agonist Use Disorder Among Older Adults","year":"2019"},{"key":"B36","doi-asserted-by":"publisher","first-page":"107","DOI":"10.3109\/08039488.2013.775342","article-title":"Socio-demographic, lifestyle and psychological predictors of benzodiazepine and z-hypnotic use patterns","volume":"68","author":"Nordfj\u00e6rn","year":"2014","journal-title":"Nord J Psychiatry."},{"key":"B37","doi-asserted-by":"publisher","first-page":"e00688","DOI":"10.1016\/j.heliyon.2018.e00688","article-title":"Patterns of benzodiazepines use in primary care adults with anxiety disorders","volume":"4","author":"Tanguay Bernard","year":"2018","journal-title":"Heliyon."},{"key":"B38","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1017\/S1121189X00000531","article-title":"Patterns of benzodiazepine use in a Canadian population sample","volume":"18","author":"Esposito","year":"2009","journal-title":"Epidemiol Psichiatr Soc."},{"key":"B39","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1186\/s41983-018-0016-0","article-title":"Insomnia among non-depressed multiple sclerosis patients: a cross-sectional study","volume":"54","author":"Alhazzani","year":"2018","journal-title":"Egypt J Neurol Psychiatry Neurosurg."},{"key":"B40","doi-asserted-by":"publisher","first-page":"e8343","DOI":"10.1136\/bmj.e8343","article-title":"Effectiveness of non-benzodiazepine hypnotics in treatment of adult insomnia: meta-analysis of data submitted to the food and drug administration","volume":"345","author":"Huedo-Medina","year":"2012","journal-title":"BMJ."},{"key":"B41","doi-asserted-by":"publisher","first-page":"84","DOI":"10.7224\/1537-2073-13.2.84","article-title":"Effect of Eszopiclone on sleep disturbances and daytime fatigue in multiple sclerosis patients","volume":"13","author":"Attarian","year":"2011","journal-title":"Int J MS Care."},{"key":"B42","doi-asserted-by":"publisher","first-page":"107","DOI":"10.7224\/1537-2073.2019-122","article-title":"Feasibility and treatment effect of a web-based cognitive behavioral therapy for insomnia program in individuals with multiple sclerosis: a pilot randomized controlled trial","volume":"23","author":"Siengsukon","year":"2020","journal-title":"Int J MS Care."},{"key":"B43","doi-asserted-by":"publisher","first-page":"1585","DOI":"10.1007\/s11064-014-1347-6","article-title":"Melatonin acts as antioxidant and improves sleep in MS patients","volume":"39","author":"Adamczyk-Sowa","year":"2014","journal-title":"Neurochem Res."},{"key":"B44","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1212\/CPJ.0000000000000230","article-title":"Differing trends in the incidence of vascular comorbidity in MS and the general population","volume":"6","author":"Marrie","year":"2016","journal-title":"Neurol Clin Pract."},{"key":"B45","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1002\/pds.3825","article-title":"Exposure to benzodiazepines (anxiolytics, hypnotics and related drugs) in seven European electronic healthcare databases: a cross-national descriptive study from the PROTECT-EU Project","volume":"25","author":"Huerta","year":"2016","journal-title":"Pharmacoepidemiol Drug Saf."},{"key":"B46","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1177\/070674370605100204","article-title":"Descriptive epidemiology of major depression in Canada","volume":"51","author":"Patten","year":"2006","journal-title":"Can J Psychiatry."},{"key":"B47","doi-asserted-by":"publisher","first-page":"1118","DOI":"10.3109\/00048670903279838","article-title":"Use of administrative data for the surveillance of mood and anxiety disorders","volume":"43","author":"Kisely","year":"2009","journal-title":"Aust N Z J Psychiatry."},{"key":"B48","doi-asserted-by":"publisher","first-page":"S33","DOI":"10.1186\/1472-6874-4-S1-S33","article-title":"Health care utilization by Canadian women","volume":"4","author":"Kazanjian","year":"2004","journal-title":"BMC Womens Health."},{"key":"B49","doi-asserted-by":"publisher","first-page":"1524","DOI":"10.1212\/01.WNL.0000095964.34294.B4","article-title":"Major depression in multiple sclerosis","volume":"61","author":"Patten","year":"2003","journal-title":"Neurology."},{"key":"B50","doi-asserted-by":"publisher","first-page":"302","DOI":"10.1016\/S1474-4422(14)70250-9","article-title":"Clinical and imaging assessment of cognitive dysfunction in multiple sclerosis","volume":"14","author":"Rocca","year":"2015","journal-title":"Lancet Neurol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1177\/1352458514538884","article-title":"Falls in people with MS\u2013an individual data meta-analysis from studies from Australia, Sweden, United Kingdom and the United States","volume":"21","author":"Nilsagard","year":"2015","journal-title":"Mult Scler."}],"container-title":["Frontiers in Neurology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2022.874724\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,14]],"date-time":"2022-04-14T10:26:15Z","timestamp":1649931975000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2022.874724\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,14]]},"references-count":51,"alternative-id":["10.3389\/fneur.2022.874724"],"URL":"https:\/\/doi.org\/10.3389\/fneur.2022.874724","relation":{},"ISSN":["1664-2295"],"issn-type":[{"value":"1664-2295","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,14]]},"article-number":"874724"}}