Long-term Benzodiazepine Users Research Articles

Remimazolam: its clinical pharmacology and evolving role in anesthesia and sedation practice.

Remimazolam is a novel benzodiazepine anesthetic/sedative, designed as a rapidly metabolized carboxylic acid. Since its recent launch, the role of remimazolam in modern anesthesia and sedation practice is still evolving. This review aims to outline the clinical pharmacology and clinical utility of remimazolam to elucidate its potential advantages and limitations. Remimazolam is "short-acting" but not ultra-short-acting compared with propofol based on context-sensitive decrement times. But compared to propofol, the availability of the benzodiazepine antagonist, flumazenil, is considered an advantage, particularly in certain emergency situations such as in patients with difficult airways. However, because flumazenil is shorter acting than remimazolam when remimazolam accumulates or is present in a high concentration, the reappearance of remimazolam sedation may occur after the initial reversal of anesthesia/sedation from flumazenil administration. Although it is beneficial that remimazolam causes less respiratory depression and hypotension than propofol, serious respiratory depression and hypotension can still occur. Remimazolam administration causes minimal or no pain on injection. Remimazolam is associated with less postoperative nausea and vomiting than inhaled anesthetics, but propofol is clearly superior in this regard. The anesthetic/sedative effects may be prolonged by severe hepatic impairment; remimazolam tolerance can occur in long-term benzodiazepine users. Remimazolam may be beneficial to use in procedural sedation and general anesthesia for patients with difficult airways or hemodynamic instability. Further clinical studies with remimazolam are warranted to identify the potential benefits in other settings and patient populations.

Prescription Patterns and Predisposing Factors of Benzodiazepine and Z-Hypnotic Use During Pregnancy: A Nationwide Cohort Study.

The use of benzodiazepines and Z-hypnotics during pregnancy has raised significant concerns in recent years. However, there are limited data that capture the prescription patterns and predisposing factors in use of these drugs, particularly among women who have been long-term users of benzodiazepines and Z-hypnotics before pregnancy. This population-based cohort study comprised 2 930 988 pregnancies between 2004 and 2018 in Taiwan. Women who were dispensed benzodiazepines or Z-hypnotics during pregnancy were identified and further stratified into groups based on their status before pregnancy: long-term users (with a supply of more than 180 days within a year), short-term users (with a supply of less than 180 days within a year), and nonusers. Trends in the use of benzodiazepines or Z-hypnotics and concomitant use with antidepressants or opioids were assessed. Logistic regression models were utilized to identify factors associated with use of these drugs during pregnancy, and interrupted time series analyses (ITSA) were employed to evaluate utilization patterns of these drugs across different pregnancy-related periods. The overall prevalence of benzodiazepine and Z-hypnotic use was 3.5% during pregnancy. Among prepregnancy long-term users, an upward trend was observed. The concomitant use of antidepressants or opioids among exposed women increased threefold (from 8.6% to 23.1%) and sixfold (from 0.3% to 1.7%) from 2004 to 2018, respectively. Women with unhealthy lifestyle behaviors, such as alcohol abuse (OR 2.48; 95% CI, 2.02-3.03), drug abuse (OR 10.34; 95% CI, 8.46-12.64), and tobacco use (OR 2.19; 95% CI, 1.96-2.45), as well as those with psychiatric disorders like anxiety (OR 6.99; 95% CI, 6.77-7.22), insomnia (OR 15.99; 95% CI, 15.55-16.45), depression (OR 9.43; 95% CI, 9.07-9.80), and schizophrenia (OR 21.08; 95% CI, 18.76-23.69), and higher healthcare utilization, were more likely to use benzodiazepines or Z-hypnotics during pregnancy. ITSA revealed a sudden decrease in use of benzodiazepines and Z-hypnotics after recognition of pregnancy (level change -0.55 percentage point; 95% CI, -0.59 to -0.51). In contrast, exposures to benzodiazepines and Z-hypnoticsincreased significantly after delivery (level change 0.12 percentage point; 95% CI, 0.09 to 0.16). In this cohort study, an increased trend of benzodiazepine and Z-hypnotic use during pregnancy among prepregnancy long-term users, as well as concomitant use with antidepressants or opioids were found. The findings have highlighted the existence of various risk factors associated with the use of these drugs during pregnancy. Utilization patterns varied across different stages of pregnancy, highlighting the need for prescription guidelines and educational services for women using these drugs during pregnancy.

Piracetam and Ginkgo biloba in the treatment of residual cognitive symptoms after the discontinuation of benzodiazepines in long-term users; case series and review of the literature

IntroductionLong-term benzodiazepine use is common although not routinely recommended. While their dependence potential is notorious, cognitive problems due to their chronic use have only recently been intensively studied. Residual cognitive symptoms may linger months after successful benzodiazepine discontinuation and significantly limit optimal functional outcome in abstinent individuals.ObjectivesWe present a series of cases, a 41-year-old man and a 33-year-old woman who successfully completed a ten-week benzodiazepine-dependence rehabilitation program at our hospital, including successful tapering and post-withdrawal integrative therapy. At subsequent monthly outpatient check-ups, abstinence was confirmed (including toxicology testing) and there was no residual anxiety or mood symptomatology. Still, patients complained of their suboptimal functioning due to residual cognitive problems, especially trouble concentrating and short-memory deficits, which were objectively confirmed via psychometric tests.MethodsDuring continuous outpatient treatment (monthly controls), patients were clinically and neurocognitively evaluated. They were reluctant to try conventional psychopharmacology agents but were open to supplement therapy. After thorough literature review, a trial of piracetam and Ginko biloba extract was suggested. Piracetam, a positive allosteric modulator of AMPA-receptors, has been used in the treatment of vascular neurocognitive changes in the elderly. Bilobalides from G. biloba, act as atypical antagonists of GABA-A receptors and were found to exert neuroprotective effects in animal models, without epileptogenic or anxiogenic risks.ResultsPatients were recommended piracetam (2.4 g a day) in divided doses and a once-daily dose of G. biloba extract (240 mg a day), in a standardized form containing 3.2% of bilobalides. No side effects were noticed. At subsequent monthly checkups, patients reported fewer cognitive problems and better everyday functioning. Neurocognitive testing confirmed subjective findings, with positive changes in all areas, but especially so in verbal memory, which may be due to this specific pharmacological combination. At the end of the observation period of sixth months, piracetam was gradually discontinued while patients were given free choice whether to continue with G. biloba supplementation.ConclusionsAccording to our findings, piracetam and G. biloba extract may prove beneficial in the treatment of residual cognitive symptoms after benzodiazepine discontinuation, in long-term benzodiazepine users. Other treatments, focusing not only on modulation of glutamate and GABA, but also on other pathways should be evaluated. Further clinical studies are warranted.Disclosure of InterestNone Declared

Linking a Survey of Clinician Benzodiazepine-Related Beliefs to Risk of Benzodiazepine Prescription Fills Among Patients in Medicare.

In this pilot study, we used a Medicare sample to identify primary care clinicians who prescribed a benzodiazepine (BZD) in 2017 and surveyed a random sample (n = 100) about BZD prescribing. Among 61 respondents, 11.5% (SD 5.9) of their patient panels filled a BZD prescription. Patients of primary care clinicians who agreed that potential harms to long-term BZD users were low had a greater BZD fill risk relative to patients of disagreeing primary care clinicians (adjusted risk ratio 1.31; 95% CI, 1.01-1.7). We highlight the potential of using Medicare claims to sample clinicians. Using claims-based objective measures presents a new method to inform the development of behavior-change interventions.

Adapting the Eliminating Medications Through Patient Ownership of End Results Protocol to Promote Benzodiazepine Cessation Among US Military Veterans: Focus Group Study With US Military Veterans and National Veterans Health Administration Leaders.

BackgroundLong-term dependence on prescribed benzodiazepines is a public health problem. Eliminating Medications Through Patient Ownership of End Results (EMPOWER) is a promising self-management intervention, delivered directly to patients as a printed booklet, that is effective in promoting benzodiazepine reduction and cessation in older adults. EMPOWER has high potential to benefit large health care systems such as the US Veterans Health Administration (VHA), which cares for many veterans who use benzodiazepines for extended periods.ObjectiveWe aimed to adapt the original EMPOWER booklet materials for electronic delivery and for use among US military veterans receiving VHA care who were long-term benzodiazepine users.MethodsWe used elements of Analysis, Design, Development, Implementation, and Evaluation, a framework commonly used in the field of instructional design, to guide a qualitative approach to iteratively adapting EMPOWER Electronic Delivery (EMPOWER-ED). We conducted 3 waves of focus groups with the same 2 groups of VHA stakeholders. Stakeholders were VHA-enrolled veterans (n=16) with medical chart evidence of long-term benzodiazepine use and national VHA leaders (n=7) with expertise in setting VHA policy for prescription benzodiazepine use and developing electronically delivered educational tools for veterans. Qualitative data collected from each wave of focus groups were analyzed using template analysis.ResultsThemes that emerged from the initial focus groups included veterans’ anxiety about self-tapering from benzodiazepines and prior negative experiences attempting to self-taper without support. Participants also provided feedback on the protocol’s look and feel, educational content, the tapering protocol, and website functionality; for example, feedback from policy leaders included listing, on the cover page, the most commonly prescribed benzodiazepines to ensure that veterans were aware of medications that qualify for self-taper using the EMPOWER-ED protocol. Both groups of stakeholders identified the importance of having access to supportive resources to help veterans manage sleep and anxiety in the absence of taking benzodiazepines. Both groups also emphasized the importance of ensuring that the self-taper could be personalized and that the taper instructions were clear. The policy leaders emphasized the importance of encouraging veterans to notify their provider of their decision to self-taper to help facilitate provider assistance, if needed, with the taper process and to help prevent medication stockpiling.ConclusionsEMPOWER-ED is the first direct-to-patient electronically delivered protocol designed to help US military veterans self-taper from long-term benzodiazepine use. We used the Analysis, Design, Development, Implementation, and Evaluation framework to guide the successful adaption of the original EMPOWER booklet for use with this population and for electronic delivery. The next step in this line of research is to evaluate EMPOWER-ED in a randomized controlled trial.

Is the Long-Term Use of Benzodiazepines Associated With Worse Cognition Performance in Highly Educated Older Adults?

Background: Benzodiazepines (BZD) are common medications for sedative, hypnotic, and anxiolytic that are especially prevalent in older adults. Previous studies have shown that BZD use could impair users' cognition, significantly affecting their quality of life. Past research has shown that higher education might play a protective role in the process of cognitive decline. Very few studies had examined the cognitive effects of BZD on highly educated older adults. The study aimed to explore how cognitive functions would be affected by benzodiazepines among highly educated older adults.Method: 140 older adults with an average education period of 14.8 years were included in this study. The subjects were divided into three separate groups, the long-term BZD users (≥180 days), short-term BZD users (<180 days), and non-users. Demographics and cognitive assessments for the three groups were analyzed using the analysis of variance (ANOVA), the chi-squared test, and the analysis of covariance (ANCOVA). To examine the association between BZD use and cognition a multiple linear aggression approach was used.Result: All three groups were significantly different from each other when looking at executive functioning in the Trail Making Test B (TMT-B). Compared to the control group, short-term BZD users showed significant defects in TMT-B time (p = 0.002) and TMT-B errors (p < 0.001); long-term BZD users showed significant defect on TMT-B time (p = 0.041). Compared to short-term BZD users, long-term BZD users showed significant merit on TMT-B errors (p = 0.001). No significant differences were found in other cognitive tasks that reflected general cognition, verbal memory, language fluency, and visual memory. After adjusting for demographic, increased BZD use over time was positively associated with scores for the revised Brief Visuospatial Memory Test (r = 0.377, p = 0.012).Conclusion: BZD use may be significantly associated with worse executive functioning in highly educated older adults. However, there is no association between the duration of BZD use and increased cognitive deficits in highly educated older adults. This study identified future experimental directions including potential longitudinal studies, within-subject studies comparing mood disorder patients' cognitive performance before and after onset of BZD use, and between-subject studies that directly compare BZD's effect on subjects with the same baseline of cognitive functioning.

S211. LONG-TERM BENZODIAZEPINE USE DURING MAINTENANCE THERAPY OF PSYCHOSIS - ASSOCIATION WITH SYMPTOMS, COGNITION AND FUNCTIONALITY

BackgroundData on benzodiazepine (BZD) use of on a long term basis (≥6 months) in outpatients with psychosis spectrum disorders (PSD) are scarce. However, prolonged BZD administration could be associated with different side effects, thus its use in actual practice must be described and questioned. According to the recent large-scale study of hospital discharge BZD prescription in Balkans, PSD patients had higher odds of receiving BZDs (80.4%) in comparison to patients with all other main ICD-10 psychiatric categories. This study explored the prevalence of long-term BZD use during maintenance therapy of patients with PSD and the associated clinical factors.MethodsOutpatients with primary diagnosis of psychosis or related disorder (ICD-10 F20-29), history of at least one lifetime psychiatric hospital admission, capacity and will to provide informed consent and a history of attending the outpatient clinic for at least 6 months were included from two sites in Serbia - one university and one general psychiatric hospital (n=60; mean age (SD) = 43.4 (10.6) years; 63.3% male). Clinical assessment included Brief Psychiatric Rating Scale (BPRS, mean (SD) = 1.73 (0.49)), the split version of General Assessment of Functioning scale (GAF Functioning/Symptom, mean (SD) = 58.5 (11.7) and 58.6 (11.7), respectively), Global Assessment of Functioning - Cognition in Schizophrenia (GAF-CogS, mean (SD) = 60.4 (12.4)) and Recovering Quality of Life (ReQoL, mean (SD) = 29.0 (9.1)). Medical chart review was used to list all psychotropic medications prescribed over 6 months preceding the examination. We used student t-test and Pearson’s correlation to analyze the data. Effect sizes were provided. Present research was conducted as a part of the larger study aiming at implementation of the psychosocial intervention DIALOG+ for patients with psychotic disorders in low- and middle-income countries in South Eastern Europe (grant agreement No 779334).ResultsThe prevalence of long term BZD use was 50.0% (30/60 patients). The mean BZD daily dose range was 0–14 mg of lorazepam equivalents (21.7% with ≥ 3mg of lorazepm equivalents). Total antipsychotic (AP) daily doses (chlorpromazine equivalents) at the time of evaluation were 371.6±191.4 mg in long-term BZD users and 275.0±214.7 mg in the other group (df=56, t= 1,811, p=0.075, Cohen’s d=0.5). The correlation between AP polypharmacy and long-term BZD use was positive (r=0.340, p=0.008). Long term BZD users were borderline older than non-users (df=58, t=1,957, p=0.055, Cohen’s d=0.5) and had higher total BPRS symptom scores (df=58, t= 2,806, p=0.007, Cohen’s d=0.7). In particular, higher symptom scores were noticed in two BPRS domains - negative symptom and reality distortion. Moreover, these patients were significantly more likely to have cognitive and functional impairments (GAF-CogS: df=56, t=-3.295, p=0.002, Cohen’s d=0.9; GAF-F: df=56, t=-3,186, p=0.002, Cohen’s d=0.8; GAF-S: df=56, t=-3,316, p=0.002, Cohen’s d=0.9). There were no between-group differences in ReQoL scores (df=58, t=-1.563, p=0.123).DiscussionThe present study demonstrated new information regarding the prescription patterns of BZD in outpatients with PSD in Serbia, amplified with clinically relevant information. High rate of long term BZD prescription could be considered as a therapeutic strategy toward patients with more severe cases of PSD, however our results could also suggest a link between long-term BZD prescription and disabling side effects, particularly related to cognitive functioning. Overall, this is an under-researched area and present findings are likely to contribute to improving clinical practice and care for patients with psychotic disorders.

Long-term users of benzodiazepines in Colombia: Patterns of use and cessation of treatment

BackgroundBenzodiazepines have low abuse potential, but patients often develop physical dependence and neurological impairments. The objective of this study was to investigate treatment cessation and use of high doses in long-term benzodiazepine users in Colombia. MethodsRetrospective study. Patients who used benzodiazepines for at least six months (long-term) were selected from a prescription database and followed from initiation of benzodiazepine treatment for up to 30 months. We investigated treatment duration and compared patients who received normal and high (≥2 mean prescribed daily dose) doses. ResultsOnly 1255 (6.1 %) out of 20,567 patientsprescribed benzodiazepines became long-term users; their mean age was 60.6 years (SD=20.0) and 61.7 % were women. Mean high doses were used by 42.5 % (n=534) of the sample. Age under 20 years was a protector, whereas the long half-life benzodiazepines and use of other neurological medications were predictors of high dosage. Overall, 44.8 % (n=563) of the sample was still using benzodiazepines at the end of the study period. The use of antidepressants, antipsychotics, and anticonvulsants were negatively associated with cessation of benzodiazepine treatment. ConclusionsA low proportion of patients starting benzodiazepines became long-term users. Nearly half of them used high doses and continued the medication for up to 30 months. Use of concomitant neurological drugs was associated with higher doses and less cessation.

Is Long-Term Benzodiazepine Use a Risk Factor for Cognitive Decline? Results of a Systematic Review.

Background and Aims Benzodiazepines have been widely used for long periods of time despite their adverse effects. The acute effects on cognition are well established. However, less is known about the long-term effects. This study critically reviewed existing evidence of the association between long-term exposure to benzodiazepines and risk of cognitive decline in adults. Methods A systematic review with narrative synthesis was conducted. PubMed and PsycINFO databases were searched using combinations of keywords related to “benzodiazepines” and “cognitive function” from database inception to 12 February 2018 to identify prospective longitudinal studies. The records were evaluated for relevance according to the inclusion and exclusion criteria. Results Fourteen studies involving 2145 long-term benzodiazepine users were included. Meta-analysis was not undertaken because the combined result would not be meaningful as the included studies differed in several key aspects such as frequency and duration of benzodiazepine use, follow-up periods, cognitive domains, cognitive tests, scoring systems, and statistical analysis. The definition of long-term benzodiazepine use was problematic in all the studies. The exposure was determined by measures which were assumed to represent the whole period in-between the follow-ups. Only 3 of the 14 studies provided support for an association between long-term benzodiazepine use and cognitive decline with a small to medium effect size. However, these three studies used different methods to assess the strength of this association. Global cognitive functioning, verbal memory, intelligence, psychomotor speed, and speed of processing were the cognitive domains affected which also varied across these three studies. Conclusions Little evidence of an association between long-term benzodiazepine use and a higher risk of cognitive decline among the general adult population was found. However, discrepancies among the results and inconsistencies regarding the cognitive domains affected and methodological limitations prevent definite conclusions. Therefore, future research with prospective studies specially designed would be of great value.

Prescription Benzodiazepine Use in Privately Insured U.S. Children and Adolescents

Benzodiazepines are commonly prescribed in the U.S. but entail safety concerns, including dependency. In pediatrics, many indications lack trial data. Authors aimed to describe youth initiating prescription benzodiazepine treatment, identify potential indications and prescribing concerns, estimate the duration of treatment by potential indication, and identify factors that predict long-term use. The study cohort included children (aged 3-12 years) and adolescents (aged 13-17 years) initiating prescription benzodiazepine treatment (≥3 days' supply) from January 2010 to September 2015 in a U.S. commercial claims database. Potential indications included selected ICD-9-CM diagnoses (≤30 days prior). Long-term (≥6 months) benzodiazepine treatment was estimated with Kaplan-Meier estimation and modified Poisson regression identified independent predictors of long-term benzodiazepine treatment (analysis completed in 2018). Of 24,504 children and 61,046 adolescents initiating benzodiazepines, 62% of the children and 68% of the adolescents had a potential indication. Anxiety disorders were the most common indication, with mental health indications more common among adolescents (45%) than children (23%) and epilepsy and movement disorders higher in children. Recent opioid prescriptions were common before benzodiazepine initiation (children, 22%; adolescents, 21%). Six percent of the initiators became long-term benzodiazepine users. Potential indication, provider contact, psychotropic medication, and chronic conditions independently predicted long-term benzodiazepine treatment in adolescents and children. U.S. children and adolescents are prescribed benzodiazepines for various mental health and other medical conditions, many lacking evidence of pediatric efficacy. Long-term benzodiazepine treatment, concurrent opioid prescriptions, psychotropic use, and prior substance use disorder diagnoses suggest safety risks among some youth prescribed benzodiazepines.

Problematic Medication With Benzodiazepines, "Z-drugs", and Opioid Analgesics.

An estimated 1.4 to 2.6 million people in German suffer from drug dependence. Most of them are long-term users of benzodiazepines (BZD), Z drugs (ZD), or opioid analgesics (OA). This analysis is based on prescription data from patients of the national statutory health insurance system in the German federal states of Schleswig-Holstein, Hamburg, Bremen, and Lower Saxony. Drug-taking trends, duration, dosage, and long-term use of BZD, ZD, and OA in the years 2006 to 2015 are analyzed; prevalences are estimated for the years 2006 to 2016. In 2006, 7.7% of patients received at least one prescription for a BZD, ZD, or OA; in 2016, 7.0% did. Over the period of analysis, a marked drop was seen in prescriptions of BZD and a slight fall in prescriptions of ZD (2006: BZD 3.5%, ZS 1.1%; 2016: BZD 2.0%, ZS 0.8%), but there was also an increase in prescriptions of OA, from 4.2% to 4.9%. The number of defined daily doses (DDD) prescribed per year fell for both BZD and ZD. For OA, the number of DDD prescribed per year rose from 2006 to 2009 and decreased by a small amount in subsequent years. The proportions of BZD and ZD patients who had long-term prescriptions fell over time, while the corresponding percentage of OA patients rose. Nearly one-fifth of all prescriptions for BZD were long-term prescriptions for an entire year, in violation of the relevant guidelines. The rising prevalence of OA use was in the expected range in view of the aging population, but the number of prescriptions rose among younger patients as well. This trend toward more common treatment with opioid analgesics should be critically examined.

Deprescribing benzodiazepines.

Deprescribing benzodiazepines.

Electroacupuncture for tapering off long-term benzodiazepine use: A randomized controlled trial

ObjectiveTo evaluate the efficacy of using electroacupuncture as an adjunct treatment in enhancing the benzodiazepine cessation rate in long-term benzodiazepine users. MethodsThis was a randomized, assessor- and subject-blinded, controlled trial. One hundred and forty-four long-term benzodiazepine users were randomly assigned to receive either electroacupuncture or placebo acupuncture (a sham itervention using non-invasive placebo needles) combined with a gradual benzodiazepine tapering schedule for 4 weeks. The primary outcome was the cessation rate of benzodiazepine use. Subjects were assessed on their benzodiazepine usage, benzodiazepine withdrawal symptoms, insomnia severity, and anxiety and depressive symptoms at baseline, week 6 and week 16. ResultsThe cessation rates of the electroacupuncture and placebo acupuncture groups at 12 weeks post-treatment were 9.17% and 10.83%, respectively. Both groups showed a reduction in benzodiazepine usage by a self-completed drug record at week 16 (compared to baseline: electroacupuncture group −40.23% versus placebo acupuncture group −48.76%). However, no significant between-group differences were found in the benzodiazepine cessation rate, reduction in benzodiazepine usage, and other secondary measures across all the study time points. ConclusionsElectroacupuncture showed a similar cessation rate in benzodiazepine use to that of non-invasive placebo acupuncture in long-term users during a 4-week gradual tapering schedule. The evidence did not support advantages of electroacupuncture over non-invasive placebo acupuncture on reducing insomnia, anxiety, depression, or other withdrawal symptoms during the gradual tapering schedule. Despite a 40% decrease in the benzodiazepine usage in both groups, the effects may be attributed to the non-specific effects of acupuncture. Trial RegistrationClinicalTrials.gov # NCT02475538.

Risk of Dementia in Long-Term Benzodiazepine Users: Evidence from a Meta-Analysis of Observational Studies.

Background and PurposeThere is conflicting evidence in the literature on the association between benzodiazepines (BDZs) and the risk of dementia. This meta-analysis aimed to determine the relationship between the long-term usage of BDZs and the risk of dementia.MethodsThe PubMed and Embase databases were systematically searched for relevant publications up to September 2017. The literature search focused on observational studies that analyzed the relationship between the long-term use of BDZs and the risk of dementia. Pooled rate ratios (RRs) with 95% confidence interval (CI) were assessed using a random-effects model. The robustness of the results was checked by performing subgroup and sensitivity analyses.ResultsTen studies were included: six case–control and four cohort studies. The pooled RR for developing dementia was 1.51 (95% CI=1.17–1.95, p=0.002) in patients taking BDZ. The risk of dementia was higher in patients taking BDZs with a longer half-life (RR=1.16, 95% CI=0.95–1.41, p=0.150) and for a longer time (RR=1.21, 95% CI=1.04–1.40, p=0.016).ConclusionsThis meta-analysis that pooled ten studies has shown that BDZ significantly increases the risk of dementia in the elderly population. The risk is higher in patients taking BDZ with a longer half-life (>20 hours) and for a longer duration (>3 years).

Patterns of benzodiazepines use in primary care adults with anxiety disorders

BackgroundBenzodiazepines are among the most commonly prescribed drugs for anxiety disorders. While they are indicated as adjunctive treatment for short-term use according to clinical practice guidelines, previous studies have shown patterns of long-term use of benzodiazepines, which is problematic due to side effects, dependence and potential of abuse. The aims of this study were to examine among a large sample of primary care adults suffering from anxiety disorders: 1) benzodiazepine use patterns; and 2) correlates of long-term benzodiazepine use. MethodsData were drawn from the “Dialogue” project, a large primary care study conducted in 64 primary care clinics in the province of Quebec, Canada. Following a mental health screening in waiting rooms, patients at risk of anxiety or depression completed the Composite International Diagnostic Interview-Simplified (CIDIS). A sample of 740 adults meeting DSM-IV criteria for Generalized Anxiety Disorder, Panic Disorder or Social Anxiety Disorder in the past 12 months took part in this study. ResultsBenzodiazepines were used by 22.6% of participants with anxiety disorders in our primary care sample. A large majority of benzodiazepine users (88.4%) met our indicator of long-term use, as defined by utilization for more than 12 weeks including regular and as-needed use. Based on a logistic regression model, individual correlates associated with long-term benzodiazepine use included: being 30 years or older, having a comorbid physical illness, meeting criteria for comorbid agoraphobia, reporting the use of sleep-aids, and concurrent SSRI utilization. LimitationData collection with self-reported questionnaires may be subject to information bias. ConclusionsDespite knowledge of the risks of long-term use of benzodiazepines, this remains a pervasive problem. Clinicians need to be mindful of patterns and risk factors leading to long-term use of benzodiazepines in patients with anxiety disorders. Results of this study should raise awareness regarding appropriate prescription practices for benzodiazepines, including decision-making in initiation, duration of prescription, and use of strategies for discontinuation in current long-term benzodiazepine users.

PHP57 - Long-Term Users of Benzodiazepines in Colombia: Patterns of use and Cessation of Treatment

Abstract Background Benzodiazepines have low abuse potential, but patients often develop physical dependence and neurological impairments. The objective of this study was to investigate treatment cessation and use of high doses in long-term benzodiazepine users in Colombia. Methods Retrospective study. Patients who used benzodiazepines for at least six months (long-term) were selected from a prescription database and followed from initiation of benzodiazepine treatment for up to 30 months. We investigated treatment duration and compared patients who received normal and high (≥2 mean prescribed daily dose) doses. Results Only 1255 (6.1 %) out of 20,567 patientsprescribed benzodiazepines became long-term users; their mean age was 60.6 years (SD=20.0) and 61.7 % were women. Mean high doses were used by 42.5 % (n=534) of the sample. Age under 20 years was a protector, whereas the long half-life benzodiazepines and use of other neurological medications were predictors of high dosage. Overall, 44.8 % (n=563) of the sample was still using benzodiazepines at the end of the study period. The use of antidepressants, antipsychotics, and anticonvulsants were negatively associated with cessation of benzodiazepine treatment. Conclusions A low proportion of patients starting benzodiazepines became long-term users. Nearly half of them used high doses and continued the medication for up to 30 months. Use of concomitant neurological drugs was associated with higher doses and less cessation.

Influence of Long-Term Benzodiazepine use on Neurocognitive Skills Related to Driving Performance in Patient Populations: A Review.

Acute benzodiazepine intoxication produces severe impairment of neurocognitive skills related to driving. It is less clear whether such impairments also occur in patients who use benzodiazepines chronically. The current review evaluated neurocognitive skills of long-term benzodiazepine users and addressed 2 major questions: do long-term users develop tolerance for the impairing effects of benzodiazepines on neurocognitive performance, and if so, does tolerance warrant a change in driver fitness classification systems that currently deem users of benzodiazepines unfit to drive? Neurocognitive impairments were reported in patients who on average used benzodiazepines for 5-15 years. In addition, sensitivity to acute benzodiazepine impairment decreased in long-term users, suggesting (partial) tolerance. Definitions of clinical relevance of neurocognitive impairments in long-term users and how these were affected by duration of benzodiazepine use were generally lacking. Also, sensitivity of neurocognitive tasks to drug effects and their validity to predict fitness to drive were generally unknown. Because of these limitations, no firm conclusion can be drawn regarding a re-classification of long-term benzodiazepine effects on driver fitness.

Multifocal cognitive dysfunction in high-dose benzodiazepine users: a cross-sectional study.

Benzodiazepines (BZDs) are the most widely prescribed drug class in developed countries, but they have high potential for tolerance, dependence and abuse. Cognitive deficits in long-term BZD users have long been known, but previous results might have been biased by patients' old age, coexisting neurological or psychiatric conditions or concurrent alcohol or psychotropic drug dependence. The study was aimed to explore the neuropsychological effect of high-dose BZD dependence, which represents an emerging addiction phenomenon. We recruited a group of high-dose BZD users with neither neurological or psychiatric comorbidity except anxiety or depression nor concurrent alcohol or psychotropic drug dependence. They underwent a battery of cognitive tests to explore verbal, visuospatial memory, working memory, attention, and executive functions. All the neuropsychological measures were significantly worse in patients than controls, and some of them were influenced by the BZD cumulative dose. The severity of depression and anxiety had a minimal influence on cognitive tests. Patients with high-dose BZD intake show profound changes in cognitive function. The impact of cognition should be considered in this population of patients, who may be involved in risky activities or have high work responsibilities.

Slow subcutaneous infusion of flumazenil for the treatment of long-term, high-dose benzodiazepine users: a review of 214 cases.

Despite the first reports concerning benzodiazepine dependence being published in the early 1960s literature, the risk of benzodiazepine addiction is still greatly debated. The severe discomfort and life threatening complications usually experienced by long-term benzodiazepine users who suddenly interrupt benzodiazepine intake have led to the development of several detoxification protocols. A successful strategy used by our Addiction Unit is abrupt benzodiazepine cessation by administering flumazenil slow subcutaneous infusion (FLU-SSI) with an elastomeric pump. Although some studies proved the efficacy of flumazenil infusion more than 20 years ago, only a few centres in the world offer this method to their patients. This paper reports the data related to 214 subjects addicted to high doses of benzodiazepine and treated with the FLU-SSI method between 2012 and 2014. This technique is less invasive and requires less nursing intervention than intravenous infusion. Our data support FLU-SSI as a possible efficient strategy for the treatment of patients with long-term, high-dose benzodiazepine addiction, and could become a routine therapy as long as the necessary further studies on dose, duration of infusion and safety issues are carried out.

Sustained Use of Benzodiazepines and Escalation to High Doses in a Canadian Population.

"Antibenzodiazepine" campaigns have been conducted worldwide to limit the prescribing of these drugs because of concerns about inappropriate use and addiction. The causal relationship between long-term use and escalation to high doses has not been proven. This study assessed the extent of dose escalation among individuals who were long-term users of benzodiazepines or Z-hypnotics. A population-based study was conducted in the Canadian province of Manitoba using administrative health databases. Sustained use was defined as continuous use for at least two years (N=12,598). Dose escalation, measured in diazepam milligram equivalents (DMEs) per day and observed at six-month intervals, was assessed by using latent-class trajectory analysis. Characteristics of individuals with sustained use were described. The analysis revealed four distinct groups. Two groups (<8% of the cohort) showed escalation to high doses (over 40 DMEs). More than 55% of high-dose escalators were in the 0- to 44-year age group, 75% lived in urban areas, and approximately 75% had a diagnosis of depression. Clonazepam was the drug most commonly involved with dose escalation; among individuals escalating to doses higher than 60 DMEs, 91% were using clonazepam. Rates of "doctor shopping" and "pharmacy hopping" were higher among younger adults, compared with older adults. Younger adults also had higher rates of concomitant antidepressant therapy. A limited segment of a population that received benzodiazepine prescriptions was classified as sustained users, and a small proportion of that group escalated to doses higher than those recommended by product monographs and clinical guidelines.