Short Half-life Benzodiazepines Research Articles

Benzodiazepine exposure in subjects with incident Alzheimer's disease and related syndromes in France: a longitudinal study 2011-2017.

Benzodiazepines are commonly used for behavioral and psychiatric symptoms of dementia, despite their numerous adverse effects and the lack of evidence regarding their efficacy in this context. We studied longitudinal benzodiazepines exposure in incident cases of Alzheimer's disease and related syndromes (ADRS) in France. We used a cohort of incident ADRS patients identified in 2012 within the national health data system. Benzodiazepines exposure was measured 1 year before, to 5 years after ADRS identification. Quarterly benzodiazepines prevalence and incidence were computed. We identified factors associated with long half-life benzodiazepines initiation. A total of 106 508 subjects were included. Quarterly benzodiazepines prevalence was stable (around 25%) but we saw an important decrease in long half-life benzodiazepines compensated by an increase in short half-life benzodiazepines. In most benzodiazepine initiations, the first episode lasted less than 3 months. Factors associated with initiating a long half-life benzodiazepine were young age, male gender, no registration with ADRS as a long-term disease, having consulted an ADRS specialist, antipsychotic reimbursement before the index date, no admission in nursing home. Prevalence of benzodiazepines use remains high in subjects with ADRS despite guidelines for their avoidance. However, indicators regarding benzodiazepine initiations (duration, benzodiazepine type) suggest some caution in their use.

Benzodiazepine Dispensing to Persons With Dementia in France, 2011-2016: A Nationwide Study

ObjectiveTo study temporal trends of benzodiazepine exposure among incident Alzheimer's disease and related dementia (ADRD) cohorts between 2011 and 2016. DesignRepeated cross-sectional study. Setting and ParticipantsThree nationwide incident ADRD cohorts (community-dwelling and institutionalized subjects) were identified in 2011, 2013, and 2016 through the French health insurance database. Subjects were followed 4 semesters around ADRD identification [Semester −2 (S−2) to Semester 2 (S2)]. MeasuresOdds ratios (ORs) for semestrial prevalent exposure, initiation, and adherence to benzodiazepine prescription recommendations (prescription duration <3 months, single reimbursement) were computed using multivariate logistic regressions for each cohort and according to benzodiazepine half-life. ResultsAmong 262,024 community-dwelling subjects, as compared to 2011, overall benzodiazepine prevalence risk decreased slightly immediately after ADRD identification [S1: aOR2013 = 0.93 (0.91-0.95), aOR2016 = 0.95 (0.93-0.97)] and did not differ during S2. Among 72,013 institutionalized subjects, it increased over time [S2: aOR2013 = 1.16 (1.11-1.21), aOR2016 = 1.26 (1.21-1.32)]. Long half-life benzodiazepine prevalence risk decreased in the 4 semesters among recent cohorts, for both populations [S2: community-dwelling: aOR2013 = 0.77 (0.74-0.79), aOR2016 = 0.61 (0.59-0.64); institutionalized: aOR2013 = 0.74 (0.68-0.80), aOR2016 = 0.58 (0.54-0.63)]. Short half-life benzodiazepine prevalence risk increased [S2: community-dwelling: aOR2013 = 1.13 (1.10-1.16), aOR2016 = 1.22 (1.20-1.25); institutionalized: aOR2013 = 1.26 (1.21-1.32), aOR2016 = 1.44 (1.38-1.50)]. The same patterns were observed for benzodiazepine initiation. Adherence to benzodiazepine prescription recommendations (based on French prescription duration) worsened over years [prescription duration <3 months: aOR2013 = 0.90 (0.86-0.95), aOR2016 = 0.90 (0.85-0.95), single reimbursement: aOR2013 = 0.95 (0.91-1.00), aOR2016 = 0.94 (0.90-0.99)]. Conclusions and ImplicationsLong half-life benzodiazepine exposure was reduced whereas short half-life benzodiazepine exposure increased, and adherence to recommendations worsened (prescription duration longer than 3 months and more than a single reimbursement in recent cohorts). Efforts from prescribers and authorities are required in order to restrict psychotropic exposure among the ADRD population. Further research among institutionalized ADRD subjects could provide useful data to disentangle the effects of changes in prescribing practices and in patients' characteristics.

Risk of hypertension associated with objective sleep alterations and long-term use of benzodiazepine receptor agonists in chronic insomnia: A study on 1272 individuals referred for polysomnography

Given conflicting data in the literature, the aim of this study was to examine the risk of hypertension associated with sleep alterations, measured during polysomnography, and long-term use of benzodiazepine receptor agonists in a large sample of insomnia sufferers. Demographic and polysomnographic data from 1272 insomnia sufferers recruited from the research database of the sleep laboratory were analyzed. Hypertension status was defined by the presence of one of the following: self-report at interview of either a physician's diagnosis or taking antihypertensive medication; or an average systolic blood pressure ≥ 140 mm Hg or an average diastolic blood pressure ≥ 90 mm Hg at the medical examination. Logistic regression analyses were conducted to examine the risk of hypertension associated with objective sleep alterations and long-term use of benzodiazepine receptor agonists in insomnia sufferers. The prevalence of hypertension in insomnia sufferers is 30.03%. After adjustment for major confounding factors associated with hypertension, multivariate logistic regression analysis revealed that short sleep duration (< 5 hours) [OR 1.91 (95% CI 1.15–3.16)], severely reduced sleep efficiency (< 65%) [OR 1.57 (95% CI 1.01–2.45)], high sleep fragmentation (sleep fragmentation index ≥ 18/hour) [OR 1.59 (95% CI 1.10–2.30)], and long-term use of short [OR 1.78 (95% CI 1.03–3.09)] or intermediate [OR 2.10 (95% CI 1.12–3.92)] half-life benzodiazepine receptor agonists were significant risk factors of hypertension in insomnia sufferers. In insomnia sufferers, objective sleep alterations and long-term use of short or intermediate half-life benzodiazepine receptor agonists are associated with higher risk of hypertension. Therefore, better management of these reversible risk factors is required to avoid the negative consequences of the co-occurrence of insomnia and hypertension.

Approach to the risk of delirium in an orthogeriatric unit

IntroductionThe objective of this study is to evaluate the efficacy of a change in the management of the risk of delirium in an orthogeriatric unit. Material and methodsProspective, comparative, non-randomised study of two cohorts of patients. One cohort (control group) treated with standard therapy with tramadol rescue and diazepam and another cohort (experimental group) treated with rescue with morphine at low doses and short half-life benzodiazepines as well as preventive treatment with neuroleptics in patients at high risk. ResultsEighty-five patients were included (42 in the control group and 43 in the experimental group). Mean age: 85 (71–105). Twenty-nine patients (34%) had an episode of delirium during the current admission, 16 patients (38%) in the control group and 13 patients (30%) in the experimental group respectively (p=0.498). The mean duration of delirium in the 29 patients who presented it was 5.3 days. This duration in the control group was 6.6 days and in the experimental group was 3.8 days (p=0.031). In the group of patients who had previous delirium, a lower incidence of delirium was seen during the current admission in the experimental group (80% vs. 17% p=0.036). ConclusionsExperimental treatment has been effective since a trend to a lower incidence of delirium has been observed. In the patients who have suffered an episode of delirium, the treatment served to decrease its duration with statistically significant differences.

Benzodiazepines and frail elderly people: how prescribing can be optimized?

In France, benzodiazepine (BZD) is frequently prescribed in elderly people (EP). Long-term efficacy is often questioned, and treatment has to be regularly re-examined, especially in EP. In our Geriatric day-hospital for assessment of frailty, a multidisciplinary team evaluates the patients and gives them preventative measures against the loss of autonomy. Medication evaluation is part of these measures. The aim of our study was to evaluate the impact of a standardized intervention on the optimization of BZD treatment. Setting and method: After a short interview and the delivery of an information booklet about BZD, patients were proposed an optimization of their BZD treatment (dosage reduction, occasional medication, switch to a short half-life BZD, or total discontinuation). Patients were followed up monthly by a phone-interview over a 6-months period. The main outcome measure was the prevalence of BZD optimized treatments after a 6 months follow-up. Results: 18 patients were included. Among them, 50% have been taking a BZD for more than 10 years, and 39% were prescribed a long half-life BZD, which can be qualified as inappropriate in EP. 50% of the subjects were frail and 44% pre-frail, according to the Fried criteria. At the end of the study, 33% of the patients had their BZD treatments optimized, including 17% of total discontinuation. Conclusion: In the frail elderly population, a standardized intervention can be useful to improve BZD treatment. An extension to this intervention would be the creation of an organization tasked with routinely monitoring the patients' withdrawal over a six month period.

Objective sleep alterations and long-term use of short or intermediate half-life benzodiazepine receptor agonists are risk factors for high blood pressure in individuals with insomnia: a study in 1272 individuals referred for sleep examinations

IntroductionGiven conflicting data in the literature, the aim of this study was to examine the risk of high blood pressure (HBP) associated with sleep alterations, measured during polysomnography, and long-term use of benzodiazepine receptor agonists in a large sample of individuals with insomnia. MethodsDemographic and polysomnographic data from 1272 individuals with insomnia recruited from the research database of the sleep laboratory of Erasme Hospital were analyzed. HBP status was defined by the presence of one of the following: self-report at interview of either a physician's diagnosis or taking antihypertensive medication; or an average systolic blood pressure ≥140 mm Hg or an average diastolic blood pressure ≥90 mm Hg at the medical examination. Logistic regression analyses were conducted to examine the risk of HBP associated with objective sleep alterations and long-term use of benzodiazepine receptor agonists in individuals with insomnia. ResultsThe prevalence of HBP in individuals with insomnia is 30.03%. After adjustment for major confounding factors associated with HBP, multivariate logistic regression analysis revealed that short sleep duration (<5 h), severely reduced sleep efficiency (<65%), high sleep fragmentation (sleep fragmentation index ≥18/h), and long-term use of short or intermediate half-life benzodiazepine receptor agonists were significant risk factors for HBP in individuals with insomnia. ConclusionIn individuals with insomnia, objective sleep alterations and long-term use of short or intermediate half-life benzodiazepine receptor agonists are associated with higher risk of HBP. Therefore, better management of these reversible risk factors is required to avoid the negative consequences of the co-occurrence of insomnia and HBP.

Abordaje del riesgo de delirium en una unidad de ortogeriatría

IntroductionThe objective of this study is to evaluate the efficacy of a change in the management of the risk of delirium in an orthogeriatric unit. Material and methodsProspective, comparative, non-randomised study of two cohorts of patients. One cohort (control group) treated with standard therapy with tramadol rescue and diazepam and another cohort (experimental group) treated with rescue with morphine at low doses and short half-life benzodiazepines as well as preventive treatment with neuroleptics in patients at high risk. ResultsEighty-five patients were included (42 in the control group and 43 in the experimental group). Mean age: 85 (71-105). Twenty-nine patients (34%) had an episode of delirium during the current admission, 16 patients (38%) in the control group and 13 patients (30%) in the experimental group respectively (P=.498). The mean duration of delirium in the 29 patients who presented it was 5.3 days. This duration in the control group was 6.6 days and in the experimental group 3.8 days (P=.031). In the group of patients who had previous delirium, a lower incidence of delirium was seen during the current admission in the experimental group (80% vs 17% P=.036). ConclusionsExperimental treatment has been effective since a trend to a lower incidence of delirium has been observed. In the patients who have suffered an episode of delirium, the treatment served to decrease its duration with statistically significant differences.

Number of illness episodes as predictor of residual symptoms in major depressive disorder

Notwithstanding major depressive disorder (MDD) is a recurring and chronic condition, relatively few variables have consistently been shown to predict its course. Residual depressive symptoms may be associated with disability and functional impairment but few studies evaluated clinical correlates associated with these symptoms and their impact on functioning after adjustment for potential confounders. Therefore, our study aimed to investigate factors associated with residual depressive symptoms and their impact on the course of MDD. The sample consisted of 210 consecutive MDD euthymic outpatients (67.6% females; mean age = 52.1 ± 15.5), admitted to the Section of Psychiatry, University of Genoa (Italy). Residuals depressive symptoms were significantly associated with female gender; use of short half-life benzodiazepines; longer duration of the current depressive episode; higher number of illness episodes; and higher duration of illness. Conversely, prior treatment with first-generation antipsychotics, later age of illness onset and first hospitalization were less frequently observed among patients with residual symptoms. After multivariate analyses, only duration of current illness episodes (ß = 0.003; p = <0.005) and substance abuse (ß = 0.042; p = <0.05) remained significantly associated with residual symptoms. Our findings indicate that residual depressive symptoms conferred a pernicious illness course in this specific cohort of MDD patients. Future trials mainly targeting these burdensome symptoms are warranted.

Trends in incident use of benzodiazepines and Z-drugs in France from 2006 to 2012: a population-based study.

To study trends in incident use of benzodiazepines in France between 2006 and 2012. A cross-sectional study repeated yearly was conducted using data from the French national healthcare insurance system. New benzodiazepine users were defined as users without any benzodiazepine dispensing in the year prior to the first dispensing of benzodiazepine in each year. Relative changes in incidence of use were calculated with the year 2006 as reference; confidence intervals for changes were estimated using the bootstrap method. Over the study period, the incident use of benzodiazepines decreased from 6.2% to 5.9%; this corresponded to a 5.1% decrease (95%CI: -6.8% to -4.2%) for 2012 compared to 2006. The decrease mainly concerned hypnotics (-15.5%; -21.2% to -15.3%) and appeared more pronounced in people aged 18-44 years. Incident use of anxiolytics remained stable overall during the period (4.0% of the population). Within anxiolytics, incident use of long half-life benzodiazepines (bromazepam, prazepam) decreased in favor of short half-life benzodiazepines (alprazolam, oxazepam). This change concerned patients aged 65-79 and patients aged 80 years and over. Nevertheless, in 2012, nearly one third of incident users aged 65 years and over started a treatment with a long half-life benzodiazepine, mostly bromazepam. A limited decrease in incident benzodiazepine use was observed in France between 2006 and 2012 that concerned only hypnotics. Although congruent with recommendations, this improvement appears insufficient with regard to the level of exposure to these drugs in France. New actions especially targeting anxiolytic benzodiazepine use should be undertaken to consolidate these results. Copyright © 2016 John Wiley & Sons, Ltd.

Benzodiazepine, psychotropic medication, and dementia: A population-based cohort study

IntroductionBenzodiazepine use has been associated with increased risk of dementia. However, it remains unclear whether the risk relates to short or long half-life benzodiazepines and whether it extends to other psychotropic drugs. MethodsProspective cohort study among 8240 individuals ≥65, interviewed on medication use. Incident dementia confirmed by an end point committee after a multistep procedure. ResultsDuring a mean of 8 years of follow-up, 830 incident dementia cases were observed. Users of benzodiazepines at baseline had a 10% increased risk of dementia (adjusted hazard ratio [HR], 1.10; 95% confidence interval, 0.90–1.34). However, long half-life (>20 hours) benzodiazepine users had a marked increased risk of dementia (HR = 1.62; 1.11–2.37) compared with short half-life users (HR = 1.05; 0.85–1.30). Users of psychotropics had an increased risk of dementia (HR = 1.47; 1.16–1.86). DiscussionResults of this large, prospective study show increased risk of dementia for long half-life benzodiazepine and psychotropic use.

Associations between Benzodiazepine Use and Neuropsychological Test Scores in Older Adults.

Benzodiazepines are widely prescribed for anxiety, although use of this class of medications has been associated with dependency and cognitive changes. This article describes the study in which we investigated the relationship between the class of benzodiazepine available for use and associated performance on neuropsychological tests in a community sample of 1,754 older Canadians from the Canadian Study of Health and Aging. Benzodiazepines were classified as short-, intermediate-, and long-acting. Associations were calculated between each class of benzodiazepine and eight neuropsychological measures, using multiple regression analysis and controlling for demographic variables. Results showed different effects of the co-variates across the three drug classes, and short half-life benzodiazepines were not associated with any neuropsychological measure. Intermediate half-life and long half-life benzodiazepine use were each associated with two measures. Increased focus on specific domains of cognitive function is needed to improve our understanding of how benzodiazepine use influences cognition.

Alzheimer's Risk Rises With Chronic Benzodiazepine Use

BERLIN – Chronic use of benzodiazepines by elderly patients is associated with a 43%–51% increased risk of being diagnosed with Alzheimer's disease 5–10 years later, according to a large case-control study. “Considering the extent to which benzodiazepines are prescribed in the elderly population and the growing incidence of dementia, unwarranted chronic use of benzodiazepines in the elderly should be viewed as a public health issue,” Sophie Billioti de Gage said at the annual congress of the European College of Neuropsychopharmacology. Her case-control study used the Quebec health insurance database. The subjects were 1,796 elderly individuals diagnosed with Alzheimer's disease, each matched with four controls based upon age, gender, and duration of follow-up. The Quebec database permitted identification of all subjects with prescriptions for benzodiazepines during 2000–2009, a period 5–10 years prior to diagnosis of Alzheimer's disease. This substantial time lag was chosen because previous studies reporting a link between benzodiazepines and dementia have often been criticized for possible confounding due to reverse causality. That is, because many earlier studies featured a shorter interval between medication use and dementia diagnosis, skeptics argued that benzodiazepines might not have caused the dementia, but rather were prescribed to treat early manifestations of the disease, such as anxiety, depressive symptoms, and insomnia, explained Ms. Billioti de Gage, a PhD student at the University of Bordeaux, France. The database enabled her to determine how many cumulative days worth of benzodiazepine prescriptions participants filled during the study years, as well as whether the medications had a short or long half-life. In a multivariate analysis adjusted for stroke, myocardial infarction, hypertension, diabetes, and use of antiplatelet agents or anticoagulants during the period 5–10 years prior to diagnosis of Alzheimer's disease, the use of benzodiazepines was independently associated with a 51% increased risk of subsequent Alzheimer's, compared with nonusers. A dose-response relationship was apparent. Individuals with prescriptions for up to 90 days worth of benzodiazepines were not at significantly greater risk for future Alzheimer's disease than nonusers. Those with a cumulative 91- to 180-day exposure had a 32% increased risk compared with nonusers, however, and patients with more than 180 days of benzodiazepine use had an 84% increased risk. The association with later Alzheimer's disease was stronger in patients who used benzodiazepines with a half-life of 20 hours or longer. In a multivariate analysis they had a 70% greater risk of Alzheimer's, compared with nonusers. Patients who used a benzodiazepine having a half-life of less than 20 hours had a 43% increase in risk. When the multivariate analyses were further adjusted for anxiety, depressive symptoms, and insomnia – all of which can be prodromes of dementia – the results were not meaningfully altered, she added. This case-control study confirms the results of an earlier prospective population-based study by Ms. Billioti de Gage and colleagues. That French study also found a roughly 50% increased risk of dementia in elderly patients who initiated chronic benzodiazepine therapy (BMJ 2012;345:e6231). However, with only 1,063 participants, 253 of whom were diagnosed with dementia during 15 years of follow-up, the sample size was too small to draw firm conclusions. The current case-control study, with 8,980 subjects representative of the Quebec community-dwelling elderly population, is more persuasive, the investigator said. Guidelines recommend preferential use of short half-life benzodiazepines and short durations of use in the elderly; however, in clinical practice the medications are often used long-term. The biologic mechanism by which chronic use of benzodiazepines by elderly individuals might predispose to Alzheimer's disease hasn't been worked out, but the medications' short-term adverse effects on memory and cognition are well recognized. The case-control study was funded by the French Ministry of Health and the Funding Agency for Health Research of Quebec as well as by university grants. Editor's NoteOne more good reason not to use benzos indiscriminately. Although I am not sure this observed increase in dementia is cause and effect, we already have plenty of evidence that these drugs can be harmful, increasing falls and causing more disinhibition of behavior. And we have better drugs for anxiety (e.g., SSRIs) and insomnia anyway. Think twice before prescribing a benzo in this population, especially a long-acting one.—Karl Steinberg, MD, CMD Editor in Chief One more good reason not to use benzos indiscriminately. Although I am not sure this observed increase in dementia is cause and effect, we already have plenty of evidence that these drugs can be harmful, increasing falls and causing more disinhibition of behavior. And we have better drugs for anxiety (e.g., SSRIs) and insomnia anyway. Think twice before prescribing a benzo in this population, especially a long-acting one. —Karl Steinberg, MD, CMD Editor in Chief

Did the new French pay-for-performance system modify benzodiazepine prescribing practices?

BackgroundFrench general practitioners (GPs) were enrolled in a new payment system in January 2012. As part of a national agreement with the French National Ministry of Health, GPs were asked to decrease the proportion of patients who continued their benzodiazepine treatment 12 weeks after its initiation and to decrease the proportion of patients older than 65 who were prescribed long half-life benzodiazepines. In return, GPs could expect an extra payment of up to 490 euros per year. This study reports the evolution of the corresponding prescribing practices of French GPs during that period regarding patients who were prescribed a benzodiazepine for the first time.MethodsThe national healthcare system's administrative database was used to report the longitudinal follow-up of two historical cohorts of French patients from the Pays de la Loire area.Study patients: The “2011” and “2012” cohorts included all patients who initiated benzodiazepine regimens from April 1 to June 30 in 2011 and 2012, respectively.The primary outcomes were the proportion of those study patients who continued benzodiazepine treatment after 12 weeks and the proportion of study patients >65 years who were prescribed long half-life benzodiazepines.Analyses were performed using a multi-level regression.ResultsIn total, 41,436 and 42,042 patients initiated benzodiazepine treatment in 2011 and 2012, respectively. A total of 18.97% of patients continued treatment for more than 12 weeks in 2012, compared with 18.18% in 2011. In all, 27.43% and 28.06% of patients >65 years continued treatment beyond 12 weeks in 2011 and 2012, respectively. The proportion of patients >65 years who were prescribed long half-life benzodiazepines decreased from 53.5% to 48.8% (p < 0.005) due to an increase in short half-life benzodiazepine prescriptions. Patients >65 years who were prescribed short half-life benzodiazepines were more likely to continue treatment after 12 weeks (p < 0.005).ConclusionsDespite the pay-for-performance strategy, the number of short half-life benzodiazepine prescriptions increased between 2011 and 2012, and the number of long half-life benzodiazepine initiations remained unchanged. Reducing the proportion of long half-life benzodiazepine prescriptions might be counterproductive because prescribing short half-life benzodiazepines was associated with higher rates of continuation beyond the recommended duration.

Psychotropic Medications and Falls in Nursing Homes: A Cross-Sectional Study

Psychotropic medications are very frequently used in nursing homes and have been associated with falls. Little is known on the potential differences between types and subtypes of these medications, and also regarding different prescription patterns. Data from 4502 residents living in 41 nursing homes belonging to a Spanish private chain were collected during a study period of 1 month and analyzed. Frequency of injurious and noninjurious falls were investigated for the following groups of psychotropic medications: typical neuroleptics; atypical neuroleptics; antidepressants; short and middle half-life benzodiazepines (BZD); long half-life BZD; BZD (of any type) administered only if needed; other hypnotic, sedative or anxiolytic drugs; cholinesterase inhibitors, and memantine. OR (95% CI) were calculated using regression analysis adjusted for age, sex, number of medications, physical restraint, and cognitive performance. Mean age (SD) was 84.3 (8.6) and 73.4% of the subjects were female. Psychotropic medication was prescribed to 2987 residents (66.3%), and there were 490 falls. Total falls were associated with use of atypical neuroleptics (OR 1.50, CI 1.17‒1.94), antidepressants (OR 1.36, CI 1.03‒1.78), short and middle half-life BZD (OR 1.27, CI 1.00‒1.60), long half-life BZD (OR 1.65, CI 1.14‒2.38), cholinesterase inhibitors (OR 1.42, CI 1.05‒1.92), and memantine (OR 1.90, CI 1.32‒2.74). Injurious falls were associated with typical neuroleptics (OR 1.77, CI 0.99‒3.17), atypical neuroleptics (OR 1.64, CI 1.11‒2.44), and long half-life BZD (OR 2.57, CI 1.56‒4.25). The use of 2 or more psychotropics in combination was also associated with a significant increase of total falls and injurious falls. Psychotropic medications were highly prescribed in the studied sample and were associated with falls. The most unsafe profile was detected for long half-life BZD, neuroleptics, and psychotropics in combination.

TO SUBSTITUTE OR NOT SUBSTITUTE-OPTIMAL TACTICS FOR THE MANAGEMENT OF BENZODIAZEPINE DEPENDENCE

I read with interest and some astonishment the work of Liebrenz et al. [1], which suggested benzodiazepine ‘substitution’, preferably with long-acting benzodiazepine (BZD), for long-term users. There are no empirical data to support the authors' view, so the discussion about the proposed procedure is academic; however, a few critical issues are apparent. Treatment of long-term benzodiazepine users is undoubtedly a difficult and often disappointing task, as is addiction medicine per se. A long-term study of patients with ‘complicated’ withdrawal showed that only 25% remained BZD free [2]. There are a number of reasons for discontinuing BZDs, including improvement of psychomotor and cognitive performance and also the risk of personality changes often seen in long-term users (something not mentioned by the Liebrenz paper). The empirical basis considering the optimal pharmacological strategy for withdrawing BZDs is limited, but the clearest strategy is to taper the medication [3,4]. A Cochrane analysis found only carbamazepine to be helpful with modest benefits in reducing withdrawal severity [5]. In addition, short half-life BZDs are associated with higher dropout rates, but switching from short-life BZDs to long half-life BZDs before gradual taper withdrawal did not receive much support from the Cochrane review. Nevertheless, Lader et al. [4] suggested that the substitution of diazepam for another BZD can be helpful, ‘at least logistically’, because diazepam is available in a liquid formulation. There are also a number of studies on optimal psychotherapeutic interventions [2,6,7], with cognitive–behavioural interventions probably having the best evidence. Terminology is sometimes important to avoid misunderstandings. As a non-native English speaker I wonder whether the term ‘substitution’ is really adequate for the suggested procedure. Maintenance may be the better term. The real question is whether or not to discontinue BZDs, which is difficult to decide based upon patient characteristics. Both high-dosage BZDs [2] and intensive craving for BZDs [8] are associated with negative outcome. No one would argue that replacing vodka with beer is a form of substitution treatment, and it is difficult to see why this should be different with respect to drugs. Taking into account the small number of clinical trials in this area, the therapeutic pessimism of the Liebrenz paper and the call for ‘agonist’ substitution seems to be a little premature. Patients with BZD dependence are undertreated compared to patients with alcohol or other substance use dependence [9], so the primary research focus might be to get more patients into treatment, and into treatment earlier, and to develop better evidence-based tactics rather than following an approach of unconditional surrender by simply replacing one BZD with another. Finally, some pharmacological comments. As outlined above, the recent Cochrane analysis does not support the authors' view on half-lives as being the essential point—although it is easy to see that a long-acting compound may be easier to handle compared with short-acting ones. Longer-acting drugs may have a higher risk of accumulating in the body and causing hangover. Many BZDs have pharmacologically active metabolites and may therefore also not be optimal for ‘substitution’ treatment. It may make sense to study other compounds such as BZD receptor modulators, as suggested by Denis et al. [5], or other psychoactive drugs, especially as most patients with BZD dependence have psychiatric disorders, rather than continuing travelling on a ship that should have been abandoned a long time ago. None.

Agonist substitution—a treatment alternative for high‐dose benzodiazepine‐dependent patients?

There is vast evidence for the superiority of agonist treatments (methadone, buprenorphine) over a withdrawal approach in opioid-dependent populations. Little research, however, has been conducted on the same approach for the treatment of high-dose benzodiazepine (BZD) dependence. Even large-scale reviews and meta-analyses discussing treatment strategies for benzodiazepine-dependent patients focus solely upon approaches that aim at achieving abstinence, namely on complete BZD withdrawal. While the types of interventions differ (e.g. gradual benzodiazepine taper with a long or a short half-life benzodiazepine, switching to non-benzodiazepine anxiolytics or prescribing adjunctive medications such as antidepressants or anticonvulsants on an in- or out-patient basis), the common aim of treatment still is total abstinence from benzodiazepines. However, the majority of patients suffering from high-dose BZD dependence do not succeed with long-term abstinence, irrespective of the procedure, and clinicians have been using BZD 'substitution' treatment in such cases for decades. Therefore, we suggest the evaluation of a substitution approach in this group, consisting of maintenance treatment with a slow-onset, long-acting BZD. Advantages of such a procedure may be improved health, less craving, fewer withdrawal complications, reduced anxiety, increased treatment retention, improvements in social functioning and less illegal activity. Cognitive impairments, the most problematic side effects of substitution treatment with benzodiazepines, could possibly be minimized by using an optimal agonist.

The Impact of Benzodiazepines on Safe Driving

Objective. Benzodiazepines are prescribed to relieve anxiety and aid sleep. Studies demonstrate that benzodiazepines increase odds of crash involvement, but little evidence exists regarding their impact on crash responsibility. We examined the impact of benzodiazepines on crash responsibility by drug half-life and driver age, using a case-control design with drivers aged 20 and over involved in fatal crashes in the United States from 1993–2006. Methods. Drivers (all with BAC = 0) were classified as having no benzodiazepines detected versus short, intermediate, or long half-life benzodiazepines. Cases were drivers with at least one potentially unsafe driving action (UDA) in relation to the crash (e.g., speeding), a proxy measure for crash responsibility; controls had no UDAs recorded. Odds ratios (ORs) of any UDA by benzodiazepines half-life exposure were calculated, with adjustment for age, sex, other medication usage, and prior driving record. Results. Compared with drivers not using benzodiazepines, drivers taking intermediate or long half-life benzodiazepines demonstrated increased odds of an UDA from ages 25 (intermediate OR: 1.59; 95% CI = 1.08, 2.33; long OR: 1.68; 95% CI = 1.34, 2.12) to 55 (intermediate OR: 1.50; 95% CI = 1.09, 2.06; long OR: 1.33; 95% CI = 1.12, 1.57). Drivers taking short half-life benzodiazepines did not demonstrate increased odds compared to drivers not using benzodiazepines. Conclusions. Given the potential impact of benzodiazepines on driver safety, further experimental research is needed to better understand the effect of benzodiazepines on crash responsibility.

Regular Prescriptions for Benzodiazepines: A Cross-Sectional Study of Outpatients at a University Hospital

To investigate 1) the patterns of regular prescriptions for benzodiazepines among department clinics in a university teaching hospital, 2) the effects of patient's characteristics on regular benzodiazepine prescriptions, and 3) the patterns of benzodiazepine prescriptions among department clinics from the perspective of pharmacological half-life. Patients were 22,099 outpatients (51% female; mean age: 56 years) who were prescribed any drug three or more times. Cross-sectional study of patient-based data (July 2002 to August 2003) from the database of a computer ordering system at a university hospital. The patterns of regular prescriptions for benzodiazepines were compared among the clinical departments (i.e., Internal Medicine, Psychiatry, and Others). A logistic regression model was used to assess the effects of patient gender and age, and the clinic visited on the issuing of regular prescriptions for benzodiazepines. Regular benzodiazepine users were 3,204 (14.5%). Benzodiazepines were more likely to be prescribed for women (61.3%) than for men and were prescribed most often by psychiatrists (31.7%), followed by internists (20.1%). Multivairate logistic regression model showed that being female and elderly, and being prescribed by a psychiatrist were significantly associated with regular benzodiazepine prescriptions. With regard to the pharmacological half-life, internists were more likely to prescribe short half-life benzodiazepines than were psychiatrists (p < 0.001). A large number of outpatients at a Japanese university hospital appeared to be maintained on a regular supply of benzodiazepine drugs. Educational programs are needed to promote the rational prescribing of benzodiazepines.

Benzodiazepine use and hip fractures in the elderly: who is at greatest risk?

It remains unclear whether benzodiazepine use increases hip fracture incidence. We studied this relationship in a large cohort, controlling for multiple potential confounders. We analyzed 42 months of New Jersey Medicaid health care claims data for all enrollees. Each eligible person-day was assigned to categories of benzodiazepine exposure and categories of other predictors, based on prior and current medication dispensing and diagnosis information. Hip fractures were identified based on hospital claims with primary discharge diagnosis International Classification of Diseases, Ninth Revision (ICD-9) codes 820.xx. Cohort members (n = 125 203) contributed 194 071 person-years and had 2312 eligible hip fractures. After adjustment for age, sex, race, Medicaid nursing home residence, exposure to other psychoactive medications, including antiparkinsonian medications, diagnoses of epilepsy and dementia, and hospitalization in the previous 6 months, the incidence rate of hip fracture was significantly higher compared with no benzodiazepine use for exposure to any benzodiazepine (incidence rate ratio [IRR], 1.24; 95% confidence interval [CI], 1.06-1.44), to a short half-life, high-potency benzodiazepine (IRR, 1.27; 95% CI, 1.01-1.59), during the first 2 weeks after starting a benzodiazepine (IRR, 2.05; 95% CI, 1.28-3.28), during the second 2 weeks after starting a benzodiazepine (IRR, 1.88; 95% CI, 1.15-3.07), and for continued use (IRR, 1.18; 95% CI, 1.03-1.35). The incidence of hip fracture appears to be associated with benzodiazepine use. Contrary to several previous studies, short half-life benzodiazepines are not safer than long half-life benzodiazepines. Hip fracture risk is highest during the first 2 weeks after starting a benzodiazepine and declines thereafter.

French general practitioners' prescribing high-dosage buprenorphine maintenance treatment: Is the existing training (good) enough?

In France, since 1996, any general practitioner (GP) can prescribe high-dosage buprenorphine maintenance treatment (BMT) for opioid-dependent patients. The health authorities initially provided mandatory specific training, but since 1998, such training is only delivered by specialized networks and the pharmaceutical industry. Among a random sample of GPs from southeastern France ( N=345), we found that many untrained GPs, as well as a significant minority of trained GPs, were likely to prescribe an ineffective dosage of buprenorphine or a potentially dangerous treatment (BMT+a short half-life benzodiazepine). These results highlight the necessity to edit clear guidelines, especially concerning situations of polyaddiction and psychiatric comorbidity, and to extend and improve BMT training in France with a renewed involvement of health authorities for quality control of such training. They even suggest that GPs' participation to specialized training sessions should become a mandatory prerequisite for prescribing BMT.