Interventions targeting the reduction or discontinuation of long-term use of benzodiazepine receptor agonists: protocol for an overview of systematic reviews

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Although guidelines recommend limiting prescriptions to short-term use (<4 weeks), BZRAs are often continued long-term. Due to the associated risks (e.g. memory impairment, falls/fractures), it is recommended that long-term BZRA use should be discontinued. Several systematic reviews have studied the effectiveness of pharmacological and non-pharmacological interventions targeting long-term BZRA use; however, an overview of the evidence across intervention types and healthcare settings is lacking. Aim To identify and narratively synthesise systematic reviews that assess the effectiveness of interventions targeting the reduction or discontinuation of long-term BZRA use. Methods An overview of systematic reviews will be conducted. Five electronic databases (MEDLINE, Embase, Web of Science, PsycINFO, CINAHL) will be searched for systematic reviews of randomised controlled trials of interventions targeting the reduction or discontinuation of long-term BZRA use in adults in any setting. All types and combinations of interventions are eligible for inclusion (e.g. psychosocial interventions, pharmacological interventions). Interventions will be evaluated against usual care. Article screening and data extraction will be conducted by two reviewers independently. Overlap in primary publications will be assessed by calculating the corrected covered area and graphically represented. Methodological quality of included reviews will be assessed using the AMSTAR-2 tool. Results will be synthesised narratively. The certainty of evidence will be assessed using the GRADE approach. Conclusions This overview of reviews will narratively synthesise the evidence from systematic reviews of the effectiveness of interventions targeting long-term BZRA use. The review will provide an extensive overview of the existing evidence, which will inform future research and policy decisions about interventions for reducing and discontinuing long-term BZRA use. 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HRB Open Res 2024, 7 :71 ( https://doi.org/10.12688/hrbopenres.13976.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Study Protocol Interventions targeting the reduction or discontinuation of long-term use of benzodiazepine receptor agonists: protocol for an overview of systematic reviews [version 1; peer review: 2 approved with reservations] Kristien Coteur https://orcid.org/0000-0002-3170-0195 1 , Cristín Ryan 2 , Susan M Smith 3 , [...] Greg Sheaf https://orcid.org/0000-0003-1571-1772 4 , Marjorie DeWert 5 , David Gardner 6 , Cathal Cadogan https://orcid.org/0000-0002-8778-0112 2 Kristien Coteur https://orcid.org/0000-0002-3170-0195 1 , Cristín Ryan 2 , [...] Susan M Smith 3 , Greg Sheaf https://orcid.org/0000-0003-1571-1772 4 , Marjorie DeWert 5 , David Gardner 6 , Cathal Cadogan https://orcid.org/0000-0002-8778-0112 2 PUBLISHED 14 Nov 2024 Author details Author details 1 Department of Public Health and Primary Care, KU Leuven, Leuven, Flanders, Belgium 2 School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin, Leinster, Ireland 3 School of Medicine, Discipline of Public Health and Primary Care Trinity College Dublin, Dublin, Leinster, Ireland 4 The Library of Trinity College, Trinity College Dublin, Dublin, Leinster, Ireland 5 none, none, USA 6 Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada Kristien Coteur Roles: Conceptualization, Investigation, Methodology, Project Administration, Writing – Original Draft Preparation Cristín Ryan Roles: Investigation, Methodology, Writing – Review & Editing Susan M Smith Roles: Investigation, Methodology, Writing – Review & Editing Greg Sheaf Roles: Data Curation, Investigation, Methodology, Resources, Software, Writing – Review & Editing Marjorie DeWert Roles: Investigation, Methodology, Writing – Review & Editing David Gardner Roles: Investigation, Methodology, Writing – Review & Editing Cathal Cadogan Roles: Conceptualization, Investigation, Methodology, Project Administration, Writing – Original Draft Preparation OPEN PEER REVIEW DETAILS REVIEWER STATUS Abstract Background Benzodiazepine receptor agonists (BZRAs) are commonly prescribed to treat anxiety and insomnia. Although guidelines recommend limiting prescriptions to short-term use (<4 weeks), BZRAs are often continued long-term. Due to the associated risks (e.g. memory impairment, falls/fractures), it is recommended that long-term BZRA use should be discontinued. Several systematic reviews have studied the effectiveness of pharmacological and non-pharmacological interventions targeting long-term BZRA use; however, an overview of the evidence across intervention types and healthcare settings is lacking. Aim To identify and narratively synthesise systematic reviews that assess the effectiveness of interventions targeting the reduction or discontinuation of long-term BZRA use. Methods An overview of systematic reviews will be conducted. Five electronic databases (MEDLINE, Embase, Web of Science, PsycINFO, CINAHL) will be searched for systematic reviews of randomised controlled trials of interventions targeting the reduction or discontinuation of long-term BZRA use in adults in any setting. All types and combinations of interventions are eligible for inclusion (e.g. psychosocial interventions, pharmacological interventions). Interventions will be evaluated against usual care. Article screening and data extraction will be conducted by two reviewers independently. Overlap in primary publications will be assessed by calculating the corrected covered area and graphically represented. Methodological quality of included reviews will be assessed using the AMSTAR-2 tool. Results will be synthesised narratively. The certainty of evidence will be assessed using the GRADE approach. Conclusions This overview of reviews will narratively synthesise the evidence from systematic reviews of the effectiveness of interventions targeting long-term BZRA use. The review will provide an extensive overview of the existing evidence, which will inform future research and policy decisions about interventions for reducing and discontinuing long-term BZRA use. READ ALL READ LESS Keywords benzodiazepines, hypnotics and sedatives, deprescribing, drug tapering, psychosocial intervention, pharmacological intervention, systematic review, umbrella review, overview of reviews Corresponding Author(s) Cathal Cadogan ( [email protected] ) Close Corresponding author: Cathal Cadogan Competing interests: No competing interests were disclosed. Grant information: Health Research Board [ILP-HSR-2022-006]. Copyright: © 2024 Coteur K 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 work is properly cited. How to cite: Coteur K, Ryan C, Smith SM et al. Interventions targeting the reduction or discontinuation of long-term use of benzodiazepine receptor agonists: protocol for an overview of systematic reviews [version 1; peer review: 2 approved with reservations] . HRB Open Res 2024, 7 :71 ( https://doi.org/10.12688/hrbopenres.13976.1 ) First published: 14 Nov 2024, 7 :71 ( https://doi.org/10.12688/hrbopenres.13976.1 ) Latest published: 14 Nov 2024, 7 :71 ( https://doi.org/10.12688/hrbopenres.13976.1 ) Introduction Benzodiazepine receptor agonists (BZRAs) – including benzodiazepines and Z-drugs (i.e. zolpidem, (es)zopiclone, zaleplon) – are commonly used for their anxiolytic and hypnotic effects. The annual rate of use among adults in ambulatory care is approximately 12% 1 , 2 . Rates are higher for older adults, women 1 – 3 , and in institutional care settings. Use rates between 32% 4 and 44% 5 have been reported for inpatients of geriatric units in hospitals, and 39% 6 to 53% 7 for residents of nursing homes. Prescribing guidelines typically recommend that BZRAs should be used at the lowest possible dose and for the shortest possible duration, with a maximum of one to two weeks for insomnia, or four weeks for anxiety 8 – 11 . However, prescribers acknowledge that their use of BZRAs typically extends beyond guideline recommendations. In a recent European survey, physicians estimated their typical duration of BZRA use for insomnia to be 15 weeks, with large differences among participating countries ranging from 8 weeks by UK participants to 23 weeks by Spanish participants 12 . Rates of long-term BZRA use are approximately 3% among the general population 13 , and between 23% 6 to 50–54% 7 , 14 in nursing homes. Long-term BZRA use is a significant healthcare issue as it is associated with considerable health risks, such as cognitive and psychomotor impairment, as well as increased risk of falls 13 , 15 – 17 . Discontinuation of BZRA use can be challenging due to the development of physical dependence which may result in withdrawal symptoms of varying severity 18 – 20 . These symptoms include but are not limited to low energy, anxiety, insomnia, concentration difficulties, irritability, abdominal and muscle cramps, tremors, and delirium 18 – 20 . Patients have reported continuing BZRA use to avoid withdrawal symptoms 21 . The effectiveness of pharmacological and non-pharmacological interventions targeting the reduction and discontinuation of long-term BZRA use has been subject of multiple reviews 22 – 34 . The gold standard approach for discontinuing long-term BZRA use is a slow, gradual dose reduction (GDR) proportionate to the existing dose 35 with regular follow-up to allow for the dose reduction plan to be adjusted as required 17 , 36 . GDR reduces the risk for withdrawal symptoms and limits symptom duration and severity 19 , 37 , 38 . However, to date, there has been no overview of the existing systematic reviews which makes it difficult to fully understand the current state of the existing evidence base. The aim of this review is to provide a comprehensive overview of the evidence from existing systematic reviews regarding the effectiveness of interventions targeting the reduction or discontinuation of long-term BZRA use. The objectives are to: 1. Identify and narratively synthesise the evidence from systematic reviews of randomised controlled trials (RCTs) regarding the effectiveness of interventions targeting the reduction or discontinuation of long-term BZRA use; 2. Appraise the quality of the identified systematic reviews. 3. Assess the certainty of the available evidence. Methods Design An overview of systematic reviews will be conducted. This protocol has been developed following PRISMA-P 39 and the guidance on overviews of reviews in the Cochrane Handbook for Systematic Reviews of Interventions 40 . The final review will be reported using the Preferred Reporting Items for Overviews of Reviews (PRIOR) checklist 41 . Eligibility criteria The Population-Intervention-Comparison-Outcomes(s) (PICO) concept was used to structure the clinical research question and align the eligibility criteria with the review’s aim. Population . Interventions in the systematic review must aim to reduce or discontinue long-term BZRA use by targeting adult (≥18 years old) patients or clinicians, in any healthcare setting. For this overview, “long-term” use is a minimum of 12 weeks or as defined by the author. Intervention and comparator(s) . Eligible systematic reviews may include all types of interventions targeting the reduction or discontinuation of long-term BZRA use, inclusive of psychosocial and pharmacological interventions. The comparator should at least consist of usual care (i.e. no intervention). Comparisons to other interventions targeting BZRA reduction or discontinuation without a comparison to usual care will be excluded. We will exclude interventions for the treatment of diagnosed substance use disorders that include BZRA dependence because they require a different therapeutic paradigm and are often delivered in specific settings managing substance use disorders. We will also exclude interventions that target BZRAs as part of a wider initiative aimed at reducing potentially inappropriate medications in patients with polypharmacy but that don’t include a specific targeted intervention. Outcomes . Eligible systematic reviews must assess the effectiveness of the intervention(s) in terms of reducing or discontinuing long-term BZRA use, as defined by the study authors. Study type . Eligible systematic reviews will focus on RCTs that compare interventions targeting the reduction or discontinuation of long-term BZRA use against usual care (i.e. no intervention). Systematic reviews are defined as reviews with a pre-defined systematic strategy for searching multiple databases, selecting studies, synthesising findings, and using a quality appraisal tool, guided by a clear aim 42 . In the event that several versions of the same systematic review exist, the most recent version will be selected. The following types of articles will be excluded: rapid reviews, scoping reviews, umbrella reviews or overviews of reviews, protocols for systematic reviews and/or meta-analysis, reviews comprising viewpoints or opinions as primary source of evidence, and conference abstracts. The reference list of all included reviews will be screened for additional references. Only systematic reviews published since 2003 will be included. A limit of 20 years per date of the first search is maintained, to ensure maximum relevancy of the included literature as more recent systematic reviews will include both older and newer RCTs. There will be no language restrictions. Search strategy The following electronic databases will be searched: MEDLINE, Embase, Web of Science, PsycINFO and CINAHL. A detailed search strategy will be developed around the following three concepts following the guidance of an information retrieval expert: (1) medication reduction/discontinuation, (2) BZRAs, and (3) systematic review of randomised controlled studies. Selection process . Following the database searches, retrieved records will be uploaded to Covidence ® , an online systematic review management software tool, to assist the screening process. All titles/abstract will be independently screened by two reviewers. If a systematic review appears to meet inclusion criteria, or its eligibility cannot be assessed based on the title and abstract alone, the full text will be retrieved and screened by two reviewers independently. Any disagreements will be resolved by discussion, and if needed consultation with a third reviewer, until consensus is reached. Data collection . Data from systematic reviews will be extracted into a predefined data charting template. The following information will be collected: a) key review characteristics (including citation details, review objectives, number of databases searched, date range, date of last search update, number of included studies and participants, quality appraisal tool used and quality ratings of primary publications), b) patient characteristics (demographics, BZRA indication, BZRA use history, co-morbidities, concomitant psychotropic medication use, exclusion criteria), c) basic characteristics of the intervention(s) and comparator(s) being reviewed (e.g. brief or complex, psychosocial or pharmacological, uni- or multidisciplinary, theoretical basis, intensity, frequency, duration, other key elements), d) the outcomes regarding reduction or discontinuation of BZRA, e) patient reported outcome measures (e.g. effect on anxiety or insomnia) and f) their certainty assessments, if available. Finally, g) descriptive characteristics of the primary publications in the systematic review (citation details, study design, geographical location) will be extracted. The data extraction template will be piloted by the reviewers to maximise consistency and amended if needed. Data extraction will also be conducted by two reviewers, working independently. Any disagreements will be resolved by discussion. If any of the required details are not available from the published systematic reviews, the reviewers will document this gap in the overview. Overlap in the primary publications will be calculated using the corrected covered area measure introduced by Pieper et al. in 2014 43 , and visually represented in a graph using the GROOVE tool 44 . Data analysis . Findings will be synthesised narratively, and also reported in tabular format. The summary of evidence table will be presented as per Cochrane guidance, including a description of the population, intervention(s), comparison(s), and outcomes, e.g. BZRA reduction, or BZRA discontinuation, and the quality of evidence. The primary outcome that will be assessed in this overview is the effectiveness of interventions regarding the reduction or discontinuation of long-term BZRA use. Secondary outcomes that are of interest to the research group include patient-reported outcome measures such as the interventions’ effect on anxiety and insomnia, quality of life, adverse drug withdrawal events, daytime dysfunction, use of healthcare services, as well as other parameters for cost-effectiveness of the intervention. Assessment of methodological quality and certainty of evidence . The Assessment of Multiple Systematic Reviews (AMSTAR) 2 tool 45 will be used to assess the methodological quality of included reviews. All included reviews will be evaluated by two reviewers, working independently. Any disagreements will be resolved through discussion. There will be two levels of certainty assessment in this overview of reviews. Firstly, assessments concerning the certainty of evidence within individual systematic reviews as conducted by its authors. The results will be extracted and presented in the overview table summarising the characteristics of the included systematic reviews, when available. Secondly, the certainty of evidence of the overview’s findings. This will be independently assessed by two reviewers using the GRADE tool 46 . The reviewers will consider the critical appraisal results, imprecision, inconsistency, indirectness, and possible publication bias, e.g. bias due to negative results not being published or inadequate reporting of missing results. Any discrepancies in the assessment will be resolved by discussion. Discussion This overview of reviews will narratively synthesise the evidence from systematic reviews about the effectiveness of interventions targeting the reduction or discontinuation of long-term BZRA use, irrespective of intervention type, target population or healthcare setting. The review will provide an extensive overview of the existing evidence, showing the amount of high quality research for particular interventions. Simultaneously, the overview will reveal gaps in the current body of evidence, which will inform future research and could help to drive improvement in healthcare. For example, it can map which patient variables have been considered in BZRA discontinuation studies. Its findings may inform future healthcare policy decisions as well as intervention development and implementation research. Given the growing interest in deprescribing as a research domain, and the ongoing development of novel interventions targeting the reduction/discontinuation of long-term BZRA use, there is a need for a comprehensive and high-quality evidence synthesis. Ethics and consent Ethics and consent is not required. Other information Dissemination of findings The overview of reviews will be submitted for publication in a peer-reviewed international journal. Study status As of the publication of this protocol, database searches and screening are completed. Data availability No underlying data are associated with this protocol. Extended data OSF: Interventions targeting the reduction or discontinuation of long-term use of benzodiazepine receptor agonists: an overview of systematic reviews. DOI: https://osf.io/697ad 47 This project contains the following extended data: Coteur et al. 2024_PRISMA-P-checklist. Coteur et al. 2024_search strategy MEDLINE Protocol registration: https://osf.io/697ad/registrations . Reporting guidelines OSF: PRISMA-P checklist for Interventions targeting the reduction or discontinuation of long-term use of benzodiazepine receptor agonists: Protocol for an overview of systematic reviews. https://doi/10.17605/OSF.IO/697AD 47 . Data are available under the terms of the Creative Commons Zero "No rights reserved" data waiver (CC0 1.0 Public domain dedication). Author contributions Kristien Coteur: Conceptualization, Investigation, Methodology, Project Administration, Writing – Original Draft Preparation Cristín Ryan: Investigation, Methodology, Writing – Review & Editing Susan M Smith: Investigation, Methodology, Writing – Review & Editing Greg Sheaf: Data Curation, Investigation, Methodology, Resources, Software, Writing – Review & Editing Marjorie DeWert : Investigation, Methodology, Writing – Review & Editing David Gardner: Investigation, Methodology, Writing – Review & Editing Cathal Cadogan: Conceptualization, Investigation, Methodology, Project Administration, Writing – Original Draft Preparation Faculty Opinions recommended References 1. Coteur K, Mamouris P, Vaes B, et al. : Evolution of Benzodiazepine Receptor Agonist prescriptions in general practice: a registry-based study. Front Public Health. 2022; 10 : 1014734. PubMed Abstract | Publisher Full Text | Free Full Text 2. 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Ashton H: Benzodiazepines: how they work and how to withdraw (aka The Ashton Manual). Reference Source 39. Moher D, Shamseer L, Clarke M, et al. : Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Revista Espanola de Nutricion Humana y Dietetica. 2016; 20 (2): 148–160. 40. Pollock M, Fernandes R, Becker L, et al. : Chapter V: Overviews of reviews. In: Higgins J, Thomas J, Chandler J, et al. , eds. Cochrane Handbook for Systematic Reviews of Interventions. version 6.3. Cochrane; 2022. Reference Source 41. Gates M, Gates A, Pieper D, et al. : Reporting guideline for overviews of reviews of healthcare interventions: development of the PRIOR statement. BMJ. 2022; 378 : e070849. PubMed Abstract | Publisher Full Text | Free Full Text 42. Martinic MK, Pieper D, Glatt A, et al. : Definition of a systematic review used in overviews of systematic reviews, meta-epidemiological studies and textbooks. BMC Med Res Methodol. 2019; 19 (1): 203. 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[Dataset], 2024. https://osf.io/697ad Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 14 Nov 2024 ADD YOUR COMMENT Comment Author details Author details 1 Department of Public Health and Primary Care, KU Leuven, Leuven, Flanders, Belgium 2 School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin, Leinster, Ireland 3 School of Medicine, Discipline of Public Health and Primary Care Trinity College Dublin, Dublin, Leinster, Ireland 4 The Library of Trinity College, Trinity College Dublin, Dublin, Leinster, Ireland 5 none, none, USA 6 Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada Kristien Coteur Roles: Conceptualization, Investigation, Methodology, Project Administration, Writing – Original Draft Preparation Cristín Ryan Roles: Investigation, Methodology, Writing – Review & Editing Susan M Smith Roles: Investigation, Methodology, Writing – Review & Editing Greg Sheaf Roles: Data Curation, Investigation, Methodology, Resources, Software, Writing – Review & Editing Marjorie DeWert Roles: Investigation, Methodology, Writing – Review & Editing David Gardner Roles: Investigation, Methodology, Writing – Review & Editing Cathal Cadogan Roles: Conceptualization, Investigation, Methodology, Project Administration, Writing – Original Draft Preparation Competing interests No competing interests were disclosed. Grant information Health Research Board [ILP-HSR-2022-006]. Article Versions (1) version 1 Published: 14 Nov 2024, 7:71 https://doi.org/10.12688/hrbopenres.13976.1 Copyright © 2024 Coteur K 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 work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics VIEWS $counts.viewCount downloads Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Coteur K, Ryan C, Smith SM et al. Interventions targeting the reduction or discontinuation of long-term use of benzodiazepine receptor agonists: protocol for an overview of systematic reviews [version 1; peer review: 2 approved with reservations] . HRB Open Res 2024, 7 :71 ( https://doi.org/10.12688/hrbopenres.13976.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Version 1 VERSION 1 PUBLISHED 14 Nov 2024 Views 0 Cite How to cite this report: Chalabianloo F. Reviewer Report For: Interventions targeting the reduction or discontinuation of long-term use of benzodiazepine receptor agonists: protocol for an overview of systematic reviews [version 1; peer review: 2 approved with reservations] . HRB Open Res 2024, 7 :71 ( https://doi.org/10.21956/hrbopenres.15341.r48318 ) The direct URL for this report is: https://hrbopenresearch.org/articles/7-71/v1#referee-response-48318 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 25 Jul 2025 Fatemeh Chalabianloo , Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway; Haukeland University Hospital, Bergen, Norway Approved with Reservations VIEWS 0 https://doi.org/10.21956/hrbopenres.15341.r48318 Thank you for the opportunity to review this manuscript. This overview of systematic reviews aims to synthesize existing evidence on the effectiveness of interventions for reducing or discontinuing long-term benzodiazepine receptor agonist (BZRA) use in adults. It ... Continue reading READ ALL Thank you for the opportunity to review this manuscript. This overview of systematic reviews aims to synthesize existing evidence on the effectiveness of interventions for reducing or discontinuing long-term benzodiazepine receptor agonist (BZRA) use in adults. It will include both pharmacological and non-pharmacological approaches across healthcare settings, providing insights to inform clinical practice and policy. Some comments are provided below to help further improve the manuscript. Introduction: This section is mainly well-written, and the rationale for the study is sufficiently argued. Please avoid unnecessary repetitions. Methods: Regarding PICO: Please consider reorganizing the formatting so that each element of PICO is explained separately, and consider adding "(included, excluded)" for clarification. For example: Population: adults ≥18 years old with long-term BZRA use Included: those with the diagnoses….., or medical indications…… Excluded: those with the diagnoses…., or other exclusion criteria The authors have presented PICO in a different way: Population: “Interventions in the systematic review must aim to reduce or discontinue long-term BZRA use by targeting adult (≥18 years old) patients or clinicians, in any healthcare setting.” First: This is not a definition of the population, but rather a description of the aim of the interventions. Second: What do the authors mean by “…or clinicians…”? Are clinicians also considered part of the target population? Third: Are there any exclusion criteria? For example, based on diagnostic categories (e.g. psychiatric disorders) or other treatment indications? Fourth: How do the authors define “reduction in use”? Does it refer to the number of patients, dosages, duration of use, or other definitions? Fifth: “For this overview, long-term use is a minimum of 12 weeks or as defined by the author.” Long-term use of benzodiazepines is most commonly defined as use extending beyond four weeks, although some studies apply thresholds of three or six months to capture more sustained or chronic use. For the purpose of identifying cases where benzodiazepine use is more persistent and likely to require targeted interventions for reduction or discontinuation, a six-month threshold seems a more appropriate operational definition of chronic use than a three-month threshold, doesn’t it? Intervention and comparator(s), as defined by the authors: “…The comparator should at least consist of usual care (i.e. no intervention)...” Previously, in the introduction, GDR was presented as the gold standard. Please clarify this potential inconsistency: what constitutes “usual care” or the comparator? Is it “no intervention” or “GDR”? Please use the formatting suggested above and describe intervention separately from comparator. Outcomes: Please specify which outcome measures will be used, using the same formatting as suggested above. Discussion: Arguably, the most important expectation from this overview is whether the interventions were effective or not — and which specific interventions proved effective or ineffective. It is stated: “This overview of reviews will narratively synthesise the evidence from systematic reviews about the effectiveness of interventions targeting the reduction or discontinuation of long-term BZRA use, irrespective of intervention type, target population or healthcare setting.” It does not seem accurate, based on the stated PICO, to claim that effectiveness will be assessed irrespective of the target population. Please consider revising this statement or clarifying what is meant. Good luck with the further work! Is the rationale for, and objectives of, the study clearly described? Partly Is the study design appropriate for the research question? Yes Are sufficient details of the methods provided to allow replication by others? Partly Are the datasets clearly presented in a useable and accessible format? Not applicable Competing Interests: No competing interests were disclosed. Reviewer Expertise: Addiction medicine, pharmacological interventions, substitution or agonist therapy for substance use disorders I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Chalabianloo F. Reviewer Report For: Interventions targeting the reduction or discontinuation of long-term use of benzodiazepine receptor agonists: protocol for an overview of systematic reviews [version 1; peer review: 2 approved with reservations] . HRB Open Res 2024, 7 :71 ( https://doi.org/10.21956/hrbopenres.15341.r48318 ) The direct URL for this report is: https://hrbopenresearch.org/articles/7-71/v1#referee-response-48318 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Keller MS. Reviewer Report For: Interventions targeting the reduction or discontinuation of long-term use of benzodiazepine receptor agonists: protocol for an overview of systematic reviews [version 1; peer review: 2 approved with reservations] . HRB Open Res 2024, 7 :71 ( https://doi.org/10.21956/hrbopenres.15341.r47964 ) The direct URL for this report is: https://hrbopenresearch.org/articles/7-71/v1#referee-response-47964 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 21 Jul 2025 Michelle Sophie Keller , University of Southern California, Los Angeles, California, USA Approved with Reservations VIEWS 0 https://doi.org/10.21956/hrbopenres.15341.r47964 This is a protocol for an overview of systematic reviews of interventions aimed at reducing the long-term use of benzodiazepine-receptor agonists. It is a very well written manuscript and is very clear and easy to follow. I have some ... Continue reading READ ALL This is a protocol for an overview of systematic reviews of interventions aimed at reducing the long-term use of benzodiazepine-receptor agonists. It is a very well written manuscript and is very clear and easy to follow. I have some minor recommendations. Abstract Although memory impairment has been found to be associated with BZRA use, it is unclear whether this association is causal or just associative (i.e., it is thought that persons developing dementia have more sleep problems, therefore are more likely to take BZRAs). Would recommend saying “e.g., falls, fractures, respiratory depression” as the associated risks. The methods should also note which study types will be accepted (RCTs only). Introduction It would be helpful for the authors to note if there were particular sub-populations of interest (e.g., older adults, adults with cognitive impairment) that they might examine separately when reviewing the effectiveness of the interventions. It would be helpful for the authors to have some definition of “long-term use.” Is it more than 4 weeks? There are different definitions in the literature, and it might be helpful to cite these. This matters because different definitions are used in inclusion criteria in different studies, which may result in different levels of effectiveness. Methods Are the authors planning on reporting results by healthcare setting? Or by intervention type? What is the GROOVE tool? Can the authors describe it briefly in the protocol paper? What about inclusion of outcomes such as falls, hospitalizations, fractures, etc? It would be helpful for the authors to use a checklist such as the TIDieR checklist when analyzing and describing the interventions ( https://www.equator-network.org/wp-content/uploads/2014/03/TIDieR-Checklist-PDF.pdf ) to provide greater detail about the intervention types. Is the rationale for, and objectives of, the study clearly described? Yes Is the study design appropriate for the research question? Yes Are sufficient details of the methods provided to allow replication by others? Yes Are the datasets clearly presented in a useable and accessible format? Not applicable Competing Interests: No competing interests were disclosed. Reviewer Expertise: Health services research, pharmacoepidemiology. I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Keller MS. Reviewer Report For: Interventions targeting the reduction or discontinuation of long-term use of benzodiazepine receptor agonists: protocol for an overview of systematic reviews [version 1; peer review: 2 approved with reservations] . HRB Open Res 2024, 7 :71 ( https://doi.org/10.21956/hrbopenres.15341.r47964 ) The direct URL for this report is: https://hrbopenresearch.org/articles/7-71/v1#referee-response-47964 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 14 Nov 2024 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 2 Version 1 14 Nov 24 read read Michelle Sophie Keller , University of Southern California, Los Angeles, USA Fatemeh Chalabianloo , University of Bergen, Bergen, Norway; Haukeland University Hospital, Bergen, Norway Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Chalabianloo F. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 25 Jul 2025 | for Version 1 Fatemeh Chalabianloo , Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway; Haukeland University Hospital, Bergen, Norway 0 Views copyright © 2025 Chalabianloo F. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Thank you for the opportunity to review this manuscript. This overview of systematic reviews aims to synthesize existing evidence on the effectiveness of interventions for reducing or discontinuing long-term benzodiazepine receptor agonist (BZRA) use in adults. It will include both pharmacological and non-pharmacological approaches across healthcare settings, providing insights to inform clinical practice and policy. Some comments are provided below to help further improve the manuscript. Introduction: This section is mainly well-written, and the rationale for the study is sufficiently argued. Please avoid unnecessary repetitions. Methods: Regarding PICO: Please consider reorganizing the formatting so that each element of PICO is explained separately, and consider adding "(included, excluded)" for clarification. For example: Population: adults ≥18 years old with long-term BZRA use Included: those with the diagnoses….., or medical indications…… Excluded: those with the diagnoses…., or other exclusion criteria The authors have presented PICO in a different way: Population: “Interventions in the systematic review must aim to reduce or discontinue long-term BZRA use by targeting adult (≥18 years old) patients or clinicians, in any healthcare setting.” First: This is not a definition of the population, but rather a description of the aim of the interventions. Second: What do the authors mean by “…or clinicians…”? Are clinicians also considered part of the target population? Third: Are there any exclusion criteria? For example, based on diagnostic categories (e.g. psychiatric disorders) or other treatment indications? Fourth: How do the authors define “reduction in use”? Does it refer to the number of patients, dosages, duration of use, or other definitions? Fifth: “For this overview, long-term use is a minimum of 12 weeks or as defined by the author.” Long-term use of benzodiazepines is most commonly defined as use extending beyond four weeks, although some studies apply thresholds of three or six months to capture more sustained or chronic use. For the purpose of identifying cases where benzodiazepine use is more persistent and likely to require targeted interventions for reduction or discontinuation, a six-month threshold seems a more appropriate operational definition of chronic use than a three-month threshold, doesn’t it? Intervention and comparator(s), as defined by the authors: “…The comparator should at least consist of usual care (i.e. no intervention)...” Previously, in the introduction, GDR was presented as the gold standard. Please clarify this potential inconsistency: what constitutes “usual care” or the comparator? Is it “no intervention” or “GDR”? Please use the formatting suggested above and describe intervention separately from comparator. Outcomes: Please specify which outcome measures will be used, using the same formatting as suggested above. Discussion: Arguably, the most important expectation from this overview is whether the interventions were effective or not — and which specific interventions proved effective or ineffective. It is stated: “This overview of reviews will narratively synthesise the evidence from systematic reviews about the effectiveness of interventions targeting the reduction or discontinuation of long-term BZRA use, irrespective of intervention type, target population or healthcare setting.” It does not seem accurate, based on the stated PICO, to claim that effectiveness will be assessed irrespective of the target population. Please consider revising this statement or clarifying what is meant. Good luck with the further work! Is the rationale for, and objectives of, the study clearly described? Partly Is the study design appropriate for the research question? Yes Are sufficient details of the methods provided to allow replication by others? Partly Are the datasets clearly presented in a useable and accessible format? Not applicable Competing Interests No competing interests were disclosed. Reviewer Expertise Addiction medicine, pharmacological interventions, substitution or agonist therapy for substance use disorders I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (0) Chalabianloo F. Peer Review Report For: Interventions targeting the reduction or discontinuation of long-term use of benzodiazepine receptor agonists: protocol for an overview of systematic reviews [version 1; peer review: 2 approved with reservations] . HRB Open Res 2024, 7 :71 ( https://doi.org/10.21956/hrbopenres.15341.r48318) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://hrbopenresearch.org/articles/7-71/v1#referee-response-48318 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Keller M. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 21 Jul 2025 | for Version 1 Michelle Sophie Keller , University of Southern California, Los Angeles, California, USA 0 Views copyright © 2025 Keller M. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions This is a protocol for an overview of systematic reviews of interventions aimed at reducing the long-term use of benzodiazepine-receptor agonists. It is a very well written manuscript and is very clear and easy to follow. I have some minor recommendations. Abstract Although memory impairment has been found to be associated with BZRA use, it is unclear whether this association is causal or just associative (i.e., it is thought that persons developing dementia have more sleep problems, therefore are more likely to take BZRAs). Would recommend saying “e.g., falls, fractures, respiratory depression” as the associated risks. The methods should also note which study types will be accepted (RCTs only). Introduction It would be helpful for the authors to note if there were particular sub-populations of interest (e.g., older adults, adults with cognitive impairment) that they might examine separately when reviewing the effectiveness of the interventions. It would be helpful for the authors to have some definition of “long-term use.” Is it more than 4 weeks? There are different definitions in the literature, and it might be helpful to cite these. This matters because different definitions are used in inclusion criteria in different studies, which may result in different levels of effectiveness. Methods Are the authors planning on reporting results by healthcare setting? Or by intervention type? What is the GROOVE tool? Can the authors describe it briefly in the protocol paper? What about inclusion of outcomes such as falls, hospitalizations, fractures, etc? It would be helpful for the authors to use a checklist such as the TIDieR checklist when analyzing and describing the interventions ( https://www.equator-network.org/wp-content/uploads/2014/03/TIDieR-Checklist-PDF.pdf ) to provide greater detail about the intervention types. Is the rationale for, and objectives of, the study clearly described? Yes Is the study design appropriate for the research question? Yes Are sufficient details of the methods provided to allow replication by others? Yes Are the datasets clearly presented in a useable and accessible format? Not applicable Competing Interests No competing interests were disclosed. Reviewer Expertise Health services research, pharmacoepidemiology. I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (0) Keller MS. Peer Review Report For: Interventions targeting the reduction or discontinuation of long-term use of benzodiazepine receptor agonists: protocol for an overview of systematic reviews [version 1; peer review: 2 approved with reservations] . HRB Open Res 2024, 7 :71 ( https://doi.org/10.21956/hrbopenres.15341.r47964) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://hrbopenresearch.org/articles/7-71/v1#referee-response-47964 Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. 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