Benzodiazepine agonist treatment for patients with benzodiazepine dependence undergoing opioid agonist treatment: a study protocol for the randomized controlled trial BMX-BAR

Benzodiazepine agonist treatment for patients with benzodiazepine dependence undergoing opioid agonist treatment: a study protocol for the randomized controlled trial BMX-BAR | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Benzodiazepine agonist treatment for patients with benzodiazepine dependence undergoing opioid agonist treatment: a study protocol for the randomized controlled trial BMX-BAR Fatemeh Chalabianloo, Lars Thore Fadnes, Jörg Assmus, Jon Mordal, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4868655/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 02 Jan, 2025 Read the published version in Trials → Version 1 posted 5 You are reading this latest preprint version Abstract Background There is a lack of knowledge on effective treatment methods for comorbid benzodiazepine dependence in populations undergoing opioid agonist treatment (OAT). Tapering and discontinuation of benzodiazepines has long been considered the standard treatment, even though there is limited evidence for this practice. There is also limited research on benzodiazepine agonist treatment, however, peer and clinical experiences indicate that such approaches may be beneficial for a subgroup of the patients with long-lasting benzodiazepine dependence not responding to other treatment approaches. A randomized controlled trial will be conducted to compare the efficacy and safety of stabilizing agonist treatment using prescribed benzodiazepines with standard treatment in reducing illicit benzodiazepine use. Methods The target sample is 108 participants at outpatient OAT clinics in five Norwegian cities/counties (Bergen/Vestland, Tønsberg/Vestfold, Skien/Telemark, Fredrikstad/Østfold and Tromsø/Troms). The main inclusion criteria are benzodiazepine dependence of ≥5 years, using ≥5 days a week during the last month, and previous attempts at tapering. Participants will be randomly assigned to receive either a 26-week benzodiazepine stabilizing treatment (15-30 mg diazepam or 50-100 mg oxazepam daily), or a 20-week tapering using the same medications and equivalent initial dosages. All participants will be given access to consultations from OAT therapists with psychosocial follow-up in accordance with current clinical practice. The primary outcome is the use of illicit benzodiazepines assessed by observed urinary tests at week 24. Secondary outcomes include mental health symptoms, quality of life, cognitive performance, violence risk, other substance use, treatment retention, and life satisfaction. Additionally, the study will assess treatment-related adverse events as well as the cost-effectiveness of the intervention. Discussion This is the first randomized controlled trial of benzodiazepine agonist treatment for benzodiazepine dependence. The research project will assess efficacy and safety of stabilizing treatment with prescribed benzodiazepines compared to benzodiazepine tapering and discontinuation regarding use of illicit benzodiazepines and accordingly well-being of patients with concurrent benzodiazepine and opioid dependence undergoing OAT. If the intervention is found to be efficacious and safe, it will be considered one of the options to standard treatment for this patient group. Trial registration EU trial number: EudraCT: 2021-004981-37. Registered on December 13, 2021 Benzodiazepines agonist treatment substitution stabilizing tapering randomized controlled trial Figures Figure 1 Administrative information Note: the numbers in curly brackets in this protocol refer to SPIRIT checklist item numbers. The order of the items has been modified to group similar items (see http://www.equator-network.org/reporting-guidelines/spirit-2013-statement-defining-standard-protocol-items-for-clinical-trials/). Title {1} Benzodiazepine agonist treatment for patients with benzodiazepine dependence undergoing opioid agonist treatment: a study protocol for the randomized controlled trial BMX-BAR Trial registration {2a and 2b}. EudraCT: 2021-004981-37. Registered on December 13, 2021 Item 2b is not applicable. Protocol version {3} Version: 4.0 Dated: 4-4-2024 Funding {4} This research is supported by public funding sources, and has not received any grants from commercial or not-for-profit sectors. The work is supported by the Norwagian governement [project number R-11141-D11722], Norwagian research center for agonist treatment of substance use disorders (NORCATS). Author details {5a} 1 Department of Addiction Medicine, Haukeland University Hospital, Bergen, Norway 2 Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway 3 Centre for Clinical Research, Haukeland University Hospital, Bergen, Norway 4 Department of Addiction Medicine, Vestfold Hospital Trust, Tønsberg, Norway 5 Norwegian Centre for Addiction Research, University of Oslo, Oslo, Norway 6 Department of R&D in Psychiatric Health Care, Akershus University Hospital, Oslo, Norway 7 Department of Addiction Medicine, Telemark Hospital Trust, Skien, Norway 8 Division of Psychiatry, Haukeland University Hospital, Bergen, Norway 9 Institute of clinical Psychology, University of Bergen, Norway BMX-BAR and NORCATS study group*: Fatemeh Chalabianloo, Lars Thore Fadnes, Kjell Arne Johansson, Christian Ohldieck, Svanhild Mellingen, Else-Marie Løberg, Christina D. Andersen, Jörg Assmus, Prayash Chaudhary, Christine Sundal, Marianne Pierron, Silvia Zavenova, Zainab Alibhai, Karoline N. Helgøy, Beathe Rønning, Henriette Moe, Cecilia E. Kvamme, Anne T. Heldal, Jon Mordal, Kristin K. Solli, Kjetil S. Dale, Britt K. Haugen, Jeanine T.H. Karlsen, Line Holtan, Heidi F. Kristiansen, Anne G. Ørmen, Richard Kaspersen, Andreas W. Blomkvist, Martin Ryssdal and all the OAT staff at Departments of Addiction Medicine, Haukeland University Hospital, Vestfold Hospital Trust, Telemark Hospital Trust, Østfold Hospital Trust, and University Hospital of North Norway, Norway. *Bergen Addiction Research (BAR) and Norwegian Research Centre for Agonist Treatment of Substance Use Disorders (NORCATS) Name and contact information for the trial sponsor {5b} Helse Bergen HF with the Department of Addiction Medicine at Haukeland University Hospital, Bergen, Norway is the trial sponsor. Contact person is the head of the department Christian Ohldieck: [email protected] Role of sponsor {5c} The sponsor is completely responsible for the study. The funder has no role in the study design; collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication; or any ultimate authority over any of these activities. The authors are funded by their respective affiliations. Introduction Background and rationale {6a} Use of benzodiazepines is common among people with substance use disorders (SUD) [1-3], with a high prevalence ranging between 61-94% reported in patients with opioid use disorders [4]. Historically, benzodiazepine dependence is recommended to be managed with short-term tapering regimens combined with non-pharmacological and psychological interventions [4,5]. The effect and safety of short-term detoxification including benzodiazepine tapering in patients with SUD is uncertain [6,7]. Tapering interventions and complete abstinence-based strategies have often not been successful, especially among those with severe and long-term dependence [6]. Short-term detoxification is even attributed to an increased risk of life-threatening complications such as seizures and psychotic reactions [8]. Although substitution treatment is not recommended, a large proportion of benzodiazepine dependent patients have continuously been prescribed benzodiazepines, mainly by primary care physicians [9]. Recent research has also confirmed such prescriptions among 30-50% of the Norwegian patients undergoing opioid agonist therapy (OAT) [1]. The Norwegian OAT guidelines recommend gradual tapering and discontinuation of benzodiazepines as the main recommendation, but also propose to consider benzodiazepine stabilizing agonist treatment for patients with severe and long-lasting dependence who have not succeeded in tapering [10]. It is acknowledged that there is limited research supporting this recommendation, however user-reported and clinical experiences indicate that such approaches may be beneficial in improving the quality of life for some patients with long-term and regular use of benzodiazepines. Reports have shown that concurrent dependency to benzodiazepines and other addictive substances in patients undergoing OAT complicates the treatment course and reduces the chance to improve health and quality of life [1,11]. These patients demonstrate more frequently symptoms of mental illness, use multiple substances, and have more impaired psychosocial functioning compared to patients without benzodiazepine dependence [12]. It is uncertain whether these findings are due to differences between patient groups (e.g., in the extent of mental illness) and/or use of benzodiazepines per se. Clinical experiences indicate that the majority relapses and continues to use benzodiazepines acquired illicitly despite tapering attempts [4,12,13]. There is a lack of evidence on the effect and safety of standard treatment approaches as well as benzodiazepine substitution treatment in populations with severe SUD including those undergoing OAT [5,14]. In a small, non-randomized controlled study on patients undergoing methadone maintenance treatment (total n=66; 33 in each group), the proportion using illegally acquired benzodiazepines was lower in patients receiving benzodiazepine substitution treatment compared with patients who tapered these agents and discontinued (77% vs. 27%, and 65% vs. 14%) after 2 and 12 months, respectively [15] . Thus, there is an urgent need to conduct randomized controlled trials on the benefit and risks of benzodiazepine stabilizing agonist treatment for patients with benzodiazepine dependence undergoing OAT as compared to standard treatment approaches. Use of benzodiazepines may in turn be related to several clinical characteristics and symptoms. Generally, it is associated with impaired cognitive functioning, in addition to an increased risk of violent behavior [16]. However, there is uncertainty to which degree these can be causally inferred. Some register-based studies have shown that patients undergoing OAT who were prescribed benzodiazepines had an increased risk of overdose death compared with those without such prescriptions [17,18]. In a Norwegian study, clonazepam was often recognized as a contributing agent in emergency units for drug intoxications [7]. In another study, it was frequently found in addition to opioids in toxicological analyses related to overdose death [19]. This is contrary to the Norwegian prescribing pattern in 2014–15 where the prescription rate of both diazepam and oxazepam (less potent than clonazepam) were 50% higher than of clonazepam. Additionally, police confiscations clearly confirm the distribution of the most common illicitly acquired benzodiazepines (among others clonazepam and alprazolam, but not diazepam or oxazepam) in drug-related intoxications [7,19]. These findings support that the increased risk is related to use of more potent and illicitly acquired benzodiazepines such as clonazepam and alprazolam rather than controlled use of prescription ones such as diazepam and oxazepam which usually are less potent and seldom used illicitly in Norway. A large comparative effectiveness study, however, among 353 576 patients receiving stable long-term treatment with benzodiazepines showed that discontinuation was associated with small absolute increases in mortality and other potential harms, including nonfatal overdose, suicide attempt, suicidal ideation, and emergency department visits [20]. These results suggest benzodiazepine discontinuation among patients prescribed for stable long-term treatment may be associated with unanticipated harms, and that efforts to promote discontinuation should carefully consider the potential risks of discontinuation relative to continuation. Despite the high disease burden and related risks among people with benzodiazepine dependence, evidence on effective treatment methods is lacking. We will conduct a multi-center randomized controlled trial on patients undergoing OAT with long-lasting and hard-to-treat concurrent benzodiazepine dependence to study the efficacy and safety of benzodiazepine agonist treatment. Objectives {7} The overall objective of the trial is to investigate the effect of stabilizing agonist treatment with prescribed benzodiazepines (diazepam or oxazepam) in reducing the use of illicitly acquired potent benzodiazepines (clonazepam and alprazolam) among people on OAT with benzodiazepine dependence compared to tapering. The central hypothesis is that stabilizing treatment with less potent prescribed benzodiazepines such as diazepam and oxazepam in patients with severe and long-lasting benzodiazepine dependence will result in significant reduction in use of illicit and more potent benzodiazepines such as clonazepam and alprazolam. Accordingly, this may reduce risk and improve health and quality of life in this population. The primary objective of the study is efficacy of stabilizing agonist treatment with daily doses of 15-30 mg diazepam or equipotent doses of 50-100 mg oxazepam in reducing illicitly acquired potent benzodiazepines use measured at 24 weeks intervention. Secondary objectives are to compare mental health symptoms, cognitive functioning, and health-related quality of life between intervention and control groups, as well as differences in violence risk, overdoses, and adverse events. Other secondary objectives are to examine differences in treatment retention and satisfaction, and use of alcohol and other substances between the groups. Trial design {8} This project is a multi-center, randomized controlled, open and flexible dose trial comparing a 26-weeks stabilizing agonist treatment by using diazepam (15-30 mg a day) or oxazepam (50-100 mg a day) with a 20-weeks gradual tapering using the same medications and equivalent initial doses. Methods: Participants, interventions and outcomes Study setting {9} This study will be conducted in outpatient OAT clinics in five Norwegian cities/counties (Bergen/Vestland, Tønsberg/Vestfold, Skien/Telemark, Fredrikstad/Østfold and Tromsø/Trom). In total, 108 patients will be recruited. Potential participants will be prescreened in person by a research nurse or OAT staff, and if potentially eligible invited to attend to a formal screening i.e., eligibility assessment by a physician in line with current clinical practice and trial protocol. The Department of Addiction Medicine, Haukeland University Hospital (Vestland county, city of Bergen, Norway) is responsible for the treatment and follow-up of more than 1000 patients with opioid dependence receiving OAT, of which almost 35% receive methadone while the remaining mainly receive buprenorphine preparations, seldomly oral morphine depot. All medical interventions are integrated with psychosocial care provided in multidisciplinary outpatient clinics as part of specialist health care system. The outpatient OAT clinics are staffed by medical consultants specialized in addiction medicine in addition to nurses, social workers, and psychologists. Dependent on the overall functioning level and decisional capacity, the follow-up of the patients ranges from daily observed medication and consultations to weekly take-home doses. All the clinical measurements and laboratory data are recorded in the hospital journal system. A similar OAT model and organization is also applied in the other involved South-East and North region counties as part of specialist health care system in Norway. The four latter centres include approximately 1000 OAT patients in total with similar clinical and sociodemographic characteristics. The applied OAT platform allows frequent and close clinical observations and follow-up of the participants to increase safety and to ensure a high quality of data collected. Eligibility criteria {10} The study population is treatment-seeking adults undergoing OAT who fulfil all the inclusion criteria and do not have any of the exclusion criteria. Inclusion criteria are including: Benzodiazepine dependence according to International Statistical Classification of Diseases and Related Health Problems 10 th Revision (ICD-10) under the following conditions: - Minimum duration of ≥5 recent years (as a cut-off for severity of dependence) - Self-reported use of ≥5 days a week during last month - Minimum dose used daily is equivalent to ≥15 mg diazepam Previous at least one failed attempt at outpatient or inpatient tapering of benzodiazepines Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form and in the study protocol. Use of illicitly acquired potent benzodiazepines (clonazepam and/or alprazolam) will be verified by a high specific urine drug screening test (UPLC MS-MS) at baseline. Failure to respond to previous treatment is defined as relapse to dependent use during tapering or after completing treatment. Exclusion criteria are including: Severe respiratory failure (Global initiative for Chronic Obstructive Lung Disease “GOLD” grade 3-4) High risk of violent behavior (current violence episodes i.e., during the last 6 months) High risk of substance related overdose (current overdoses i.e., during the last 3 months) Severe cognitive impairment (IQ<70; assessed if needed based on clinical decision) Severe psychosis (current psychotic symptoms and functioning i.e., during the last 6 months based on clinical decision) Severe depression and high suicide risk (current episodes i.e., during the last 6 months based on clinical decision) Patients who are already being stabilized with continuously prescribed benzodiazepines (including diazepam or oxazepam during the last 4 weeks prior to baseline assessment) Pregnancy and breastfeeding (female participants should use a safe method of contraception; in doubtful cases, a negative pregnancy test will be required) Challenges related to ability to understand, consent, or willingness to collaborate in following-up of the study protocol. The risk of possible drug interactions will be considered individually at the time of eligibility assessments, which in some cases may result in exclusion from participation. Combination of benzodiazepines with opioids, alcohol and other central nervous system depressants may cause respiratory depression and increase the risk of overdose. Otherwise, there are few known clinical important interactions between benzodiazepines and other medications. Who will take informed consent? {26a} Participants will receive comprehensive information about the study during recruitment visits to ensure informed consent and assent. Trained research staff will obtain written informed consent from the patients who wish to attend. Additional consent provisions for collection and use of participant data and biological specimens {26b} Participants will be asked if they are willing to participate in an ancillary qualitative study investigating self-perceived effects of the interventions. If so, an additional written informed consent will be obtained. Interventions Explanation for the choice of comparators {6b} The comparator is tapering with diazepam or oxazepam in maximum 20 weeks according to the applied clinical procedure in OAT clinics which is based on the Norwegian OAT guidelines recommending gradual tapering and discontinuation of benzodiazepines as the standard treatment of benzodiazepine dependence. Intervention description {11a} Participants in the intervention arm will receive stabilizing agonist treatment with 15-30 mg/d diazepam or equivalent dosages of 50-100 mg/d oxazepam in 26 weeks. Participants in the standard arm will receive tapering with diazepam or oxazepam in maximum 20 weeks according to the applied clinical procedure in OAT clinics. The type of benzodiazepine prescribed (diazepam or oxazepam), the start dosages and the duration of tapering will be based on the degree of dependence, the dosages of illicit benzodiazepines used prior to study entrance and the individual’s clinical condition [21]. Accordingly, a customized tapering plan will be suggested to each participant within the framework of the study procedures. For both arms, treatment initiation and follow-up will be conducted at OAT outpatient clinic where they already receive OAT and relevant care including voluntary psychosocial interventions. The study medications will be prescribed by the physicians in the OAT clinics in accordance with the protocol and will be delivered either at the OAT clinic or at a pharmacy in line with the applied standards for OAT follow-up. Commercial tablets and standard medication labels will be used, tagged with trial log numbers. All the costs related to the medications, preparations and observed intakes will be covered by the OAT clinics (through public assigned funds). The medications will be used in line with national guidelines, and the project will strive to comply with the Good Clinical Practice (GCP) [10, 22]. Criteria for discontinuing or modifying allocated interventions {11b} The stop criteria for the individual participant are defined at least based on non-compliance, unexpected adverse events, or other safety considerations such as use of large amounts of highly potent street benzodiazepines with clinically observed signs of overdosing. In addition, medication can be withheld in the case of deviation from urinary test procedures that can affect measuring the trial primary outcome. Participants who have discontinued protocol-based treatment will be motivated to continue to participate in all remaining research interviews and assessments. For those participants who revoke their consent for the entire study, no further data will be collected from the participant. Strategies to improve adherence to interventions {11c} Medication choice between oxazepam and diazepam will be individualized based on patient preferences, medical history, and present health condition. The prescription method will also be assessed individually and based on the patient’s treatment course (i.e., prescribed by the clinic physician and ordered through the related clinic or pharmacy). All participants will be encouraged to initiate the treatment according to the protocol, with data collected on prescription pickup and treatment initiation dates. In addition, for those receiving medications in the clinics, frequencies, and observation of doses taken will be noted. Self-reported data on medication adherence and compliance will be obtained for all participants. Medication adherence and compliance will be assessed through a combination of prescription pickup frequency, self-reported adherence, observed intake and urinary tests. Related authorized clinical study-monitoring organs in each health county will visit the study sites on a regular basis to ensure the following requirements: informed consent process, reporting of adverse events and all other safety data, adherence to protocol, maintenance of required regulatory documents, facilities, and data completion on the case report files (CRFs) including source data verification. Additionally, a data monitoring committee (DMC) comprising two independent professionals (a clinician and a researcher) and a statistician will ensure the safety and wellbeing of trial patients and will assist and advice the coordinating and principal investigators to protect the validity and credibility of the trial. Relevant concomitant care permitted or prohibited during the trial {11d} All the participants will receive OAT and the related care as usual. Study medications will mainly be administered under supervision by the OAT clinic or pharmacy staff. Individually assessed, the participants will receive some of the doses as take-home-dosages for self-administration. Assessments of observed intake frequency and “take-home doses” will follow the same agreement that applies to OAT medications, and any changes will be assessed by the prescribing OAT physician after discussion in interdisciplinary team. Project managers will be informed of any changes. In any case, all participants should attend the OAT outpatient clinic daily or at least once weekly for clinical observations. Every participant should, regardless of the delivery agreement, have frequently clinical observations and assessments for the first two weeks after starting prescription (in both study arms) to ensure treatment safety. After this period, they follow the delivery agreement as before. Clinical and biological follow-up of participants and systematic report of potential adverse effects will be organised according to international GCP guidelines. The participants will be assigned to the scheduled assessments by research nurses and/or clinic physicians in line with the study protocol. The assessments will be performed at baseline, and at week 24 in addition to a follow-up assessment at week 52 after entering the trial. The OAT staff or research nurses will follow up the participants weekly at OAT clinics or by home-based visits if needed, with consultations including self-reports on illicit use of benzodiazepines and other substances, adverse events as well as monthly randomized urine drug screening tests during the trial period (Figure 1 and Table 1). (please insert Figure 1 here). Provisions for post-trial care {30} At the end of trial period, each participant will be individually assessed to receive further clinical follow-up as indicated. Participants who receive stabilizing treatment with prescription benzodiazepines during the 26-week study period will undergo individual clinical assessments upon trial completion. Some participants may continue with stabilizing treatment, while others will have their prescriptions stepped down and discontinued following current guidelines. Participants in the standard treatment arm will receive ongoing treatment and follow-up using conventional approaches after tapering of medications. Participants will be informed about these individual assessments at the project’s conclusion. Clinical observations throughout the study period will provide insights into outcomes for participants in each study arm. Decision-making following the project's conclusion will be based on these outcomes, aligning with the conditions governing benzodiazepine continuation outlined in the study protocol. Assessments will occur both upon completion of the intervention (after week 26) and at the end of the project period (after week 52). Outcomes {12} Primary outcome measure is: The difference between the groups in the use of illicit benzodiazepines based on supervised urine drug screening tests measured at week 24. Secondary outcome measures collected at baseline and week 24 will include: Mental health symptoms score using Hopkins symptom checklist (SCL-10) [23] Health-related quality of life score using 5-dimensional, 5-level Euro Quality of life questionnaire (EQ-5D-5L) [24] Reaction time for cognitive performance using a simple reaction time test [25] Risk of violence behavior using Brøset violence checklist (BVC) [26] Satisfaction with the treatment using visual analogue scale (VAS) from 0-10 Retention rate in OAT (number of drop-out days during the trial period) Frequency of use of other illicit substances and alcohol by self-reports and urine drug screening tests, and use of illicit benzodiazepines by self-reports Number of non-fatal overdoses and death (if any) Cost-effectiveness of intervention Participant timeline {13} The time schedule of enrolment, interventions, assessments, and visits for participants is shown in table 1 (please insert here). Sample size {14} The sample size calculation is based on clinical experiences due to no existing empiric assumption. We set the minimal clinically relevant difference between the groups to 0.3, and the required power to 0.8 at two-sided significance level of 0.05. There is no valid data to estimate the standard deviation. Assuming a risk of 0.5 to 0.8 for the use of illicit benzodiazepines in the standard treatment group, we need 43 patients per group. Assuming a drop-out rate of 20% we need 54 patients in each group, 108 in total, to achieve sufficient power [27]. Recruitment {15} Enrollment will be commenced during 2022 and continue until the required number of eligible participants are enrolled in the trial. For both arms, all the clinical stages of the study—including recruitment, information, obtaining written consent, clinical interviews, and completing the study surveys using appropriate instruments, and treatments—will be performed by research nurses and/or physicians to ensure independency. Five OAT sites are involved in the trial conduction to obtain the required sample size. Assignment of interventions: allocation Sequence generation {16a} Eligible participants will be randomized digitally with a 1:1 ratio into intervention or standard treatment for inclusion in the trial. A computer-generated blocked, site stratified randomization schedule will be developed by an independent statistician and uploaded to the study database. Concealment mechanism {16b} Randomization will be performed by research nurse or the trial site investigator within the study database and technically secured against manipulation in the database. Implementation {16c} The allocation sequence will be generated by an independent statistician. The research nurses or physicians will enrol participants in the study and assign them to the interventions. An independent statistician not involved in providing the clinical data will analyze the data collected. Assignment of interventions: Blinding Who will be blinded {17a} Complete blinding is not considered practiced although some masking measures such as blinded analyses of the data will be taken (blinding for the trial analytes). Randomization will be disclosed to the researchers, participants and clinical staff providing treatment and follow-up. Patients will be informed of key elements in the delivery of the respective intervention or standard treatment and follow-up they are randomized to, but not on the hypotheses for the study. Procedure for unblinding if needed {17b} Not applicable. The trial is not blinded for the participants, researchers, or care givers. Data collection and management Plans for assessment and collection of outcomes {18a} To ensure correct operation according to standard operating procedures (SOPs) all system users will be trained and evaluated on a regular basis. The research nurses will collect the trial data at baseline and at trial week 24, in addition to weekly self-reported substance use, adverse events and other research-related data, as well as the randomized monthly urinary screen tests according to table 1. The urine drug screening tests as the measure of primary outcome will be taken at the OAT clinics or other planned units under the observation of the staff. A high specific laboratory analysis method (UPLC MS-MS) will be used to differentiate between the benzodiazepine types identified in the urinary samples (those illicitly acquired i.e., clonazepam and alprazolam, and the prescribed ones i.e., diazepam and oxazepam). The samples will be taken randomly in one out of the four weeks in each month. Randomization will be programmed by an independent researcher and is aimed to reduce the effect of any variations in the intake of illicit benzodiazepines between the intervention and the standard arm in relation to the time of sampling. The patients will be informed Monday of the week that they need to provide an observed urinary test before Friday the given week. In case of no show for a urine sample, the patient will receive a warning to take it the subsequent week (up to once). In the event of a missing urine sample or two delays in a month, study medication will be stopped. Other outcomes will be assessed using standard or semi-structured questionnaires based on table 1. The study assessments will be completed for each participant at scheduled visits during the study. Secondary endpoints assessed are: Treatment initiation and medication adherence: Treatment initiation will be assessed as the proportion taking at least one tablet while medication adherence will assess the proportion taking their medicines at least 6 days per week (>80%) throughout the entire treatment period. Both outcomes will be assessed and reported as a combination of self-reported adherence and observed intake. Weekly self-reported substance use : The weekly self-reported substance use will be assessed for each week and at week 24. Changes in mental health symptoms : Mental health symptoms will be assessed using Hopkins symptom checklist score (SCL-10) at baseline, and at week 24. The SCL-10 is a structured self-administrated instrument to measure symptoms of mental health disorders and psychological distress. Scores range from 1 (not bothered at all) to 4 (extremely bothered) for each item. To derive the mean item score, the scores will be summed up and divided by the number of items. A mean score of 1.85 or higher will indicate the presence of symptoms of mental and psychological disorders. The records at week 24 will be compared to baseline across the arms. Changes in quality of life : Quality of life will be assessed using EQ-5D-5L at baseline and week 24. The instrument describes and values quality of life, consisting of the EQ visual analog scale and the EQ-5D descriptive system. The EQ VAS records the patient's self-reported health on a vertical scale ranging from 0 "Worst Health You Can Imagine" to 100 "Best Health You Can Imagine", reflecting the patient's own opinion about the quality of their health condition. The Descriptive System includes five dimensions (5D): mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has five levels (5L): No problems, minor problems, moderate problems, serious problems and extreme problems. Patients will indicate their health status by selecting the most appropriate statement in each dimension, resulting in a 5-digit number that describes their health status. The records at week 24 will be compared to baseline across the arms. Risk of violence : This secondary outcome will be assessed using the BVC at baseline and week 24. BVC is a 6-item checklist designed to predict imminent violent behavior within a 24-hour perspective. The 6 items that reflect that mood setting are confused, irritable, boisterous, physical threats, verbal threats, and attacking objects. Each item is scored as 0 for the absence of behavior and 1 for the presence of behavior, with a maximum total score of 6. The records at week 24 will be compared to baseline across the arms. Reaction time (cognitive performance ): The cognitive performance will be based on the reaction time test (measured 3 consequent times according to the time used to react in milliseconds) at week 24 compared to the baseline. Satisfaction with treatment: Satisfaction with the treatment will be assessed at week 24 after initiation of treatment compared to baseline using VAS from 0-100 where 0 means no satisfaction and 100 means very satisfied. Plans to promote participant retention and complete follow-up {18b} Study participants will be encouraged to retain and complete study follow-up. They will also receive a limited economic compensation (500 Norwegian Krones) for the use of time and to increase the motivation to complete the data collections, measurements, and assessments. A list of outcome data will be collected for participants who discontinue or deviate from intervention protocols. Data management {19} All the OAT clinics in the participating sites will use electronic CRFs that will be entered online in a study database through the data collection softwares (REDCap and Viedoc). Alternatively, paper based CRF will be used by the sites, and then the collected data will be entered in the central electronic CRF by coordinating research nurse. The softwares is accredited by Helse Bergen for health research and clinical integration. A central data manager at Helse Bergen will assist in designing the CRF, train data collectors in use of the CRF and aid data export. Confidentiality {27} Only authorised study personnel including the principal investigator, research nurses and coordinating physicians will have access to CRFs and supporting documents. Data capture and storage will be undertaken using computer systems compliant to GCP. The research data will be stored in an encrypted data server for research with access limited for the principal investigators and coordinating research nurse. Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33} Not applicable. Genetic specimens will not be taken in this trial. Statistical methods Statistical methods for primary and secondary outcomes {20a} Analysis methods will follow the CONSORT guidelines as far as possible [28]. All tests will be two-sided. Descriptive results and the estimated efficacy will be presented with 95% confidence intervals (CI). Categorical variables will be summarized as percentages and continuous variables as medians with interquartile ranges or means with standard deviations for variables with a Gaussian distribution. Analyses for the primary endpoint will be undertaken on an intention-to-treat (ITT) basis and reported upon as such. All the randomized and eligible participants will be analysed based on initial group allocation. The main endpoint is difference between the two study arms in the use of illicit benzodiazepines (as assessed by monthly supervised urine drug screening tests) measured at week 24. The primary endpoint is then dichotomous. The difference between the groups at the primary time point (week 24) will be reported using cross table, risk difference and odds ratio with 95% confidence intervals and tested using the chi-square-test, asymptotic or exact depending on the marginal distributions. For the analyses of secondary endpoints and based on the type of outcomes, appropriate analysis methods will be used including ANCOVA, t-test, cross table, risk difference and odds ratio with confidence intervals as well as the chi-square-test, asymptotic or exact depending on the marginal distributions. We have three types of secondary outcomes: Continuous outcomes with baseline measurement: These include weekly/monthly urinary tests and weekly self-reports on illicit drug and alcohol use, and weekly self-reports on illicit benzodiazepine use. These outcomes are analyzed using the ANCOVA, i.e., the linear regression model of the outcome at the primary time point (24 weeks) depending on the randomization group adjusted for the baseline value of the outcome. The mean difference with confidence interval, coefficient with confidence interval and the p-value will be reported. Continuous outcomes without baseline measurement: These include adverse events. These outcomes are analyzed using the t-test for differences in the outcome at the primary time point (24 weeks). The mean difference with confidence interval and the p-value will be reported. Dichotomous outcomes: These include SCL-10, EQ-5D-5L, BVC, reaction time, treatment retention, overdose, and treatment satisfaction. These outcomes are analyzed in the same way as for the primary outcome, i.e., measuring the difference between the groups at the primary time point (24 weeks) and will be reported using the cross table, risk difference and odds ratio with confidence intervals and tested using the chi-square-test, asymptotic or exact depending on the marginal distributions. Additionally, we will estimate a linear mixed effects model for continuous outcome variables at all time points depending on time, randomization group and the interaction between time and randomization group, adjusted using an individual random intercept. We will use a simple contrast. For the outcomes appearing to have linear dependence on time we will also use a linear contrast. For all regression models we will present the regression table, and for the linear mixed model we will provide the graphics with mean and 95% confidence interval for each follow up time point. For the dichotomous variables, we will provide a bar plot of the proportions for each available time point. The ITT analyses will be repeated with the per-protocol dataset. There will be conducted per-protocol analyses as part of sensitivity analyses. Interim analyses {21b} An interim analysis for efficacy of the primary endpoint will be done when 50% of planned sample size is assessed at week 24. We will use a group sequential design without futility and the O’Brien-Fleming alpha spending approach. The interim analysis will be performed by the DMC. The DMC will give a recommendation whether the study should be continued or stopped. Even if not in the model, the DMC can recommend stopping the study for futility [29] . Methods for additional analyses (e.g., subgroup analyses) {20b} All patients enrolled in the study will be evaluated with respect to safety-related outcomes according to the treatment they receive. Safety analyses will include summaries of the incidence of all adverse events and serious adverse events that are possibly or probably related to the study intervention and occur during the study treatment period or within 30 days of the last dose of study treatment. Safety analysis will be specified by DMC. Sub-group analyses will be conducted for exploratory purposes only, due to their inherently low statistical power. These analyses will focus on the primary endpoint and confirmatory secondary endpoints to assess the consistency of the investigational intervention effect across various subgroups such as age groups and sex. If a subgroup contains fewer than 10% of the total participants, the subgroup categories may be redefined. The analyses will be conducted using a test for heterogeneity and results will be presented on forest plots presenting the estimated study arm difference and 95% confidence intervals. Further details on the statistical analysis will be provided in the statistical analysis plan. A cost-effectiveness analysis will employ a prospective economic evaluation approach. Effectiveness will be measured with quality adjusted life years (QALYs), building on primary and secondary results combined with a prospective Markov model. Cost data will be collected alongside the clinical trial employing both healthcare and societal perspective. The analysis will follow the current guidelines and will be conducted by a health economist [30]. Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c} Participants who withdraw from the study treatment will not be censored, as treatment discontinuation is likely to be related to allocation. Deaths will be censored at the last outcome measurement. We will also have a sensitivity analysis assuming missing urine samples is similar as last urine sample taken (to manage missed data for the primary outcome measure). Robustness of the primary outcome will be checked with sensitivity analyses considering censoring and adjusting for potential baseline imbalances. Plans to give access to the full protocol, participant level-data and statistical code {31c} There are no plans for granting public access to the full protocol, participant-level dataset, and statistical code. However, this will be considered by the sponsor if indicated. Oversight and monitoring Composition of the coordinating center and trial steering committee {5d} The trial will be administrated and coordinated by Bergen Addiction Research Group (BAR) and Norwegian Research Centre for Agonist Treatment of Substance Use Disorders (NORCATS) at Department of Addiction Medicine, Haukeland University Hospital, Vestland, Bergen in collaboration with the other sites at Vestfold, Telemark, Østfold and Troms. The research consortium brings together and profits from expertise on addiction medicine and clinical trial implementation in the interdisciplinary and highly specialized clinics together with research expertise from BAR and NORCATS in The Department of Addiction Medicine at Haukeland University Hospital and University of Bergen, in addition to the user expertise ProLAR employed in the department. Then, the project group is multidisciplinary, involving national and local collaborators, including several partners with extensive clinical experience, members with user perspectives, and researchers from related field. The coordination unit will be led by the principal investigator in close cooperation with the project manager and will have ongoing communication as well as regular meetings with the other sites. The Steering committee (SC) will be responsible for the conduct of the study. The coordination unit will report regularly to the SC for updates on trial progress and potential issues. The SC is the trial decision body, for all scientific and administrative aspects. It will send technical reports to the funder, ethical committees, and regulatory bodies particularly the monitoring organs in Helse Bergen, and financial reports to the funder. SC participants will meet on regular conference calls with customized frequencies. The coordinating and managing unit will oversee the day-to-day conduct of the trial. It will centralise all study information and will report to the steering committee. The coordination unit will coordinate analysis and writing of different outcomes from the study. The trial coordination will also rely on other units, which can be considered as SC sub-committees. These are including: Clinical care unit which will oversee elaborating the clinical procedures for the trial. It will also support the local physicians on the treatment protocols. Physicians in the coordination unit, and the participating sites and coordinating research nurse will be members of this unit. Study site units which will oversee day-to-day implementation at each study clinic in collaboration with the coordination unit. The clinic leaders will generally be involved in the site units. Composition of the data monitoring committee, its role and reporting structure {21a} The main aim of DMC is to ensure the safety and wellbeing of trial patients and to assist and advise the coordinating investigator, steering committee, and the principal investigators, so as to protect the validity and credibility of the trial. The DMC will be comprising two independent clinicians and researchers and a statistician. An agreed DMC charter will describe the roles and responsibilities of the committee, including the timing of meetings, methods of providing information to and from the DMC, frequency and format of meetings, statistical issues, and relationships with other committees. The charter will be in place before the first patient is included. Adverse event reporting and harms {22} Potential adverse events among participants will be managed according to the treatment guidelines [10]. A low rate of adverse effects and toxicity is expected with the applied benzodiazepines. Complete lists on the reported adverse effects are described in the summaries of product characteristics for oxazepam and diazepam [31,32] as the reference safety information. All serious adverse events (SAE) reported to the sponsor will be assessed against the reference safety information to consider whether the event is unexpected (suspected unexpected serious adverse reaction “SUSAR”) or not. Regular clinical observations by the OAT clinic staff and physicians will secure prompt identification of potential adverse events. Any side effects or suspicious clinical conditions such as symptoms of intoxication that are observed by the clinic staff or registered using weekly questionaries, will promptly be reported to the responsible clinic physicians and the trial investigator. Emergency intoxication care and acute antidote medication (naloxone) will be available at the involved OAT clinics, and further transport to the emergency unit will be secured when close and continuous clinical monitoring is needed. Clinical and biological safety will be assessed according to the standardized scales of toxicity [33]. All unexplained grade III or IV events will lead to temporary interruption of the study medication before a new assessment is made by clinic physician and study investigators. A rapid report system for the management of severe SAE and SUSAR will be available. Frequency and plans for auditing trial conduct {23} The decision to initiate the study will be taken in the agreement between the coordination unit and the sponsor. The study sponsor may wish to do audit visits on sites to ensure the trial is conducted according to the protocol and GCP guidelines. Plans for communicating important protocol amendments to relevant parties (e.g., trial participants, ethical committees) {25} Any important protocol modifications (e.g., changes to eligibility criteria, outcomes, or analyses) will be communicated to relevant parties (e.g., investigators, ethical committees, trial participants, trial registries, journals, and regulatory organs). Dissemination plans {31a} The findings will be presented in relevant national and international conferences and will also be presented to politicians and the health and welfare administration at all levels. The aspect in this study is considered relevant to a public audience, and several of the researchers has extensive experience with communicating research to the public through various media, as well as informing patients and other health workers. The results from the study will also be published in articles in peer-reviewed scientific journals in line with the ICMJE guidelines [34]. Open access journals indexed in PubMed/Medline will be preferred. Discussion This is the first randomized controlled trial of benzodiazepine stabilizing agonist treatment for benzodiazepine dependence. The research project will provide knowledge on the impact of such intervention on patient outcomes. We will assess efficacy and safety of stabilizing treatment with prescribed benzodiazepines compared to benzodiazepine tapering and discontinuation regarding use of illicit benzodiazepines and accordingly well-being of patients with concurrent benzodiazepine and opioid dependence undergoing OAT. Our trial involves some limitations and several strengths. For the trial it is difficult to ensure complete blinding, however, some masking measures will be taken including blinded assessments of the study analyses by independent research staff. The study is also funded from public sources to ensure independency form pharmaceutical companies. We also have a biological primary outcome. Thus, substantial information biases are considered unlikely. The study is individually randomized, which minimizes potential confounding. The proposed sample size is powered to detect a medium effect size in between-group differences in the primary outcome. Participants will be closely monitored with weekly clinic visits and research reviews at outpatient OAT clinics where they usually are being treated and followed-up. This will promote participants’ safety and retention in the study. The study protocol proposes to deliver the medication in an outpatient setting allowing participants take-home dosages to more closely mimic the service delivery situations in which the medication will be used. However, absence of a structured psychosocial intervention as a supplementary treatment, and not fully observed daily dosages are among the trial limitations. Other limitations include a non-blinded design and a possible (although low) risk of using illicitly acquired diazepam and/or oxazepam which cannot be detected by urinary analyses. However, the results of self-reported use of illicit benzodiazepines can provide additive information on the drug use patterns. If the intervention is found to be efficacious and safe, it will be considered one of the options to standard treatment of patients with opioid and benzodiazepine co-dependency. Trial status Recruiting started in September 2022. The current protocol is version 4.0 of 4-4-2024. Currently (5th of Aug 2024), we included 62 patients. Patient recruitment is estimated to be completed around December 2025. Abbreviations AE Adverse event ANRS Adults scaling instrument to grade the severity of adverse events BAR Bergen Addiction Research BVC Brøset violence checklist CI Confidence interval CONSORT Consolidated Standards of Reporting Trials CRF Case Report Files DMC Data Monitoring Committee EQ-5D-5L Euro Quality of life, 5-dimensional, 5-level questionnaire GCP Good Clinical Practice ICMJE International Committee of Medical Journal Editors MD Medical doctor NORCATS Norwegian Research Center for Agonist Treatment of Substance Use Disorders OAT Opioid agonist treatment PhD A Doctor of Philosophy ProLAR User organisation for patients receiving OAT in Norway REC Regional Ethical Committee SAE Severe adverse event SC Steering committee SOP Standard Operating Procedure SPIRIT Standard Protocol Items: Recommendations for Interventional Trials VAS Visual analogue scale SCL-10 Symptom Check List Declarations Acknowledgements We will thank the patients for their time, commitment, and willingness to participate in this trial; all the dedicated clinical and research staff at the Department of Addiction Medicine, Haukeland University Hospital, as well as the other involved hospitals i.e., Vestfold, Telemark, Østfold and Troms Hospital trust for their incredible contributions in data collection and follow-up of the participants during the study period; the laboratories at Haukenad University Hospital and St. Olavs Hospital for analyzing the urinary samples; and the responsible monitoring teams and DMC members for the close collaboration and valuable supports and services. Authors contributions {31b} All the authors have been involved in design of the study, contributed to implementation and writing protocol. FC, LTF, KAJ, CO and EML conceived the study and designed it primarily. KAJ, LTF and FC are the principal investigators. KAJ, LTF, FC and JA led statistical analyses. FC wrote the first draft for the paper. All the authors have reviewed the manuscript for intellectual content, and approved the final version of the manuscript. Funding {4} This research is supported by public funding sources, and has not received any grants from commercial or not-for-profit sectors. The work is supported by the Norwagian governement [project number R-11141-D11722], Norwagian Research Center for Agonist Treatment of Substance Use Disorders (NORCATS). The funder has no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors are funded by their respective affiliations. Availability of data and material {29} The datasets analyzed during the current study are available from the corresponding author on reasonable request. Ethics approval and consent to participate {24} The study is approved by regional ethical committee (Reference number 345516- REK Vest) and drug administration authorities in Norway and registered at www.clinicaltrials.gov. Written informed consent will be obtained from all the participants before commencing to the study. Consent for publication {32} This manuscript does not contain individual personal data and the participants have given written informed consent for the publication of the study findings. Competing interests statement {28} The authors have declared that they have no cometing interests. References Vold JH, Skurtveit S, Aas C, Chalabianloo F, Kloster PS, Johansson KA, Fadnes LT. Dispensations of benzodiazepines, z-hypnotics, and gabapentinoids to patients receiving opioid agonist therapy; a prospective cohort study in Norway from 2013 to 2017. BMC Health Serv Res. 2020; 20(1): 352. Votaw VR, Geyer R, Rieselbach MM, McHugh RK. The epidemiology of benzodiazepine misuse: A systematic review. Drug Alcohol Depend. 2019;200: 95-114. Abrahamsson T, Berge J, Ojehagen A, Hakansson A. Benzodiazepine, z-drug and pregabalin prescriptions and mortality among patients in opioid maintenance treatment-A nation-wide register-based open cohort study. Drug Alcohol Depend. 2017;174: 58-64. Liebrenz M, Boesch L, Stohler R, Caflisch C. Agonist substitution—a treatment alternative for high-dose benzodiazepine-dependent patients? Addiction. 2010;105(11), 1870-4. Waal H, Clausen T. Kan substitusjonsbehandling være et alternativ ved avhengighet av amfetamin/metamfetamin, kokain, cannabis og benzodiazepiner? Senter for rus-og avhengighetsorskning (SERAF). Oslo, 2020. https://www.med.uio.no/klinmed/forskning/sentre/seraf/publikasjoner/rapporter/2020/seraf-rapport-2-2020-substitusjonbehandling-andre-rusmidler.pdf Liebrenz M, Boesch L, Stohler R, Caflisch C. Benzodiazepine dependence: when abstinence is not an option. Addiction. 2010;105(11):1877-8. Andersson JA, Brekke M, Vallersnes OM. Akutt forgiftning ved rusrelatert bruk av benzodiazepiner. Tidsskri Nor Legeforen. 2020;140(10):1027-30. Pétursson H. The benzodiazepine withdrawal syndrome. Addiction. 1994;89(11):1455-9. Petitjean S, Ladewig D, Meier CR, Amrein R, Wiesbeck GA. Benzodiazepine prescribing to the Swiss adult population: results from a national survey of community pharmacies. Int Clin Psychopharmacol. 2007;22:292–8. Norwegian Health Directorate. National guidelines for the treatment of opioid dependence. Behandling ved opioidavhengighet - Helsedirektoratet. 2022. Aas CF, Vold JH, Skurtveitt S, Lim AG, Ruths S, Islam K, Askildsen JE, Løberg E-M, Fadnes LT, Johansson KA, INTRO-HCV Study Group. Health-related quality of life of long-term patients receiving opioid agonist therapy: a nested prospective cohort study in Norway. Subst Abuse Treat Prev Policy. 2020;15(1):68. Lintzeris N, Nielsen S. Benzodiazepines, methadone and buprenorphine: interactions and clinical management. Am J Addict. 2010;19(1): 59-72. Sabioni P, Bertram J, Le Foll B. Off-Label Use of Medications for Treatment of Benzodiazepine Use Disorder. Curr Pharm Des. 2015 ; 21(23): 3306-10. Skeie I. Kunnskapsgrunnlag vedrørende substitusjonsbehandling med benzodiazepiner hos personer i LAR som også har benzodiazepin-avhengighet 2020. [Upublisert]. Weizman T, Gelkopf M, Melamed Y, Adelson M, Bleich A. Treatment of Benzodiazepine Dependence in Methadone Maintenenace Treatment Patients: A Comparison of Two Therapeutic Modalities and the Role of Psychiatric Comorbidity. Australian & New Zealand Journal of Psychiatry. 2003;37(4): 458-63. Barker MJ, Greenwood KM, Jackson M, Crowe SF. Cognitive effects of long-term benzodiazepine use: a meta-analysis. CNS Drugs. 2004;18(1): 37-48. Park TW, Larochelle MR, Saitz R, Wang N, Bernson D, Walley AY. (2020). Associations between prescribed benzodiazepines, overdose death and buprenorphine discontinuation among people receiving buprenorphine. Addiction. 2020;115(5): 924-32. Macleod J, Steer C, Tilling K, Cornish R, Marsden J, Millar T, Hickman M. Prescription of benzodiazepines, z-drugs, and gabapentinoids and mortality risk in people receiving opioid agonist treatment: Observational study based on the UK Clinical Practice Research Datalink and Office for National Statistics death records. PLoS Med. 2019;16(11), e1002965. Edvardsen HME, Clausen T. Opioidrelaterte dødsfall 2000-2017 Oslo: Oslo Universitetssykehus. SERAF. 2020. Maust DT, Petzold K, Strominger J, Kim HM, Bohnert ASB. Discontinuation and Mortality Among Patients With Long-Term Benzodiazepine Therapy. JAMA Network Open. 2023;6(12):e2348557. doi:10.1001/jamanetworkopen.2023.48557 Voshaar RC, Gorgels WJ, Mol AJ, van Balkom AJ, Mulder J, van de Lisdonk EH, et al. Predictors of long-term benzodiazepine abstinence in participants of a randomized controlled benzodiazepine withdrawal program. Can J Psychiatry. 2006;51:445–52. SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials). 2013.http://www.spirit-statement.org/ Derogatis LR, Lipman RS, Rickels K, Uhlenhuth EH, Covi L. The Hopkins Symptom Checklist (HSCL): a self-report symptom inventory. Behav Sci. 1974;19(1):1-15. Herdman M, Gudex C, Lloyd A, Janssen Mf, Kind P, Parkin D, Bonsel G, Badia X. Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res. 2011;20(10):1727-36. Reaction time test (online version). How old are your reactions? https://www.justpark.com/creative/reaction-time-test/. Accessed 15 Aug 2022. Almvik R, Woods P, Rasmussen K. The Brøset Violence Checklist: Sensitivity, specificity and interrater reliability. Journal of Interpersonal Violence. 2000;15:1284-96. Rosner B. Fundamentals of Biostatistics . 7 th ed. Boston, MA: Brooks/Cole;2011. Moher D, Schulz KF, Altman DG. The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomised trials. Lancet. 2001;357(9263):1191-94. DAMOCLES Study Group. A proposed charter for clinical trial data monitoring committees: helping them to do their job well. Lancet. 2005;365(9460):711-22. Ramsey SD, Willke RJ, Glick H, Reed SD, Augustovski F, Jonsson B, Briggs A, Sullivan SD. Cost-Effectiveness Analysis Alongside Clinical Trials II—An ISPOR Good Research Practices Task Force Report. Value Health. 2015;18(2):161-72. Oksazepam (Sobril). Preparatomtale (SPC). Statens legemiddelverk. Updated April 2021. Diazepam (Valium). Preparatomtale (SPC). Statens legemiddelverk. Updated October 2019. ANRS scale to grade the severity of adverse events in adults. 2008. http://www.anrs.fr/content/download/2242/12805/file/ANRS-GradeEI-V1-En-2008.pdf International committee of medical journal editors. Updated January 2024. http://www.icmje.org/recommendations/ Table Table 1. Schedule of activities during the study period. Pre-screening and screening by research nurse/physician Assessment at Baseline by research nurse/physician Assessment at week 24 by research nurse/physician Assessment at week 52 by research nurse/physician Weekly/monthly follow-up by research nurse/clinic staff Eligibility criteria Written Informed consent Randomization X X X Observed urinary tests X X X X Self-reported drug use X X X X SCL-10 X X X EQ-5D-5L X X X BVC X X X Reaction time X X X Treatment satisfaction X X X Days out of treatment X X X X Recorded overdose X X X X Adverse effects X X SCL-10: Hopkins symptom checklist; EQ-5D-5L: Euro Quality of life, 5-dimensional, 5-level questionnaire; BVC: Brøset violence checklist. Cite Share Download PDF Status: Published Journal Publication published 02 Jan, 2025 Read the published version in Trials → Version 1 posted Editorial decision: Minor revision 04 Nov, 2024 Reviewers agreed at journal 30 Aug, 2024 Reviewers invited by journal 30 Aug, 2024 Editor assigned by journal 22 Aug, 2024 First submitted to journal 09 Aug, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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12:59:32","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4868655/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4868655/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13063-024-08692-8","type":"published","date":"2025-01-02T15:57:27+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":66937832,"identity":"4f0b860d-c83a-4f8d-ad1e-1b3af53807ca","added_by":"auto","created_at":"2024-10-18 08:35:01","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":191711,"visible":true,"origin":"","legend":"\u003cp\u003eTitle: Flow-chart of the study procedures.\u003c/p\u003e\n\u003cp\u003eLegend: Potential participants will be screened for eligibility. Individuals, who meet the eligibility criteria and provide written informed consent to participate, will be randomized either to a stabilizing dose with diazepam or oxazepam, or tapering using the same medications. The primary endpoint is at week 24 with a follow visit at week 52. OAT: opioid agonist treatment.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4868655/v1/b6d1760976f4b99d569e7bb7.png"},{"id":73093251,"identity":"6ac4e3db-3948-4692-90d1-bba25a50a551","added_by":"auto","created_at":"2025-01-06 16:12:02","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1216402,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4868655/v1/b98d7ad9-dafa-4d8c-ab43-bf0aef5bd8f0.pdf"}],"financialInterests":"","formattedTitle":"Benzodiazepine agonist treatment for patients with benzodiazepine dependence undergoing opioid agonist treatment: a study protocol for the randomized controlled trial BMX-BAR","fulltext":[{"header":"Administrative information","content":"\u003cp\u003eNote: the numbers in curly brackets in this protocol refer to SPIRIT checklist item numbers. The order of the items has been modified to group similar items (see http://www.equator-network.org/reporting-guidelines/spirit-2013-statement-defining-standard-protocol-items-for-clinical-trials/).\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" align=\"left\" width=\"639\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 29.375%;\"\u003e\n \u003cp\u003eTitle\u0026nbsp;{1}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70.625%;\"\u003e\n \u003cp\u003eBenzodiazepine agonist treatment for patients with benzodiazepine dependence undergoing opioid agonist treatment: a study protocol for the randomized controlled trial BMX-BAR\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 29.375%;\"\u003e\n \u003cp\u003eTrial registration {2a and 2b}.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70.625%;\"\u003e\n \u003cp\u003eEudraCT: 2021-004981-37. Registered on December 13, 2021\u003c/p\u003e\n \u003cp\u003eItem 2b is not applicable.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 29.375%;\"\u003e\n \u003cp\u003eProtocol version {3}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70.625%;\"\u003e\n \u003cp\u003eVersion: 4.0\u003c/p\u003e\n \u003cp\u003eDated: 4-4-2024\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 29.375%;\"\u003e\n \u003cp\u003eFunding {4}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70.625%;\"\u003e\n \u003cp\u003eThis research is supported by public funding sources, and has not received any grants from commercial or not-for-profit sectors. The work is supported by the Norwagian governement [project number R-11141-D11722], Norwagian research center for agonist treatment of substance use disorders (NORCATS).\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 29.375%;\"\u003e\n \u003cp\u003eAuthor details {5a}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70.625%;\"\u003e\n \u003cp\u003e\u003csup\u003e1\u003c/sup\u003eDepartment of Addiction Medicine, Haukeland University Hospital, Bergen, Norway\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e2\u003c/sup\u003eDepartment of Global Public Health and Primary Care, University of Bergen, Bergen, Norway\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e3\u003c/sup\u003eCentre for Clinical Research, Haukeland University Hospital, Bergen, Norway\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e4\u003c/sup\u003eDepartment of Addiction Medicine, Vestfold Hospital Trust, T\u0026oslash;nsberg, Norway\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e5\u003c/sup\u003eNorwegian Centre for Addiction Research, University of Oslo, Oslo, Norway\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e6\u003c/sup\u003eDepartment of R\u0026amp;D in Psychiatric Health Care, Akershus University Hospital, Oslo, Norway\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e7\u003c/sup\u003eDepartment of Addiction Medicine, Telemark Hospital Trust, Skien, Norway\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e8\u003c/sup\u003eDivision of Psychiatry, Haukeland University Hospital, Bergen, Norway\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e9\u003c/sup\u003eInstitute of clinical Psychology, University of Bergen, Norway\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eBMX-BAR and NORCATS study group*:\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eFatemeh Chalabianloo, Lars Thore Fadnes, Kjell Arne Johansson,\u0026nbsp;Christian Ohldieck, Svanhild Mellingen, Else-Marie L\u0026oslash;berg,\u0026nbsp;Christina D. Andersen,\u0026nbsp;J\u0026ouml;rg Assmus,\u0026nbsp;Prayash Chaudhary, Christine Sundal, Marianne Pierron, Silvia Zavenova, Zainab Alibhai, Karoline N. Helg\u0026oslash;y, Beathe R\u0026oslash;nning, Henriette Moe, Cecilia E. Kvamme, Anne T. Heldal, Jon Mordal, Kristin K. Solli, Kjetil S. Dale, Britt K. Haugen, Jeanine T.H. Karlsen, Line Holtan, Heidi F. Kristiansen, Anne G. \u0026Oslash;rmen, Richard Kaspersen, Andreas W. Blomkvist, Martin Ryssdal and all the OAT staff at Departments of Addiction Medicine, Haukeland University Hospital, Vestfold Hospital Trust, Telemark Hospital Trust, \u0026Oslash;stfold Hospital Trust, and University Hospital of North Norway, Norway.\u003c/p\u003e\n \u003cp\u003e*Bergen Addiction Research (BAR) and Norwegian Research Centre for Agonist Treatment of Substance Use Disorders (NORCATS)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 29.375%;\"\u003e\n \u003cp\u003eName and contact information for the trial sponsor {5b}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70.625%;\"\u003e\n \u003cp\u003eHelse Bergen HF with the Department of Addiction Medicine at Haukeland University Hospital, Bergen, Norway is the trial sponsor. Contact person is the head of the department Christian Ohldieck:\u0026nbsp;\u003c/p\u003e\n \u003cp\[email protected]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 29.375%;\"\u003e\n \u003cp\u003eRole of sponsor {5c}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70.625%;\"\u003e\n \u003cp\u003eThe sponsor is completely responsible for the study. The funder has no role in the study design; collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication; or any ultimate authority over any of these activities. The authors are funded by their respective affiliations.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Introduction","content":"\u003cp\u003e\u003cstrong\u003eBackground and rationale {6a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eUse of benzodiazepines is common among people with substance use disorders (SUD) [1-3], with a high prevalence ranging between 61-94% reported in patients with opioid use disorders [4]. Historically, benzodiazepine dependence is recommended to be managed with short-term tapering regimens combined with non-pharmacological and psychological interventions [4,5]. The effect and safety of short-term detoxification including benzodiazepine tapering in patients with SUD is uncertain [6,7]. Tapering interventions and complete abstinence-based strategies have often not been successful, especially among those with severe and long-term dependence [6]. Short-term detoxification is even attributed to an increased risk of life-threatening complications such as seizures and psychotic reactions [8]. Although substitution treatment is not recommended, a large proportion of benzodiazepine dependent patients have continuously been prescribed benzodiazepines, mainly by primary care physicians [9]. Recent research has also confirmed such prescriptions among 30-50% of the Norwegian patients undergoing opioid agonist therapy (OAT) [1]. The Norwegian OAT guidelines recommend gradual tapering and discontinuation of benzodiazepines as the main recommendation, but also propose to consider benzodiazepine stabilizing agonist treatment for patients with severe and long-lasting dependence who have not succeeded in tapering [10]. It is acknowledged that there is limited research supporting this recommendation, however user-reported and clinical experiences indicate that such approaches may be beneficial in improving the quality of life for\u0026nbsp;some patients with long-term and regular use of benzodiazepines.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eReports have shown that concurrent dependency to benzodiazepines and other addictive substances in patients undergoing OAT complicates the treatment course and reduces the chance to improve health and quality of life [1,11]. These patients demonstrate more frequently symptoms of mental illness, use multiple substances, and have more impaired psychosocial functioning compared to patients without benzodiazepine dependence [12]. It is uncertain whether these findings are due to differences between patient groups (e.g., in the extent of mental illness) and/or use of benzodiazepines per se. Clinical experiences indicate that the majority relapses and continues to use benzodiazepines acquired illicitly despite tapering attempts [4,12,13]. There is a lack of evidence on the effect and safety of standard treatment approaches as well as benzodiazepine substitution treatment in populations with severe SUD including those undergoing OAT [5,14]. In a small, non-randomized controlled study on patients undergoing methadone maintenance treatment (total n=66; 33 in each group), the proportion using illegally acquired benzodiazepines was lower in patients receiving benzodiazepine substitution treatment compared with patients who tapered these agents and discontinued (77% vs. 27%, and 65% vs. 14%) after 2 and 12 months, respectively [15]\u003cstrong\u003e.\u0026nbsp;\u003c/strong\u003eThus, there is an urgent need to conduct randomized controlled trials on the benefit and risks of benzodiazepine stabilizing agonist treatment for patients with benzodiazepine dependence undergoing OAT as compared to standard treatment approaches.\u003c/p\u003e\n\u003cp\u003eUse of benzodiazepines may in turn be related to several clinical characteristics and symptoms. Generally, it is associated with impaired cognitive functioning, in addition to an increased risk of violent behavior [16]. However, there is uncertainty to which degree these can be causally inferred. Some register-based studies have shown that patients undergoing OAT who were prescribed benzodiazepines had an increased risk of overdose death compared with those without such prescriptions [17,18]. In a Norwegian study, clonazepam was often recognized as a contributing agent in emergency units for drug intoxications [7]. In another study, it was frequently found in addition to opioids in toxicological analyses related to overdose death [19]. This is contrary to the Norwegian prescribing pattern in 2014\u0026ndash;15 where the prescription rate of both diazepam and oxazepam (less potent than clonazepam) were 50% higher than of clonazepam. Additionally, police confiscations clearly confirm the distribution of the most common illicitly acquired benzodiazepines (among others clonazepam and alprazolam, but not diazepam or oxazepam) in drug-related intoxications [7,19]. These findings support that the increased risk is related to use of more potent and illicitly acquired benzodiazepines such as clonazepam and alprazolam rather than controlled use of prescription ones such as diazepam and oxazepam which usually are less potent and seldom used illicitly in Norway. A\u0026nbsp;large comparative effectiveness study, however, among 353 576 patients receiving stable long-term treatment with benzodiazepines showed that discontinuation was associated with small absolute increases in mortality and other potential harms, including nonfatal overdose, suicide attempt, suicidal ideation, and emergency department visits\u0026nbsp;[20].\u0026nbsp;These results suggest benzodiazepine discontinuation among patients prescribed for stable long-term treatment may be associated with unanticipated harms, and that efforts to promote discontinuation should carefully consider the potential risks of discontinuation relative to continuation.\u003c/p\u003e\n\u003cp\u003eDespite the high disease burden and related risks among people with benzodiazepine dependence, evidence on effective treatment methods is lacking. We will conduct a multi-center randomized controlled trial on patients undergoing OAT with long-lasting and hard-to-treat concurrent benzodiazepine dependence to study the efficacy and safety of benzodiazepine agonist treatment.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjectives {7}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe overall objective of the trial is to investigate the effect of stabilizing agonist treatment with prescribed benzodiazepines (diazepam or oxazepam) in reducing the use of illicitly acquired potent benzodiazepines (clonazepam and alprazolam) among people on OAT with benzodiazepine dependence compared to tapering. The central hypothesis is that stabilizing treatment with less potent prescribed benzodiazepines such as\u0026nbsp;diazepam and oxazepam in patients with severe and long-lasting benzodiazepine dependence will result in significant reduction in use of illicit and more potent benzodiazepines such as clonazepam and alprazolam. Accordingly, this may reduce risk and improve health and quality of life in this population.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe primary objective of the study is efficacy of stabilizing agonist treatment with daily doses of 15-30 mg diazepam or equipotent doses of 50-100 mg oxazepam in reducing illicitly acquired potent benzodiazepines use measured at 24 weeks intervention. Secondary objectives are to compare mental health symptoms, cognitive functioning, and health-related quality of life between intervention and control groups, as well as differences in violence risk, overdoses, and adverse events. Other secondary objectives are to examine differences in treatment retention and satisfaction, and use of alcohol and other substances between the groups.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial design {8}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis project is a multi-center, randomized controlled, open and flexible dose trial comparing a 26-weeks stabilizing agonist treatment by using diazepam (15-30 mg a day) or oxazepam (50-100 mg a day) with a 20-weeks gradual tapering using the same medications and equivalent initial doses.\u0026nbsp;\u003c/p\u003e"},{"header":"Methods: Participants, interventions and outcomes","content":"\u003cp\u003e\u003cstrong\u003eStudy setting {9}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study will be conducted in outpatient OAT clinics\u0026nbsp;in five\u0026nbsp;Norwegian cities/counties (Bergen/Vestland, T\u0026oslash;nsberg/Vestfold, Skien/Telemark, Fredrikstad/\u0026Oslash;stfold and Troms\u0026oslash;/Trom). In total, 108 patients will be recruited. Potential participants will be prescreened in person by a research nurse or OAT staff, and if potentially eligible invited to attend to a formal screening i.e., eligibility assessment by a physician in line with current clinical practice and trial protocol.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe Department of Addiction Medicine, Haukeland University Hospital (Vestland county, city of Bergen, Norway) is responsible for the treatment and follow-up of more than 1000 patients with opioid dependence receiving OAT, of which almost 35% receive methadone while the remaining mainly receive buprenorphine preparations, seldomly oral morphine depot. All medical interventions are integrated with psychosocial care provided in multidisciplinary outpatient clinics as part of specialist health care system. The outpatient OAT clinics are staffed by medical consultants specialized in addiction medicine in addition to nurses, social workers, and psychologists. Dependent on the overall functioning level and decisional capacity, the follow-up of the patients ranges from daily observed medication and consultations to weekly take-home doses. All the clinical measurements and laboratory data are recorded in the hospital journal system. A similar OAT model and organization is also applied in the other involved South-East and North region counties as part of specialist health care system in Norway. The four latter centres include approximately 1000 OAT patients in total with similar clinical and sociodemographic characteristics. \u0026nbsp;The applied OAT platform allows frequent and close clinical observations and follow-up of the participants to increase safety and to ensure a high quality of data collected.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEligibility criteria {10}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study population is treatment-seeking adults undergoing OAT who fulfil all the inclusion criteria and do not have any of the exclusion criteria.\u003c/p\u003e\n\u003cp\u003eInclusion criteria are including:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eBenzodiazepine dependence according to\u0026nbsp;International Statistical Classification of Diseases and Related Health Problems 10\u003csup\u003eth\u003c/sup\u003e Revision\u0026nbsp;(ICD-10) under the following conditions:\u0026nbsp;\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e- Minimum duration of \u0026ge;5 recent years (as a cut-off for severity of dependence)\u003c/p\u003e\n\u003cp\u003e- Self-reported use of \u0026ge;5 days a week during last month\u003c/p\u003e\n\u003cp\u003e-\u0026nbsp; Minimum dose used daily is equivalent to \u0026ge;15 mg diazepam\u0026nbsp;\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003ePrevious at least one failed attempt at outpatient or inpatient tapering of benzodiazepines\u003c/li\u003e\n \u003cli\u003eCapable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form and in the study protocol.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eUse of illicitly acquired potent benzodiazepines (clonazepam and/or alprazolam) will be verified by a high specific urine drug screening test (UPLC MS-MS) at baseline. Failure to respond to previous treatment is defined as relapse to dependent use during tapering or after completing treatment.\u003c/p\u003e\n\u003cp\u003eExclusion criteria\u0026nbsp;are including:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eSevere respiratory failure (Global initiative for Chronic Obstructive Lung Disease \u0026ldquo;GOLD\u0026rdquo; grade 3-4)\u003c/li\u003e\n \u003cli\u003eHigh risk of violent behavior (current violence episodes i.e., during the last 6 months)\u003c/li\u003e\n \u003cli\u003eHigh risk of substance related overdose (current overdoses i.e., during the last 3 months)\u003c/li\u003e\n \u003cli\u003eSevere cognitive impairment (IQ\u0026lt;70; assessed if needed based on clinical decision)\u003c/li\u003e\n \u003cli\u003eSevere psychosis (current psychotic symptoms and functioning i.e., during the last 6 months based on clinical decision)\u003c/li\u003e\n \u003cli\u003eSevere depression and high suicide risk (current episodes i.e., during the last 6 months based on clinical decision)\u003c/li\u003e\n \u003cli\u003ePatients who are already being stabilized with continuously prescribed benzodiazepines\u0026nbsp;(including diazepam or oxazepam during the last 4 weeks prior to baseline assessment)\u003c/li\u003e\n \u003cli\u003ePregnancy and breastfeeding (female participants should use a safe method of contraception; in doubtful cases, a negative pregnancy test will be required)\u003c/li\u003e\n \u003cli\u003eChallenges related to ability to understand, consent, or willingness to collaborate in following-up of the study protocol.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eThe risk of possible drug interactions will be considered individually at the time of eligibility assessments, which in some cases may result in exclusion from participation. Combination of benzodiazepines with opioids, alcohol and other central nervous system depressants may cause respiratory depression and increase the risk of overdose. Otherwise, there are few known clinical important interactions between benzodiazepines and other medications.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWho will take informed consent? {26a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipants will receive comprehensive information about the study during recruitment visits to ensure informed consent and assent. Trained research staff will obtain written informed consent from the patients who wish to attend.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdditional consent provisions for collection and use of participant data and biological specimens {26b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipants will be asked if they are willing to participate in an ancillary qualitative study investigating self-perceived effects of the interventions. If so, an additional written informed consent will be obtained.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInterventions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExplanation for the choice of comparators {6b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe comparator is\u0026nbsp;tapering with diazepam or oxazepam in maximum 20 weeks according to the applied clinical procedure in OAT clinics which is based on the Norwegian OAT guidelines recommending gradual tapering and discontinuation of benzodiazepines as the standard treatment of benzodiazepine dependence.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIntervention description {11a}\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;Participants in the intervention arm\u0026nbsp;will receive\u0026nbsp;stabilizing agonist treatment with 15-30 mg/d diazepam or equivalent dosages of 50-100 mg/d oxazepam in 26 weeks. Participants in the standard arm\u0026nbsp;will receive\u0026nbsp;tapering with diazepam or oxazepam in maximum 20 weeks according to the applied clinical procedure in OAT clinics.\u0026nbsp;The type of benzodiazepine prescribed (diazepam or oxazepam), the start dosages and the duration of tapering will be based on the degree of dependence, the dosages of illicit benzodiazepines used prior to study entrance and the individual\u0026rsquo;s clinical condition\u0026nbsp;[21]. Accordingly, a customized tapering plan will be suggested to each participant within the framework of the study procedures.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFor both arms, treatment initiation and follow-up will be conducted at OAT outpatient clinic where they already receive OAT and relevant care including voluntary psychosocial interventions.\u0026nbsp;The study medications will be prescribed by the physicians in the OAT clinics in accordance with the protocol and will be delivered either at the OAT clinic or at a pharmacy\u0026nbsp;in line with the applied standards for OAT follow-up.\u0026nbsp;Commercial tablets and standard medication\u0026nbsp;labels will be used, tagged with trial log numbers.\u0026nbsp;All the costs related to the medications, preparations and observed intakes will be covered by the OAT clinics (through public assigned funds). The medications will be used in line with national guidelines,\u0026nbsp;and the project will strive to comply with the Good Clinical Practice (GCP)\u0026nbsp;[10, 22].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCriteria for discontinuing or modifying allocated interventions {11b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe stop criteria for the individual participant are defined at least based on non-compliance, unexpected adverse events, or other safety considerations such as use of large amounts of highly potent street benzodiazepines with clinically observed signs of overdosing. In addition, medication can be withheld in the case of deviation from urinary test procedures that can affect measuring the trial primary outcome.\u0026nbsp;Participants who have discontinued protocol-based treatment will be motivated to continue to participate in all remaining research interviews and assessments. For those participants who revoke their consent for the entire study, no further data will be collected from the participant.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStrategies to improve adherence to interventions {11c}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMedication choice between oxazepam and diazepam will be individualized based on patient preferences, medical history, and present health condition. The prescription method will also be assessed individually and based on the patient\u0026rsquo;s treatment course (i.e., prescribed by the clinic physician and ordered through the related clinic or pharmacy). All participants will be encouraged to initiate the treatment according to the protocol,\u0026nbsp;with data collected on prescription pickup and treatment initiation dates. In addition, for those receiving medications in the clinics, frequencies, and observation of doses taken will be noted. Self-reported data on medication adherence and compliance will be obtained for all participants. Medication adherence and compliance will be assessed through a combination of prescription pickup frequency, self-reported adherence, observed intake and urinary tests.\u003c/p\u003e\n\u003cp\u003eRelated\u0026nbsp;authorized clinical study-monitoring organs in each health county will visit the study sites on a regular basis to ensure the following requirements: informed consent process, reporting of adverse events and all other safety data, adherence to protocol, maintenance of required regulatory documents, facilities, and data completion on the case report files (CRFs) including source data verification. Additionally, a data monitoring committee (DMC)\u0026nbsp;comprising two independent professionals (a clinician and a researcher) and a statistician will ensure the safety and wellbeing of trial patients and will assist and advice the coordinating\u0026nbsp;and principal investigators to protect the validity and credibility of the trial.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRelevant concomitant care permitted or prohibited during the trial {11d}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll the participants will receive OAT and the related care as usual. Study medications will mainly be administered under supervision by the OAT clinic or pharmacy staff. Individually assessed, the participants will receive some of the doses as take-home-dosages for self-administration. Assessments of observed intake frequency and \u0026ldquo;take-home doses\u0026rdquo; will follow the same agreement that applies to OAT medications, and any changes will be assessed by the prescribing OAT physician after discussion in interdisciplinary team. Project managers will be informed of any changes. In any case, all participants should attend the OAT outpatient clinic daily or at least once weekly for clinical observations. Every participant should, regardless of the delivery agreement, have frequently clinical observations and assessments for the first two weeks after starting prescription (in both study arms) to ensure treatment safety. After this period, they follow the delivery agreement as before.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eClinical and biological follow-up of participants and systematic report of potential adverse effects will be organised according to international GCP guidelines.\u0026nbsp;The\u0026nbsp;participants\u0026nbsp;will be assigned to the scheduled assessments by research nurses and/or clinic physicians in line with the study protocol.\u0026nbsp;The assessments will be performed at baseline, and at week 24 in addition to a follow-up assessment at week 52 after entering the trial.\u0026nbsp;The OAT staff or research nurses will follow up the participants weekly at OAT clinics or by home-based visits if needed, with consultations including self-reports on illicit use of benzodiazepines and other substances, adverse events as well as monthly randomized urine drug screening tests during the trial period (Figure 1 and Table 1).\u0026nbsp;(please insert Figure 1 here).\u003cstrong\u003e\u003cbr\u003e\u0026nbsp;Provisions for post-trial care {30}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAt the end of trial period, each participant will be individually assessed to receive further clinical follow-up as indicated.\u0026nbsp;Participants who receive stabilizing treatment with prescription benzodiazepines during the 26-week study period will undergo individual clinical assessments upon trial completion. Some participants may continue with stabilizing treatment, while others will have their prescriptions stepped down and discontinued following current guidelines. Participants in the standard treatment arm will receive ongoing treatment and follow-up using conventional approaches after tapering of medications.\u003c/p\u003e\n\u003cp\u003eParticipants will be informed about these individual assessments at the project\u0026rsquo;s conclusion. Clinical observations throughout the study period will provide insights into outcomes for participants in each study arm. Decision-making following the project\u0026apos;s conclusion will be based on these outcomes, aligning with the conditions governing benzodiazepine continuation outlined in the study protocol. Assessments will occur both upon completion of the intervention (after week 26) and at the end of the project period (after week 52).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcomes {12}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePrimary outcome measure is:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eThe difference between the groups in the use of illicit benzodiazepines based on supervised urine drug screening tests measured at week 24.\u0026nbsp;\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eSecondary outcome measures collected at baseline and week 24 will include:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eMental health symptoms score using Hopkins symptom checklist (SCL-10) [23]\u003c/li\u003e\n \u003cli\u003eHealth-related quality of life score using\u0026nbsp;5-dimensional,\u0026nbsp;5-level\u0026nbsp;Euro Quality of life questionnaire\u0026nbsp;(EQ-5D-5L) [24]\u003c/li\u003e\n \u003cli\u003eReaction time for cognitive performance using a simple reaction time test [25]\u003c/li\u003e\n \u003cli\u003eRisk of violence behavior using Br\u0026oslash;set violence checklist (BVC) [26]\u003c/li\u003e\n \u003cli\u003eSatisfaction with the treatment using \u003cem\u003evisual analogue scale\u003c/em\u003e (VAS) from 0-10\u003c/li\u003e\n \u003cli\u003eRetention rate in OAT (number of drop-out days during the trial period)\u003c/li\u003e\n \u003cli\u003eFrequency of use of other illicit substances and alcohol by self-reports and urine drug screening tests, and use of illicit benzodiazepines by self-reports\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eNumber of non-fatal overdoses and death (if any)\u003c/li\u003e\n \u003cli\u003eCost-effectiveness of intervention\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eParticipant timeline {13}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe time schedule of enrolment, interventions, assessments, and visits for participants is shown in table 1 (please insert here).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSample size {14}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe sample size calculation is based on clinical experiences due to no existing empiric assumption. We set the minimal clinically relevant difference between the groups to 0.3, and the required power to 0.8 at two-sided significance level of 0.05. There is no valid data to estimate the standard deviation. Assuming a risk of 0.5 to 0.8 for the use of illicit benzodiazepines in the standard treatment group, we need 43 patients per group. Assuming a drop-out rate of 20% we need 54 patients in each group, 108 in total, to achieve sufficient power\u0026nbsp;[27]. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRecruitment {15}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEnrollment will be commenced during 2022 and continue until the required number of eligible participants are enrolled in the trial. For both arms, all the clinical stages of the study\u0026mdash;including recruitment, information, obtaining written consent, clinical interviews, and completing the study surveys using appropriate instruments, and treatments\u0026mdash;will be performed by research nurses and/or physicians to ensure independency. Five OAT sites are involved in the trial conduction to obtain the required sample size.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAssignment of interventions: allocation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSequence generation {16a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEligible participants will be randomized digitally with a 1:1 ratio into intervention or standard treatment for inclusion in the trial. A computer-generated blocked, site stratified randomization schedule will be developed by an independent statistician and uploaded to the study database.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConcealment mechanism {16b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRandomization will be performed by research nurse or the trial site investigator within the study database and technically secured against manipulation in the database.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eImplementation {16c}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe allocation sequence will be generated by an independent statistician. The research nurses or physicians will enrol participants in the study and assign them to the interventions.\u0026nbsp;An independent statistician not involved in providing the clinical data will analyze the data collected.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAssignment of interventions: Blinding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWho will be blinded {17a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eComplete blinding is not considered practiced although some masking measures such as blinded analyses of the data will be taken (blinding for the trial analytes). Randomization will be disclosed to the researchers, participants and clinical staff providing treatment and follow-up. Patients will be informed of key elements in the delivery of the respective intervention or standard treatment and follow-up they are randomized to, but not on the hypotheses for the study.\u0026nbsp;\u003cstrong\u003e\u003cbr\u003e\u0026nbsp;Procedure for unblinding if needed {17b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable. The trial is not blinded for the participants, researchers, or care givers.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData collection and management\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans for assessment and collection of outcomes {18a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo ensure correct operation according to standard operating procedures (SOPs) all system users will be trained and evaluated on a regular basis. The research nurses will collect the trial data at baseline and at trial week 24, in addition to weekly self-reported substance use, adverse events and other research-related data, as well as the randomized monthly urinary screen tests according to table 1.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe urine drug screening tests\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003eas the measure of primary outcome will be taken at the OAT clinics or other planned units under the observation of the staff. A high specific laboratory analysis method (UPLC MS-MS) will be used to differentiate between the benzodiazepine types identified in the urinary samples (those illicitly acquired i.e., clonazepam and alprazolam, and the prescribed ones i.e., diazepam and oxazepam).\u0026nbsp;The samples will be taken randomly in one out of the four weeks in each month. Randomization will be programmed by an independent researcher and is aimed to reduce the effect of any variations in the intake of illicit benzodiazepines between the intervention and the standard arm in relation to the time of sampling. The patients will be informed Monday of the week that they need to provide an observed urinary test before Friday the given week. In case of no show for a urine sample, the patient will receive a warning to take it the subsequent week (up to once). In the event of a missing urine sample or two delays in a month, study medication will be stopped.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOther outcomes will be assessed using standard or semi-structured questionnaires based on table 1.\u0026nbsp;The study assessments will be completed for each participant at scheduled visits during the study. Secondary endpoints assessed are: \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eTreatment initiation and medication adherence:\u0026nbsp;\u003c/em\u003eTreatment initiation will be assessed as the proportion taking at least one tablet while medication adherence will assess the proportion taking their medicines at least 6 days per week (\u0026gt;80%) throughout the entire treatment period. Both outcomes will be assessed and reported as a combination of self-reported adherence and observed intake. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eWeekly self-reported substance use\u003c/em\u003e: The weekly self-reported substance use will be assessed for each week and at week 24.\u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eChanges in mental health symptoms\u003c/em\u003e:\u0026nbsp;Mental health symptoms will be assessed\u0026nbsp;using Hopkins symptom checklist score (SCL-10)\u0026nbsp;at baseline, and at week 24.\u0026nbsp;The SCL-10 is a structured self-administrated instrument to measure symptoms of mental health disorders and psychological distress. Scores range from 1 (not bothered at all) to 4 (extremely bothered) for each item. To derive the mean item score, the scores will be summed up and divided by the number of items. A mean score of 1.85 or higher will indicate the presence of symptoms of mental and psychological disorders. The records at week 24 will be compared to baseline across the arms. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eChanges in quality of life\u003c/em\u003e:\u0026nbsp;Quality of life will be assessed using\u0026nbsp;EQ-5D-5L\u0026nbsp;at baseline and week 24.\u0026nbsp;The instrument describes and values quality of life, consisting of the EQ visual analog scale and the EQ-5D descriptive system. The EQ VAS records the patient\u0026apos;s self-reported health on a vertical scale ranging from 0 \u0026quot;Worst Health You Can Imagine\u0026quot; to 100 \u0026quot;Best Health You Can Imagine\u0026quot;, reflecting the patient\u0026apos;s own opinion about the quality of their health condition. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe Descriptive System includes five dimensions (5D): mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has five levels (5L): No problems, minor problems, moderate problems, serious problems and extreme problems. Patients will indicate their health status by selecting the most appropriate statement in each dimension, resulting in a 5-digit number that describes their health status. \u0026nbsp;The records at week 24 will be compared to baseline across the arms.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eRisk of violence\u003c/em\u003e: This\u0026nbsp;secondary outcome will be assessed using\u0026nbsp;the BVC\u0026nbsp;at baseline and week 24.\u0026nbsp;BVC is a 6-item checklist designed to predict imminent violent behavior within a 24-hour perspective. The 6 items that reflect that mood setting are confused, irritable, boisterous, physical threats, verbal threats, and attacking objects. Each item is scored as 0 for the absence of behavior and 1 for the presence of behavior, with a maximum total score of 6. The records at week 24 will be compared to baseline across the arms.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eReaction time (cognitive performance\u003c/em\u003e): The cognitive performance will be based on the reaction time test (measured 3 consequent times according to the time used to react in milliseconds) at week 24 compared to the baseline. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSatisfaction with treatment:\u0026nbsp;\u003c/em\u003eSatisfaction with the treatment will be assessed at week 24 after initiation of treatment compared to baseline using VAS from 0-100 where 0 means no satisfaction and 100 means very satisfied. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans to promote participant retention and complete follow-up {18b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStudy participants will be encouraged to retain and complete study follow-up. They will also receive a limited economic compensation (500 Norwegian Krones) for the use of time and to increase the motivation to complete the data collections, measurements, and assessments. A list of outcome data will be collected for participants who discontinue or deviate from intervention protocols.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData management {19}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll the OAT clinics in the participating sites will use electronic CRFs that will be entered online in a study database through the data collection softwares (REDCap and Viedoc). Alternatively, paper based CRF will be used by the sites, and then the collected data will be entered in the central electronic CRF by coordinating research nurse. The softwares is accredited by Helse Bergen for health research and clinical integration. A central data manager at Helse Bergen will assist in designing the CRF, train data collectors in use of the CRF and aid data export.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConfidentiality {27}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOnly authorised study personnel including the principal investigator, research nurses and coordinating physicians will have access to CRFs and supporting documents. Data capture and storage will be undertaken using computer systems compliant to GCP. The research data will be stored in an encrypted data server for research with access limited for the principal investigators and coordinating research nurse. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable. Genetic specimens will not be taken in this trial.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical methods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical methods for primary and secondary outcomes {20a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAnalysis methods will follow the CONSORT guidelines\u0026nbsp;as far as possible\u0026nbsp;[28]. All tests will be two-sided. Descriptive results and the estimated efficacy will be presented with 95% confidence intervals (CI). Categorical variables will be summarized as percentages and continuous variables as medians with interquartile ranges or means with standard deviations for variables with a Gaussian distribution. Analyses for the\u0026nbsp;primary\u0026nbsp;endpoint will be undertaken on an intention-to-treat (ITT) basis and reported upon as such.\u0026nbsp;All the randomized and eligible participants will be analysed based on initial group allocation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe main endpoint is difference between the two study arms in the use of illicit benzodiazepines (as assessed by monthly supervised urine drug screening tests) measured at week 24.\u0026nbsp;The primary endpoint is then dichotomous. The difference between the groups at the primary time point (week 24) will be reported using cross table, risk difference and odds ratio with 95% confidence intervals and tested using the chi-square-test, asymptotic or exact depending on the marginal distributions.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFor the analyses\u0026nbsp;of\u0026nbsp;secondary endpoints\u0026nbsp;and based\u0026nbsp;on the type of outcomes,\u0026nbsp;appropriate analysis methods will be used including ANCOVA,\u0026nbsp;t-test, cross table, risk difference and odds ratio with confidence intervals as well as the chi-square-test, asymptotic or exact depending on the marginal distributions.\u0026nbsp;We have three types of secondary outcomes:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eContinuous outcomes with baseline measurement:\u003c/em\u003e These include weekly/monthly urinary tests and weekly self-reports on illicit drug and alcohol use, and weekly self-reports on illicit benzodiazepine use. These outcomes are analyzed using the ANCOVA, i.e., the linear regression model of the outcome at the primary time point (24 weeks) depending on the randomization group adjusted for the baseline value of the outcome. The mean difference with confidence interval, coefficient with confidence interval and the p-value will be reported.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eContinuous outcomes without baseline measurement:\u003c/em\u003e These include adverse events. These outcomes are analyzed using the t-test for differences in the outcome at the primary time point (24 weeks). The mean difference with confidence interval and the p-value will be reported.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eDichotomous outcomes:\u003c/em\u003e These include SCL-10, EQ-5D-5L, BVC, reaction time, treatment retention, overdose, and treatment satisfaction. These outcomes are analyzed in the same way as for the primary outcome, i.e., measuring the difference between the groups at the primary time point (24 weeks) and will be reported using the cross table, risk difference and odds ratio with confidence intervals and tested using the chi-square-test, asymptotic or exact depending on the marginal distributions.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAdditionally, we will estimate a linear mixed effects model for continuous outcome variables at all time points depending on time, randomization group and the interaction between time and randomization group, adjusted using an individual random intercept. We will use a simple contrast. For the outcomes appearing to have linear dependence on time we will also use a linear contrast.\u0026nbsp;For all regression models we will present the regression table, and for the linear mixed model we will provide the graphics with mean and 95% confidence interval for each follow up time point.\u0026nbsp;For the dichotomous variables, we will provide a bar plot of the proportions for each available time point.\u0026nbsp;The ITT analyses will be repeated with the per-protocol dataset.\u0026nbsp;There will be conducted per-protocol analyses as part of sensitivity analyses.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInterim analyses {21b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e An interim analysis for efficacy of the primary endpoint will be done when 50% of planned sample size is assessed at week 24. We will use a group sequential design without futility and the O\u0026rsquo;Brien-Fleming alpha spending approach. The interim analysis will be performed by the DMC. The DMC will give a recommendation whether the study should be continued or stopped. Even if not in the model, the DMC can recommend stopping the study for futility\u0026nbsp;\u0026nbsp;[29]\u003cem\u003e. \u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods for additional analyses (e.g., subgroup analyses) {20b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll patients enrolled in the study will be evaluated with respect to safety-related outcomes according to the treatment they receive. Safety analyses will include summaries of the incidence of all adverse events and serious adverse events that are possibly or probably related to the study intervention and occur during the study treatment period or within 30 days of the last dose of study treatment. Safety analysis will be specified by DMC.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSub-group analyses will be conducted for exploratory purposes only, due to their inherently low statistical power.\u0026nbsp;These analyses will focus on the primary endpoint and confirmatory secondary endpoints to assess the consistency of the investigational intervention effect across various subgroups such as age groups and sex.\u0026nbsp;If a subgroup contains fewer than 10% of the total participants, the subgroup categories may be redefined. The analyses will be conducted using a test for heterogeneity and results will be presented on forest plots presenting the estimated study arm difference and 95% confidence intervals. Further details on the statistical analysis will be provided in the statistical analysis plan.\u003cem\u003e \u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eA cost-effectiveness analysis will employ a prospective economic evaluation approach. Effectiveness will be measured with quality adjusted life years (QALYs), building on primary and secondary results combined with a prospective Markov model. Cost data will be collected alongside the clinical trial employing both healthcare and societal perspective. The\u0026nbsp;analysis will follow the current guidelines and will be conducted by a health economist\u0026nbsp;[30].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipants who withdraw from the study treatment will not be censored, as treatment discontinuation is likely to be related to allocation. Deaths will be censored at the last outcome measurement.\u0026nbsp;\u0026nbsp;We will also have a sensitivity analysis assuming missing urine samples is similar as last urine sample taken (to manage missed data for the primary outcome measure). Robustness of the primary outcome will be checked with sensitivity analyses considering censoring and adjusting for potential baseline imbalances.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans to give access to the full protocol, participant level-data and statistical code {31c}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere are no plans for granting public access to the full protocol, participant-level dataset, and statistical code. However, this will be considered by the sponsor if indicated.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOversight and monitoring\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eComposition of the coordinating center and trial steering committee {5d}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe trial will be administrated and coordinated by Bergen Addiction Research Group (BAR) and Norwegian Research Centre for Agonist Treatment of Substance Use Disorders (NORCATS) at Department of Addiction Medicine, Haukeland University Hospital, Vestland, Bergen in collaboration with the other sites at Vestfold, Telemark, \u0026Oslash;stfold and Troms. The research consortium brings together and profits from expertise on addiction medicine and clinical trial implementation in the interdisciplinary and highly specialized clinics together with research expertise from BAR and NORCATS in The Department of Addiction Medicine at Haukeland University Hospital and University of Bergen, in addition to the user expertise ProLAR employed in the department. Then, the project group is multidisciplinary, involving national and local collaborators, including several partners with extensive clinical experience, members with user perspectives, and researchers from related field. The coordination unit will be led by the principal investigator in close cooperation with the project manager and will have ongoing communication as well as regular meetings with the other sites.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe Steering committee (SC)\u0026nbsp;will be responsible for the conduct of the study. The coordination unit will report regularly to the SC for updates on trial progress and potential issues. The SC is the trial decision body, for all scientific and administrative aspects. It will send technical reports to the funder, ethical committees, and regulatory bodies particularly the monitoring organs in Helse Bergen, and financial reports to the funder. SC participants will meet on regular conference calls with customized frequencies.\u003c/p\u003e\n\u003cp\u003eThe coordinating and managing unit will oversee the day-to-day conduct of the trial. It will centralise all study information and will report to the steering committee. The coordination unit will coordinate analysis and writing of different outcomes from the study. The trial coordination will also rely on other units, which can be considered as SC sub-committees. These are including:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eClinical care unit\u003c/em\u003e which will oversee elaborating the clinical procedures for the trial. It will also support the local physicians on the treatment protocols. Physicians in the coordination unit, and the participating sites and coordinating research nurse will be members of this unit.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eStudy site units\u003c/em\u003e which will oversee day-to-day implementation at each study clinic in collaboration with the coordination unit. The clinic leaders will generally be involved in the site units.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eComposition of the data monitoring committee, its role and reporting structure {21a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe main aim of DMC is to ensure the safety and wellbeing of trial patients and to assist and advise the coordinating investigator, steering committee, and the principal investigators, so as to protect the validity and credibility of the trial. The DMC will be comprising two independent clinicians and researchers and a statistician.\u0026nbsp;An agreed DMC charter will describe the roles and responsibilities of the committee, including the timing of meetings, methods of providing information to and from the DMC, frequency and format of meetings, statistical issues, and relationships with other committees. The charter will be in place before the first patient is included.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdverse event reporting and harms {22}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePotential adverse events among participants will be managed according to the treatment guidelines\u0026nbsp;[10]. A low rate of adverse effects and toxicity is expected with the applied benzodiazepines. Complete lists on the reported adverse effects are described in the summaries of product characteristics for oxazepam and diazepam\u0026nbsp;[31,32] as the reference safety information. All serious adverse events (SAE) reported to the sponsor will be assessed against the reference safety information to consider whether the event is unexpected (suspected unexpected serious adverse reaction \u0026ldquo;SUSAR\u0026rdquo;) or not.\u0026nbsp;Regular clinical observations by the OAT clinic staff and physicians will secure prompt identification of potential adverse events. Any side effects or suspicious clinical conditions such as symptoms of intoxication that are observed by the clinic staff or registered using weekly questionaries, will promptly be reported to the responsible clinic physicians and the trial investigator. Emergency intoxication care and acute antidote medication (naloxone) will be available at the involved OAT clinics, and further transport to the emergency unit will be secured when close and continuous clinical monitoring is needed.\u0026nbsp;Clinical and biological safety will be assessed according to the standardized scales of toxicity\u0026nbsp;[33].\u0026nbsp;All unexplained grade III or IV events will lead to temporary interruption of the study medication before a new assessment is made by clinic physician and study investigators. A rapid report system for the management of severe SAE and SUSAR will be available.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFrequency and plans for auditing trial conduct {23}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe decision to initiate the study will be taken in the agreement between the coordination unit and the sponsor. The study sponsor may wish to do audit visits on sites to ensure the trial is conducted according to the protocol and GCP guidelines.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans for communicating important protocol amendments to relevant parties (e.g., trial participants, ethical committees) {25}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAny important\u0026nbsp;protocol modifications (e.g., changes to eligibility criteria, outcomes, or analyses) will be communicated to relevant parties (e.g., investigators, ethical committees, trial participants, trial registries, journals, and regulatory organs).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDissemination plans {31a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe findings will be presented in relevant national and international conferences and will also be presented to politicians and the health and welfare administration at all levels. The aspect in this study is considered relevant to a public audience, and several of the researchers has extensive experience with communicating research to the public through various media, as well as informing patients and other health workers. The results from the study will also be published in articles in peer-reviewed scientific journals in line with the ICMJE guidelines [34]. Open access journals indexed in PubMed/Medline will be preferred.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis is the first randomized controlled trial of benzodiazepine stabilizing agonist treatment for benzodiazepine dependence. The research project will provide knowledge on the impact of such intervention on patient outcomes. We will assess efficacy and safety of stabilizing treatment with prescribed benzodiazepines compared to benzodiazepine tapering and discontinuation regarding use of illicit benzodiazepines and accordingly well-being of patients with concurrent benzodiazepine and opioid dependence undergoing OAT.\u003c/p\u003e \u003cp\u003eOur trial involves some limitations and several strengths. For the trial it is difficult to ensure complete blinding, however, some masking measures will be taken including blinded assessments of the study analyses by independent research staff. The study is also funded from public sources to ensure independency form pharmaceutical companies. We also have a biological primary outcome. Thus, substantial information biases are considered unlikely. The study is individually randomized, which minimizes potential confounding. The proposed sample size is powered to detect a medium effect size in between-group differences in the primary outcome. Participants will be closely monitored with weekly clinic visits and research reviews at outpatient OAT clinics where they usually are being treated and followed-up. This will promote participants\u0026rsquo; safety and retention in the study. The study protocol proposes to deliver the medication in an outpatient setting allowing participants take-home dosages to more closely mimic the service delivery situations in which the medication will be used. However, absence of a structured psychosocial intervention as a supplementary treatment, and not fully observed daily dosages are among the trial limitations. Other limitations include a non-blinded design and a possible (although low) risk of using illicitly acquired diazepam and/or oxazepam which cannot be detected by urinary analyses. However, the results of self-reported use of illicit benzodiazepines can provide additive information on the drug use patterns.\u003c/p\u003e \u003cp\u003eIf the intervention is found to be efficacious and safe, it will be considered one of the options to standard treatment of patients with opioid and benzodiazepine co-dependency.\u003c/p\u003e"},{"header":"Trial status","content":"\u003cp\u003eRecruiting started in September 2022. The current protocol is version 4.0 of 4-4-2024. Currently (5th of Aug 2024), we included 62 patients. Patient recruitment is estimated to be completed around December 2025.\u003c/p\u003e "},{"header":"Abbreviations","content":"\u003cp\u003eAE Adverse event \u003c/p\u003e\n\u003cp\u003eANRS Adults scaling instrument to grade the severity of adverse events\u003c/p\u003e\n\u003cp\u003eBAR Bergen Addiction Research\u003c/p\u003e\n\u003cp\u003eBVC Br\u0026oslash;set violence checklist \u003c/p\u003e\n\u003cp\u003eCI Confidence interval \u003c/p\u003e\n\u003cp\u003eCONSORT Consolidated Standards of Reporting Trials \u003c/p\u003e\n\u003cp\u003eCRF Case Report Files \u003c/p\u003e\n\u003cp\u003eDMC Data Monitoring Committee \u003c/p\u003e\n\u003cp\u003eEQ-5D-5L Euro Quality of life, 5-dimensional, 5-level questionnaire\u003c/p\u003e\n\u003cp\u003eGCP Good Clinical Practice \u003c/p\u003e\n\u003cp\u003eICMJE International Committee of Medical Journal Editors \u003c/p\u003e\n\u003cp\u003eMD Medical doctor \u003c/p\u003e\n\u003cp\u003eNORCATS Norwegian Research Center for Agonist Treatment of Substance Use Disorders \u003c/p\u003e\n\u003cp\u003eOAT Opioid agonist treatment \u003c/p\u003e\n\u003cp\u003ePhD A Doctor of Philosophy \u003c/p\u003e\n\u003cp\u003eProLAR User organisation for patients receiving OAT in Norway\u003c/p\u003e\n\u003cp\u003eREC Regional Ethical Committee \u003c/p\u003e\n\u003cp\u003eSAE Severe adverse event \u003c/p\u003e\n\u003cp\u003eSC Steering committee \u003c/p\u003e\n\u003cp\u003eSOP Standard Operating Procedure \u003c/p\u003e\n\u003cp\u003eSPIRIT Standard Protocol Items: Recommendations for Interventional Trials \u003c/p\u003e\n\u003cp\u003eVAS Visual analogue scale \u003c/p\u003e\n\u003cp\u003eSCL-10 Symptom Check List \u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe will thank the patients for their time, commitment, and willingness to participate in this trial;\u0026nbsp;all the dedicated clinical and research staff at the Department of Addiction Medicine, Haukeland University Hospital, as well as the other involved hospitals i.e., Vestfold, Telemark, \u0026Oslash;stfold and Troms Hospital trust for their incredible contributions in data collection and follow-up of the participants during the study period; the laboratories at Haukenad University Hospital and St. Olavs Hospital for analyzing the urinary samples; and the responsible monitoring teams and DMC members for the close collaboration and valuable supports and services. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors contributions\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e{31b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll the authors have been involved in design of the study, contributed to implementation and writing\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eprotocol. FC, LTF, KAJ, CO and EML conceived the study and designed it primarily. KAJ, LTF and\u003c/p\u003e\n\u003cp\u003eFC are the principal investigators. KAJ, LTF, FC and JA led statistical analyses. FC wrote the first draft for the paper. All the authors have reviewed the manuscript for intellectual content, and approved the final version of the manuscript.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e{4}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research is supported by public funding sources, and has not received any grants from commercial or not-for-profit sectors. The work is supported by the Norwagian governement [project number R-11141-D11722], Norwagian Research Center for Agonist Treatment of Substance Use Disorders (NORCATS). The funder has no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors are funded by their respective affiliations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;{29}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;{24}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study is approved by regional ethical committee (Reference number 345516- REK Vest) and drug administration authorities in Norway and registered at www.clinicaltrials.gov. Written informed consent will be obtained from all the participants before commencing to the study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;{32}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis manuscript does not contain individual personal data and the participants have given written informed consent for the publication of the study findings.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests statement\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e{28}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have declared that they have no cometing interests.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eVold JH, Skurtveit S, Aas C, Chalabianloo F, Kloster PS, Johansson KA, Fadnes LT. 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Can J Psychiatry. 2006;51:445\u0026ndash;52.\u003c/li\u003e\n\u003cli\u003eSPIRIT (Standard Protocol Items: Recommendations for Interventional Trials). 2013.http://www.spirit-statement.org/\u003c/li\u003e\n\u003cli\u003eDerogatis LR, Lipman RS, Rickels K, Uhlenhuth EH, Covi L. The Hopkins Symptom Checklist (HSCL): a self-report symptom inventory. Behav Sci. 1974;19(1):1-15.\u003c/li\u003e\n\u003cli\u003eHerdman M, Gudex C, Lloyd A, Janssen Mf, Kind P, Parkin D, Bonsel G, Badia X. Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res. 2011;20(10):1727-36.\u003c/li\u003e\n\u003cli\u003eReaction time test (online version). How old are your reactions? https://www.justpark.com/creative/reaction-time-test/. Accessed 15 Aug 2022.\u003c/li\u003e\n\u003cli\u003eAlmvik R, Woods P, Rasmussen K. The Br\u0026oslash;set Violence Checklist: Sensitivity, specificity and interrater reliability. Journal of Interpersonal Violence. 2000;15:1284-96.\u003c/li\u003e\n\u003cli\u003eRosner B. \u003cem\u003eFundamentals of Biostatistics\u003c/em\u003e. 7\u003csup\u003eth\u003c/sup\u003e ed. Boston, MA: Brooks/Cole;2011.\u003c/li\u003e\n\u003cli\u003eMoher D, Schulz KF, Altman DG. The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomised trials. Lancet. 2001;357(9263):1191-94.\u003c/li\u003e\n\u003cli\u003eDAMOCLES Study Group. A proposed charter for clinical trial data monitoring committees: helping them to do their job well. Lancet. 2005;365(9460):711-22.\u003c/li\u003e\n\u003cli\u003eRamsey SD, Willke RJ, Glick H, Reed SD, Augustovski F, Jonsson B, Briggs A, Sullivan SD. Cost-Effectiveness Analysis Alongside Clinical Trials II\u0026mdash;An ISPOR Good Research Practices Task Force Report. Value Health. 2015;18(2):161-72. \u003c/li\u003e\n\u003cli\u003eOksazepam (Sobril). Preparatomtale (SPC). Statens legemiddelverk. Updated April 2021.\u003c/li\u003e\n\u003cli\u003eDiazepam (Valium). Preparatomtale (SPC). Statens legemiddelverk. Updated October 2019.\u003c/li\u003e\n\u003cli\u003eANRS scale to grade the severity of adverse events in adults. 2008. http://www.anrs.fr/content/download/2242/12805/file/ANRS-GradeEI-V1-En-2008.pdf\u003c/li\u003e\n\u003cli\u003eInternational committee of medical journal editors. Updated January 2024. http://www.icmje.org/recommendations/\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table","content":"\u003cp\u003e\u003cstrong\u003eTable 1.\u003c/strong\u003e Schedule of activities during the study period.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" align=\"\" width=\"595\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26.8908%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.9664%;\"\u003e\n \u003cp\u003ePre-screening and screening by research nurse/physician\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.2857%;\"\u003e\n \u003cp\u003eAssessment at Baseline by research nurse/physician\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.2857%;\"\u003e\n \u003cp\u003eAssessment at week 24 by research nurse/physician\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.2857%;\"\u003e\n \u003cp\u003eAssessment at week 52 by research nurse/physician\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.2857%;\"\u003e\n \u003cp\u003eWeekly/monthly\u003c/p\u003e\n \u003cp\u003efollow-up by research nurse/clinic staff\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26.8908%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEligibility criteria\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eWritten Informed consent\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eRandomization\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.9664%;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.2857%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.2857%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.2857%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.2857%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26.8908%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eObserved urinary tests\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.9664%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.2857%;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.2857%;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.2857%;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.2857%;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26.8908%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSelf-reported drug use\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.9664%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.2857%;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.2857%;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.2857%;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.2857%;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26.8908%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSCL-10\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.9664%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.2857%;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.2857%;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.2857%;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.2857%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26.8908%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEQ-5D-5L\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.9664%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.2857%;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.2857%;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.2857%;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.2857%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26.8908%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBVC\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.9664%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.2857%;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.2857%;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.2857%;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.2857%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26.8908%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eReaction time\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.9664%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.2857%;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.2857%;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.2857%;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.2857%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26.8908%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTreatment satisfaction\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.9664%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.2857%;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.2857%;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.2857%;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.2857%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26.8908%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDays out of treatment\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.9664%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.2857%;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.2857%;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.2857%;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.2857%;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26.8908%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRecorded overdose\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.9664%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.2857%;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.2857%;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.2857%;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.2857%;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26.8908%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAdverse effects\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.9664%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.2857%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.2857%;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.2857%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.2857%;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eSCL-10: Hopkins symptom checklist; EQ-5D-5L: Euro Quality of life, 5-dimensional, 5-level questionnaire; BVC: Br\u0026oslash;set violence checklist.\u0026nbsp;\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Benzodiazepines, agonist treatment, substitution, stabilizing, tapering, randomized controlled trial","lastPublishedDoi":"10.21203/rs.3.rs-4868655/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4868655/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere is a lack of knowledge on effective treatment methods for comorbid benzodiazepine dependence in populations undergoing opioid agonist treatment (OAT). Tapering and discontinuation of benzodiazepines has long been considered the standard treatment, even though there is limited evidence for this practice. There is also limited research on benzodiazepine agonist treatment, however, peer and clinical experiences indicate that such approaches may be beneficial for a subgroup of the patients with long-lasting benzodiazepine dependence not responding to other treatment approaches. A randomized controlled trial will be conducted to compare the efficacy and safety of stabilizing agonist treatment using prescribed benzodiazepines with standard treatment in reducing illicit benzodiazepine use.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe target sample is 108 participants at outpatient OAT clinics in five Norwegian cities/counties (Bergen/Vestland, Tønsberg/Vestfold, Skien/Telemark, Fredrikstad/Østfold and Tromsø/Troms). The main inclusion criteria are benzodiazepine dependence of ≥5 years, using ≥5 days a week during the last month, and previous attempts at tapering. Participants will be randomly assigned to receive either a 26-week benzodiazepine stabilizing treatment (15-30 mg diazepam or 50-100 mg oxazepam daily), or a 20-week tapering using the same medications and equivalent initial dosages. All participants will be given access to consultations from OAT therapists with psychosocial follow-up in accordance with current clinical practice.\u003c/p\u003e\n\u003cp\u003eThe primary outcome is the use of illicit benzodiazepines assessed by observed urinary tests at week 24. Secondary outcomes include mental health symptoms, quality of life, cognitive performance, violence risk, other substance use, treatment retention, and life satisfaction. Additionally, the study will assess treatment-related adverse events as well as the cost-effectiveness of the intervention.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDiscussion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis is the first randomized controlled trial of benzodiazepine agonist treatment for benzodiazepine dependence. The research project will assess efficacy and safety of stabilizing treatment with prescribed benzodiazepines compared to benzodiazepine tapering and discontinuation regarding use of illicit benzodiazepines and accordingly well-being of patients with concurrent benzodiazepine and opioid dependence undergoing OAT. If the intervention is found to be efficacious and safe, it will be considered one of the options to standard treatment for this patient group.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEU trial number: EudraCT: 2021-004981-37. Registered on December 13, 2021\u003c/p\u003e","manuscriptTitle":"Benzodiazepine agonist treatment for patients with benzodiazepine dependence undergoing opioid agonist treatment: a study protocol for the randomized controlled trial BMX-BAR","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-10-18 08:34:56","doi":"10.21203/rs.3.rs-4868655/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Minor revision","date":"2024-11-04T07:06:34+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2024-08-30T09:31:59+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-08-30T04:51:45+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-08-22T08:36:52+00:00","index":"","fulltext":""},{"type":"submitted","content":"Trials","date":"2024-08-10T02:46:36+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9303ebf2-5327-42e7-94f6-c8d55c822abb","owner":[],"postedDate":"October 18th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-01-06T16:01:24+00:00","versionOfRecord":{"articleIdentity":"rs-4868655","link":"https://doi.org/10.1186/s13063-024-08692-8","journal":{"identity":"trials","isVorOnly":false,"title":"Trials"},"publishedOn":"2025-01-02 15:57:27","publishedOnDateReadable":"January 2nd, 2025"},"versionCreatedAt":"2024-10-18 08:34:56","video":"","vorDoi":"10.1186/s13063-024-08692-8","vorDoiUrl":"https://doi.org/10.1186/s13063-024-08692-8","workflowStages":[]},"version":"v1","identity":"rs-4868655","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4868655","identity":"rs-4868655","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}