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      Benzodiazepine prescribing for children, adolescents, and young adults from 2006 through 2013: A total population register-linkage study

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          Abstract

          Background

          Pharmacoepidemiological studies have long raised concerns on widespread use of benzodiazepines and benzodiazepine-related drugs (BZDs), in particular long-term use, among adults and the elderly. In contrast, evidence pertaining to the rates of BZD use at younger ages is still scarce, and the factors that influence BZD utilisation and shape the different prescribing patterns in youths remain largely unexplored. We examined the prevalence rates, relative changes in rates over time, and prescribing patterns for BZD dispensation in young people aged 0–24 years in Sweden during the period January 1, 2006–December 31, 2013, and explored demographic, clinical, pharmacological, and prescriber-related attributes of BZD prescribing in this group.

          Methods and findings

          Through the linkage of 3 nationwide Swedish health and administrative registers, we collected data on 17,500 children (0–11 years), 15,039 adolescents (12–17 years), and 85,200 young adults (18–24 years) with at least 1 dispensed prescription for a BZD during 2006–2013, out of 3,726,818 Swedish inhabitants aged 0–24 years. Age-specific annual prevalence rates of BZD dispensations were adjusted for population growth, and relative changes in rates were calculated between 2006 and 2013. We analysed how BZD dispensation varied by sex, psychiatric morbidity and epilepsy, concurrent dispensation of psychotropic medication, type of dispensed BZD, and type of healthcare provider prescribing the BZD. Prescribing patterns were established in relation to duration (3 months, >3 to ≤6 months, or >6 months), dosage (<0.5 defined daily dosage [DDD]/day, ≥0.5 to <1.5 DDD/day, or ≥1.5 DDD/day), and “user category” (“regular users” [≥0.5 to <1.5 DDD/day for ≥1 year], “heavy users” [≥1.5 DDD/day for ≥1 year], or otherwise “occasional users”). Multinomial regression models were fitted to test associations between BZD prescribing patterns and individual characteristics of study participants. Between 2006 and 2013, the prevalence rate of BZD dispensation among individuals aged 0–24 years increased by 22% from 0.81 per 100 inhabitants to 0.99 per 100 inhabitants. This increase was mainly driven by a rise in the rate among young adults (+20%), with more modest increases in children (+3%) and adolescents (+7%). Within each age category, overall dispensation of BZD anxiolytics and clonazepam decreased over time, while dispensation of BZD hypnotics/sedatives, including Z-drugs, showed an increase between 2006 and 2013. Out of 117,739 study participants with dispensed BZD prescriptions, 65% initiated BZD prescriptions outside of psychiatric services (92% of children, 60% of adolescents, 60% of young adults), and 76% were dispensed other psychotropic drugs concurrently with a BZD (46% of children, 80% of adolescents, 81% of young adults). Nearly 30% of the participants were prescribed a BZD for longer than 6 months (18% of children, 31% of adolescents, 31% of young adults). A high dose prescription (≥1.5 DDD/day) and heavy use were detected in 2.6% and 1.7% of the participants, respectively. After controlling for potential confounding by demographic and clinical characteristics, the characteristics age above 11 years at the first BZD dispensation, lifetime psychiatric diagnosis or epilepsy, and concurrent dispensation of other psychotropic drugs were found to be associated with higher odds of being prescribed a BZD for longer than 6 months, high dose prescription, and heavy use. Male sex was associated with a higher likelihood of high dose prescription and heavy use, but not with being prescribed a BZD on a long-term basis (> 6 months). The study limitations included lack of information on actual consumption of the dispensed BZDs and unavailability of data on the indications for BZD prescriptions.

          Conclusions

          The overall increase in prevalence rates of BZD dispensations during the study period and the unexpectedly high proportion of individuals who were prescribed a BZD on a long-term basis at a young age indicate a lack of congruence with international and national guidelines. These findings highlight the need for close monitoring of prescribing practices, particularly in non-psychiatric settings, in order to build an evidence base for safe and efficient BZD treatment in young persons.

          Author summary

          Why was this study done?
          • Benzodiazepines and benzodiazepine-related drugs (BZDs) are among the most widely used psychotropic medications in the world and have long raised public health concerns due to the risk for their users of developing dependence and severe adverse effects, in particular among long-term users.

          • The prevalence rates and attributes of BZD use have been well described in adults and the elderly.

          • In contrast, evidence regarding BZD prescribing for younger populations is scarce and fragmented, and factors influencing BZD utilisation in children, adolescents, and young adults remain largely unexplored.

          What did the researchers do and find?
          • We linked nationwide Swedish health and administrative registers on 3,726,818 individuals aged 0–24 years living in Sweden between 2006–2013, among whom 17,500 children (0–11 years), 15,039 adolescents (12–17 years), and 85,200 young adults (18–24 years) were dispensed a BZD prescription at least once during that period.

          • The prevalence rate of BZD dispensation has increased by 22% between 2006 and 2013, and has increased particularly in young adults.

          • For nearly 65% of all study participants with 1 or more dispensed BZD prescriptions, the first prescription was issued outside specialised psychiatric services. Most first prescriptions originated from primary care (41%) and non-psychiatric specialist settings (24%) such as paediatrics and internal medicine.

          • Over 75% of study participants were dispensed other psychotropic medication concurrently with a BZD, raising concerns about the potential risk of drug interactions.

          • Almost 30% were prescribed a BZD for longer than 6 months, contradicting international and national guidelines that advise against BZD use beyond 2–4 weeks for adults and generally discourage prescribing BZDs for ages below 18 years.

          What do these findings mean?
          • There is a need for clinicians, particularly those working in non-psychiatric services, to implement strategies to avoid potentially harmful patterns of prescribing BZDs to young people.

          • Young individuals who are prescribed BZDs should be closely monitored, in particular, with respect to duration of BZD treatment and concurrent prescription of other psychotropic drugs.

          Related collections

          Most cited references 32

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          British Association for Psychopharmacology consensus statement on evidence-based treatment of insomnia, parasomnias and circadian rhythm disorders.

          Sleep disorders are common in the general population and even more so in clinical practice, yet are relatively poorly understood by doctors and other health care practitioners. These British Association for Psychopharmacology guidelines are designed to address this problem by providing an accessible up-to-date and evidence-based outline of the major issues, especially those relating to reliable diagnosis and appropriate treatment. A consensus meeting was held in London in May 2009. Those invited to attend included BAP members, representative clinicians with a strong interest in sleep disorders and recognized experts and advocates in the field, including a representative from mainland Europe and the USA. Presenters were asked to provide a review of the literature and identification of the standard of evidence in their area, with an emphasis on meta-analyses, systematic reviews and randomized controlled trials where available, plus updates on current clinical practice. Each presentation was followed by discussion, aimed to reach consensus where the evidence and/or clinical experience was considered adequate or otherwise to flag the area as a direction for future research. A draft of the proceedings was then circulated to all participants for comment. Key subsequent publications were added by the writer and speakers at draft stage. All comments were incorporated as far as possible in the final document, which represents the views of all participants although the authors take final responsibility for the document.
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            Association between concurrent use of prescription opioids and benzodiazepines and overdose: retrospective analysis

            Objectives To identify trends in concurrent use of a benzodiazepine and an opioid and to identify the impact of these trends on admissions to hospital and emergency room visits for opioid overdose. Design Retrospective analysis of claims data, 2001-13. Setting Administrative health claims database. Participants 315 428 privately insured people aged 18-64 who were continuously enrolled in a health plan with medical and pharmacy benefits during the study period and who also filled at least one prescription for an opioid. Interventions Concurrent benzodiazepine/opioid use, defined as an overlap of at least one day in the time periods covered by prescriptions for each drug. Main outcome measures Annual percentage of opioid users with concurrent benzodiazepine use; annual incidence of visits to emergency room and inpatient admissions for opioid overdose. Results 9% of opioid users also used a benzodiazepine in 2001, increasing to 17% in 2013 (80% relative increase). This increase was driven mainly by increases among intermittent, as opposed to chronic, opioid users. Compared with opioid users who did not use benzodiazepines, concurrent use of both drugs was associated with an increased risk of an emergency room visit or inpatient admission for opioid overdose (adjusted odds ratio 2.14, 95% confidence interval 2.05 to 2.24; P<0.001) among all opioid users. The adjusted odds ratio for an emergency room visit or inpatient admission for opioid overdose was 1.42 (1.33 to 1.51; P<0.001) for intermittent opioid users and 1.81 (1.67 to 1.96; P<0.001) chronic opioid users. If this association is causal, elimination of concurrent benzodiazepine/opioid use could reduce the risk of emergency room visits related to opioid use and inpatient admissions for opioid overdose by an estimated 15% (95% confidence interval 14 to 16). Conclusions From 2001 to 2013, concurrent benzodiazepine/opioid use sharply increased in a large sample of privately insured patients in the US and significantly contributed to the overall population risk of opioid overdose.
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              Benzodiazepines revisited--will we ever learn?

               M Lader (2011)
              To re-examine various aspects of the benzodiazepines (BZDs), widely prescribed for 50 years, mainly to treat anxiety and insomnia. It is a descriptive review based on the Okey Lecture delivered at the Institute of Psychiatry, King's College London, in November 2010. A search of the literature was carried out in the Medline, Embase and Cochrane Collaboration databases, using the codeword 'benzodiazepine(s)', alone and in conjunction with various terms such as 'dependence', 'abuse', etc. Further hand-searches were made based on the reference lists of key papers. As 60,000 references were found, this review is not exhaustive. It concentrates on the adverse effects, dependence and abuse. Almost from their introduction the BZDs have been controversial, with polarized opinions, advocates pointing out their efficacy, tolerability and patient acceptability, opponents deprecating their adverse effects, dependence and abuse liability. More recently, the advent of alternative and usually safer medications has opened up the debate. The review noted a series of adverse effects that continued to cause concern, such as cognitive and psychomotor impairment. In addition, dependence and abuse remain as serious problems. Despite warnings and guidelines, usage of these drugs remains at a high level. The limitations in their use both as choice of therapy and with respect to conservative dosage and duration of use are highlighted. The distinction between low-dose 'iatrogenic' dependence and high-dose abuse/misuse is emphasized. The practical problems with the benzodiazepines have persisted for 50 years, but have been ignored by many practitioners and almost all official bodies. The risk-benefit ratio of the benzodiazepines remains positive in most patients in the short term (2-4 weeks) but is unestablished beyond that time, due mainly to the difficulty in preventing short-term use from extending indefinitely with the risk of dependence. Other research issues include the possibility of long-term brain changes and evaluating the role of the benzodiazepine antagonist, flumazenil, in aiding withdrawal. © 2011 The Author, Addiction © 2011 Society for the Study of Addiction.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: SoftwareRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: SoftwareRole: ValidationRole: VisualizationRole: Writing – review & editing
                Role: MethodologyRole: ResourcesRole: SoftwareRole: ValidationRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: ValidationRole: Writing – review & editing
                Role: Funding acquisitionRole: MethodologyRole: ResourcesRole: SoftwareRole: ValidationRole: Writing – review & editing
                Role: MethodologyRole: ResourcesRole: SoftwareRole: ValidationRole: Writing – review & editing
                Role: ValidationRole: Writing – review & editing
                Role: ConceptualizationRole: InvestigationRole: MethodologyRole: Project administrationRole: SupervisionRole: ValidationRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: SupervisionRole: ValidationRole: Writing – review & editing
                Role: Academic Editor
                Journal
                PLoS Med
                PLoS Med
                plos
                plosmed
                PLoS Medicine
                Public Library of Science (San Francisco, CA USA )
                1549-1277
                1549-1676
                7 August 2018
                August 2018
                : 15
                : 8
                Affiliations
                [1 ] Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
                [2 ] Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden
                [3 ] Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
                [4 ] Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, United Kingdom
                London School of Hygiene and Tropical Medicine, UNITED KINGDOM
                Author notes

                I have read the journal's policy and the authors of this manuscript have the following competing interests: CH received financial support from the health care commissioner in the Stockholm County Council (public), during the conduct of the study, and received personal fees related to giving a lecture sponsored by Shire, outside the submitted work; AS and KI received financial support (via institution) from the health care commissioner in the Stockholm County Council, during the conduct of the study; LFC received grants from the Swedish Research Council for Health, Working Life and Welfare and personal fees from UpToDate and Wolters Kluwer Health for contributing articles, outside the submitted work; DMC received personal fees from UpToDate, Wolters Kluwer Health for contributing articles, personal fees from Elsevier for acting as an associated editor, and grants from the Swedish Research Council, NIMH, the Swedish Research Council for Health, Working Life and Welfare, outside the submitted work; YM, PL, ZC, and JF have nothing to declare; no other relationships or activities that could appear to have influenced the submitted work.

                Article
                PMEDICINE-D-18-00888
                10.1371/journal.pmed.1002635
                6080748
                30086134
                © 2018 Sidorchuk et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Figures: 2, Tables: 5, Pages: 22
                Product
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100004348, Stockholms Läns Landsting;
                Award Recipient :
                This research was financially supported by the Stockholm County Council, Stockholm, Sweden ( www.sll.se; to CH). Funders had no role in the design and conduct of the study, collection, management, analysis, or interpretation of data, preparation of the manuscript or decision to submit the manuscript for publication.
                Categories
                Research Article
                People and Places
                Population Groupings
                Age Groups
                Children
                Adolescents
                People and Places
                Population Groupings
                Families
                Children
                Adolescents
                People and Places
                Population Groupings
                Age Groups
                Young Adults
                Medicine and Health Sciences
                Neurology
                Epilepsy
                Medicine and Health Sciences
                Mental Health and Psychiatry
                People and places
                Geographical locations
                Europe
                European Union
                Sweden
                Medicine and Health Sciences
                Health Care
                Health Care Providers
                Medicine and Health Sciences
                Health Care
                Primary Care
                Medicine and Health Sciences
                Diagnostic Medicine
                Custom metadata
                Sharing of the individual-level data is restricted by Swedish data protection laws and data underlying the reported findings cannot be deposited in publicly accessible archives. In this study, data were obtained from the Prescribed Drug Register and the National Patient Register held by the Swedish National Board of Health and Welfare (Socialstyrelsen; http://www.socialstyrelsen.se/english), and the Total Population Register maintained by Statistics Sweden (SCB; http://www.scb.se/en/). For further information or enquiries about access to the data, any interested parties can contact the data owners, Socialstyrelsen via registerservice@ 123456socialstyrelsen.se and SCB via information@ 123456scb.se .

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