Impact of narcotics information management system on inappropriate benzodiazepine receptor agonist prescriptions: A quasi-experimental analysis in South Korea.

AIMS: The South Korean government implemented the narcotics information management system (NIMS) on 18 May 2018 to manage benzodiazepine receptor agonists (BzRAs) and narcotics effectively and establish a reporting mechanism for these drugs. This study assessed the effects of NIMS on inappropriate use of BzRAs. METHODS: Using national patient sample data from 2016 to 2020, we analysed adult outpatients who were prescribed oral BzRAs. We conducted a time series and segmented regression analysis using selected indicators to analyse the monthly variations related to the inappropriate use of these medications. RESULTS: The study revealed no significant changes in the indicators of inappropriate BzRA use following the NIMS implementation. Contrary to expectations, there was a significant increase in the proportion of patients exceeding defined daily dose (DDD) and in those receiving concurrent prescriptions of multiple BzRAs, following the implementation of NIMS. The immediate impact of the COVID-19 pandemic was an increase in DDD exceedance; however, overall, this did not significantly affect BzRA use. CONCLUSIONS: The introduction of NIMS did not significantly enhance the management of BzRA misuse. Additional measures, including continuous monitoring, system improvements and comprehensive education for prescribers and patients, are recommended to ensure the appropriate use of psychotropic medications.

Gestational exposure to benzodiazepines or z-hypnotics and neurodevelopmental disorders in offspring: Systematic review and meta-analysis.

INTRODUCTION: Benzodiazepine (BDZP) and/or z-hypnotic dispensing during pregnancy has increased globally, as have rates of autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD). This systematic review and meta-analysis aimed to estimate the association between gestational exposure to BDZP and/or z-hypnotics and diagnosis of ASD or ADHD in offspring. METHODS: We searched MEDLINE, EMBASE, and SCOPUS from inception till December 2023 for relevant English-language articles. Outcomes of interest were risk of ASD and ADHD, two independent primary outcomes, in children exposed anytime during pregnancy to BDZP and/or z-hypnotics versus those unexposed. Secondary outcomes were trimester-wise analyses. Using a random effects model, we pooled the overall and trimester-wise hazard ratios (HRs), with 95% confidence intervals (CIs), separately for risk of ASD and ADHD. RESULTS: We found six eligible retrospective cohort studies and no case-control studies. There was no increased risk of ASD associated with anytime gestational BDZP and/or z-hypnotic exposure (primary outcome, HR, 1.10; 95% CI, 0.81-1.50; 4 studies; n = 3,783,417; 80,270 exposed, 3,703,147 unexposed) nor after first trimester exposure (HR, 1.15; 95% CI, 0.83-1.58; 3 studies; n = 1,539,335; 70,737 exposed, 1,468,598 unexposed) or later trimester exposures. A very small but significantly increased risk of ADHD was noted with anytime gestational exposure to these drugs (primary outcome, HR, 1.07; 95% CI, 1.03-1.12; 4 studies; n = 2,000,777; 78,912 exposed, 1,921,865 unexposed) and also with (only) second trimester exposure (HR, 1.07; 95% CI, 1.03-1.12; 3 studies; n = 1,539,281; 33,355 exposed, 1,505,926 unexposed). Findings were consistent in sensitivity analyses. CONCLUSION: Gestational exposure to benzodiazepines or z-hypnotics was not associated with an increased risk of ASD and with only a marginally increased risk of ADHD in offspring. Given the likelihood of confounding by indication and by unmeasured variables in the original studies, our findings should reassure women who need these medications for severe anxiety or insomnia during pregnancy.

Association between nocturnal falls and hypnotic drug use in older patients at acute care hospitals.

PURPOSE: Although hypnotic drug use is a known risk factor for falls, few reports have analyzed fall risk associated with individual hypnotic drugs after adjusting for confounding factors. While it is recommended that benzodiazepine receptor agonists not be prescribed for older adults, it is unknown whether melatonin receptor agonists and orexin receptor antagonists are safe in this population. Here, we aimed to assess the influence of various hypnotic drugs on fall risk in older patients admitted to acute care hospitals. METHODS: We investigated the relationship between nocturnal falls and sleeping pill use in 8,044 hospitalized patients aged > 65 years. We used a propensity score matching method to homogenize characteristics of patients with and without nocturnal falls (n = 145 patients per group) using 24 extracted factors (excluding hypnotic drugs) as covariates. RESULTS: Our analysis of fall risk for each hypnotic drug revealed that benzodiazepine receptor agonists were the only drugs significantly associated with falls, suggesting that use of the drugs is a risk factor for falls in older adults (p = 0.003). In addition, a multivariate analysis of 24 selected factors, excluding hypnotic drugs, revealed that patients with advanced recurrent malignancies were at greatest risk of experiencing falls (OR: 2.62; 95% CI: 1.23-5.60; p = 0.013). CONCLUSION: Benzodiazepine receptor agonists should be avoided in older hospitalized patients since they increase fall risk, with melatonin receptor agonists and orexin receptor antagonists used instead. Particularly, fall risk associated with hypnotic drugs should be considered in patients with advanced recurrent malignancies.

Prevalence of and factors associated with acute withdrawal symptoms after 24 weeks of eszopiclone treatment in patients with chronic insomnia: a prospective, interventional study.

BACKGROUND: Although long-term use of benzodiazepines and benzodiazepine receptor agonists (BZDs) has been associated with an increased risk of dependence, the incidence, details of clinical manifestations, and triggering factors of withdrawal symptoms associated with long-term BZD use at common clinical doses remain unclear. METHODS: In a multicenter, open-label study of 123 Japanese patients with insomnia, patients were given a common clinical dose of eszopiclone (2 mg) for 24 weeks, and then treatment was abruptly discontinued. Withdrawal symptoms were evaluated using the Benzodiazepine Hypnotics Withdrawal Symptom Scale (BHWSS). The Insomnia Severity Index (ISI) was used to rate insomnia severity during treatment and 2 weeks after discontinuation. Dependence and poor compliance during treatment without strict medication controls were evaluated with the Benzodiazepine Dependence Self Report Questionnaire short version (Bendep-SRQ SV) subscale sum scores for problematic use, preoccupation, and lack of compliance. Associations between the presence of clinically relevant withdrawal symptoms (BHWSS≥7) and demographic measures, ISI scores at Week 24, and Bendep-SRQ SV subscale sum scores were evaluated by multivariable stepwise logistic regression analyses. RESULTS: Seventy-six patients completed treatment and 2 weeks of withdrawal; eight (10.5%) had clinically relevant withdrawal symptoms. On multiple logistic regression analysis, Bendep-SRQ SV subscale sum scores were correlated with withdrawal symptoms (odds ratio, 1.650; 95% confidence interval, 1.105-2.464; p = 0.014). Exacerbation of post-discontinuation insomnia was not significantly different between patients who showed clinically relevant withdrawal symptoms and those who did not (p = 0.245). CONCLUSIONS: Dependence and poor compliance may contribute to withdrawal symptoms with long-term BZD use. Providing guidance to ensure proper compliance is thought to be the best way to mitigate withdrawal symptoms. TRIAL REGISTRATION: UMIN000024462 (18/10/2016).

An explorative approach to understanding individual differences in driving performance and neurocognition in long-term benzodiazepine users.

OBJECTIVE: Previous research reported cognitive and psychomotor impairments in long-term users of benzodiazepine receptor agonists (BZRAs). This article explores the role of acute intoxication and clinical complaints. METHODS: Neurocognitive and on-road driving performance of 19 long-term (≥6 months) regular (≥twice weekly) BZRA users with estimated plasma concentrations, based on self-reported use, exceeding the therapeutic threshold (CBZRA +), and 31 long-term regular BZRA users below (CBZRA -), was compared to that of 76 controls. RESULTS: BZRA users performed worse on tasks of response speed, processing speed, and sustained attention. Age, but not CBZRA or self-reported clinical complaints, was a significant covariate. Road-tracking performance was explained by CBZRA only. The CBZRA  + group exhibited increased mean standard deviation of lateral position comparable to that at blood-alcohol concentrations of 0.5 g/L. CONCLUSIONS: Functional impairments in long-term BZRA users are not attributable to self-reported clinical complaints or estimated BZRA concentrations, except for road-tracking, which was impaired in CBZRA + users. Limitations to address are the lack of assessment of objective clinical complaints, acute task related stress, and actual BZRA plasma concentrations. In conclusion, the results confirm previous findings that demonstrate inferior performance across several psychomotor and neurocognitive domains in long-term BZRA users.

Long-Term Use of Benzodiazepines and Benzodiazepine-Related Drugs: A Register-Based Danish Cohort Study on Determinants and Risk of Dose Escalation.

OBJECTIVE: The authors investigated the frequency and determinants of long-term use and risk of dose escalation of benzodiazepines and benzodiazepine-related drugs (benzodiazepine receptor agonists, or BZRAs). METHODS: All adults ages 20-80 years living in Denmark on January 1, 2000 (N=4,297,045) were followed for redeemed prescriptions of BZRAs in the Danish National Prescription Registry from January 1, 2000, to December 31, 2020. For each drug class, we calculated long-term use for more than 1 or 7 years, and dose escalation measured as increase in dose to a level above the recommended level. Associations were examined using logistic regression. RESULTS: The authors identified 950,767 incident BZRA users, of whom 15% and 3% became long-term users for more than 1 or 7 years, respectively. These percentages were highest for individuals who initiated Z-drugs (17.8% and 4%). Among the 5% of BZRA users who had at least 3 years of continuous use, there was no indication of dose escalation, as the median dose remained relatively stable. However, 7% (N=3,545) of BZRA users escalated to doses above the recommended level. Psychiatric comorbidity, especially substance use disorder, was associated with higher risk of long-term use and dose escalation. CONCLUSIONS: A limited portion of the population that received BZRA prescriptions were classified as continuous users, and only a small proportion of this group escalated to doses higher than those recommended in clinical guidelines. Thus, this study does not, under the current regulations, support the belief that BZRA use frequently results in long-term use or dose escalation.

Association Between Hypnotic Use and All-Cause Mortality in Patients with Chronic Obstructive Pulmonary Disease and Insomnia.

Purpose: Hypnotics are commonly prescribed in patients with COPD to manage insomnia. Given the considerable risks associated with these drugs, the aim of the study was to evaluate the risk of all-cause mortality associated with hypnotics in a cohort of veterans with COPD presenting with insomnia. Methods: We conducted a retrospective cohort study that used Veterans Health Administration Corporate Data Warehouse with data supplemented by linkage to Medicare, Medicaid, and National Death Index data from 2010 through 2019. The primary outcome was all-cause mortality. Analyses were conducted using propensity score 1:1 matching to balance baseline characteristics. Results: Of the 5759 veterans with COPD (mean [SD] age, 71.7 [11.2]; 92% men), 3585 newly initiated hypnotic agents during the study period. During a mean follow-up of 7.4 (SD, 2.7) years, a total of 2301 deaths occurred, with 65.2 and 48.7 total deaths per 1000 person-years among hypnotic users and nonusers, respectively. After propensity matching, hypnotic use was associated with a 22% increased risk of mortality compared with hypnotic nonusers (hazard ratio [HR] 1.22; 95% confidence interval [CI],1.11-1.35). The benzodiazepine receptor agonists (BZRAs) group experienced a higher incidence rate of all-cause mortality compared to hypnotic nonusers (Incidence rate ratio [IRR] 1.27; 95% CI, 1.14-1.43). Conversely, the mortality rate of non-BZRA hypnotics decreased after the first 2 years and was not significantly different for hypnotic nonusers (IRR 1.04; 95% CI, 0.82-1.11). Conclusion: Among patients with COPD and insomnia, treatment with hypnotics was associated with a higher risk of all-cause mortality. The association was observed in patients prescribed BZRAs. The risk of mortality for non-BZRAs moderated after the first 2 years, indicating a class effect.

Adaptation and validation of the revised Patients' Attitudes towards Deprescribing (rPATD) questionnaire for benzodiazepine receptor agonists.

BACKGROUND: The revised Patients' Attitudes Towards Deprescribing (rPATD) questionnaire explores older adults' views on deprescribing in general. Those views may differ, however, when the target is a specific drug such as benzodiazepine receptor agonists (BZRA). OBJECTIVE: This study aimed to adapt the 22-item French rPATD questionnaire to create a BZRA-specific instrument and to assess the psychometric properties of this new tool. METHODS: The adaptation of the questionnaire comprised 3 steps: 1) item transformation during group discussions with 8 healthcare providers and 8 BZRA users (aged ≥65 years), 2) pre-test of the questionnaire with 12 other older adults to ensure items understanding, 3) evaluation of the psychometric properties of the new questionnaire with 221 older BZRA users recruited in Belgium, France, and Switzerland. Construct validity was assessed using exploratory factor analysis (EFA), internal consistency with Cronbach's alpha, and test-retest reliability with intraclass correlation coefficient (ICC). RESULTS: After the pre-test, the questionnaire had 24 items (19 adapted from the French rPATD, 3 removed, and 5 added). The EFA, however, found that several items performed poorly. Eleven items were consequently removed, based on statistical performance and clinical relevance. Three factors were extracted from the EFA performed on the 11 retained items and were named "Concerns about stopping BZRA", "BZRA inappropriateness", and "Dependence on BZRA". The questionnaire also includes two global questions about willingness to reduce BZRA dosage and willingness to discontinue BZRA. All factors showed acceptable internal consistency (0.68 ≤ Cronbach's alpha ≤0.74). Two factors showed acceptable test-retest reliability. The "Concerns about stopping BZRA" factor was found to vary over time (ICC [95%CI]: 0.35[-0.02; 0.64]). CONCLUSIONS: We developed and validated a 13-item questionnaire to evaluate the attitudes of older people towards BZRA deprescribing. Despite some limitations, this questionnaire appears to be a useful tool for facilitating shared decision-making on BZRA deprescribing.

Trends in Prescriptions for Insomnia in a Province in China Between 2015 and 2019.

Background: The inappropriate use of pharmacological treatments for insomnia may increase patients' risk of serious adverse events. However, few epidemiological studies on the use of medications for insomnia in China have been conducted to date. Objective: We aimed to investigate the current pharmacological treatments for insomnia and guide the rational use of drugs. Methods: The prescription data of outpatients with insomnia between 2015 and 2019 in Zhejiang province were extracted from the Hospital Prescription Analysis Cooperative Project of China and evaluated. The demographic characteristics of insomnia and the proportion and prescription trends of different drugs were analyzed along with multidrug combinations for insomnia. Results: The number of patients with insomnia who were prescribed medications for insomnia increased from 2,385 in 2015 to 3,919 in 2019, with an increase of 64.32%, whereas the mean age of these patients decreased from 64.07 years to 60.94 years. There were nearly 1.42 times as many female patients prescribed medications for insomnia as male patients, and female patients tended to be younger than male patients. Benzodiazepines (53.99%) were the most common type of medicine for insomnia. The incidence of benzodiazepine usage decreased significantly yearly (P < 0.01), whereas the incidences of non-benzodiazepine receptor agonist (nBZRA) and antidepressant usage increased (P < 0.05). The most common benzodiazepine, nBZRA, antidepressant, and antipsychotic were estazolam, zolpidem, trazodone, and olanzapine, respectively. A total of 13.97% of outpatients with insomnia were prescribed multiple drugs for insomnia, even though nearly half of the drug combinations had similar pharmacological mechanisms. Conclusions: Benzodiazepines remained the most common medication for insomnia, but the prescription rates of nBZRAs and antidepressants increased. Attention should be paid to multidrug combinations for insomnia, which may lead to an increased risk of serious adverse effects.

Hazardous use of benzodiazepine receptor agonists in psychiatric clinics in China: electronic prescription database study.

BACKGROUND: Benzodiazepine receptor agonists (BZRAs) are commonly used clinically and data on their hazardous use from large populations of psychiatric patients is limited. AIMS: To assess the current status of hazardous BZRA use and related factors in Chinese out-patient psychiatric settings. METHOD: The study included out-patients with at least one BZRA prescription from five psychiatric settings in east, central and west China in 2018. Demographic and prescription information were extracted from the electronic prescription database. We defined the co-occurrence of overdose and long-term use as hazardous use, and patients whose recorded diagnoses did not meet any indications approved by the Chinese Food and Drug Administration as over-indication users. Additionally, 200 hazardous users were randomly selected for follow-up interview to confirm the actual situation. RESULTS: Among 720 054 out-patients, 164 450 (22.8%) had at least one BZRA prescription; 55.9% of patients were prescribed over-indication and 3% were defined as hazardous users. Multilevel multivariate regression analysis with hospital as a random effect showed that factors associated with hazardous use were older age (18-64 years: ß = 0.018; 95% CI 0.013-0.023; >65 years: ß = 0.015; 95% CI 0.010-0.021), male (ß = 0.005, 95% CI 0.003-0.007), over-indication (ß = 0.013, 95% CI 0.012-0.015), more out-patient visits (ß = 0.006, 95% CI 0.006-0.006) and more visits to different doctors (ß = 0.007, 95% CI 0.007-0.008); 98.5% of hazardous users (197/200) could not be contacted. CONCLUSIONS: BZRAs are commonly used and there is a relatively large proportion of over-indication users among Chinese psychiatric out-patients. However, only a small proportion of hazardous users were detected. The study highlights how to use prescription data to support improvements in clinical practice.

A protocol for a randomized controlled trial comparing Sleepwell, EMPOWER, and treatment-as-usual for benzodiazepine receptor agonist discontinuation in older adults: the your answers when needing sleep in New Brunswick (YAWNS NB) study.

Background: Chronic benzodiazepine receptor agonist (BZRA) use among older adults is a public health concern given cognitive and physical risks. One in four older adults in New Brunswick, Canada, is a long-term user of BZRAs. Previous studies using a direct-to-patient approach as the primary intervention target have shown promise in reducing BZRA use. The Your Answers When Needing Sleep in New Brunswick (YAWNS NB) study aims to reduce the long-term use of BZRAs in older adults and increase the use of cognitive behavioural therapy for insomnia (CBTi), which is the recommended first line treatment. Methods: The trial (ClinicalTrials.gov registration NCT04406103) is a three arm, open-label, parallel randomized controlled trial in NB, Canada. Eligible participants 65 years and older using BZRAs long-term will be randomly allocated to: the Eliminating Medications through Patient Ownership of End Results (EMPOWER) information package group; the Sleepwell information package group; or treatment-as-usual (TAU). Information packages will be mailed via Canada Post. The primary outcome of BZRA discontinuation at 6 months will be compared across groups. Secondary outcomes include participants with ≥25% BZRA dose reduction, and switching to newly prescribed alternate sedative-hypnotics. Several exploratory outcomes will also be examined. Discussion: Targeting participants with information packages informing them of appropriate use, dangers, and approaches to reducing BZRA use and increasing CBTi use may be beneficial in a region of Canada with the highest rate of chronic BZRA use in older adults. Comparing information packages and TAU will provide insights into the effectiveness of direct-to-patient interventions for BZRA reduction.

Association of Benzodiazepine Receptor Agonist Use With Changes in Psoriasis Severity in Adult Population: A Population-Based Study.

To date, it remains uncertain whether benzodiazepine receptor agonists (BZRAs) are aggravating factors even though these drugs can elevate the levels of biomarkers associated with the development of psoriasis. Therefore, this study aimed to investigate the association of BZRA use with changes in psoriasis severity. All data were sourced from the National Health Insurance system in Taiwan. We conducted a population-based retrospective cross-sectional study of 15,727 psoriasis patients who received BZRAs (BZRA users), and 18,856 psoriasis patients who did not receive BZRAs (nonusers). At least a 1-year washout period without any BZRA prescriptions was required. The main outcome was the change in psoriasis severity between before and after BZRA exposure. This study detected the exacerbation of psoriasis severity in mild psoriasis population by using a logistic model. Then, this study carried another logistic model among those patients who had severe psoriasis to calculate the odds ratios (ORs) for the improvement of the psoriasis severity. Among patients with mild psoriasis, BZRA users had a significantly higher probability of psoriasis severity exacerbation (IPTW-adjusted OR = 1.46). Mild psoriasis patients who received high and low doses of BZRAs had 1.70- and 1.39-fold higher probabilities of psoriasis severity exacerbation, respectively, than the non-users. Furthermore, in the severe psoriasis population, more low-dose BZRA users improved psoriasis severity than non-users. In conclusion, this study provided clinical evidence of the effects of BZRA use on patients with psoriasis severity. Among patients with mild psoriasis, high-dose BZRA users may be associated with the changes in psoriasis severity. However, low-dose BZRA exposure only slightly exacerbated disease severity among patients with mild psoriasis. Accordingly, clinicians should evaluate the risks and benefits of the BZRA usage.

The Association between Use of Benzodiazepine Receptor Agonists and the Risk of Obstructive Sleep Apnea: A Nationwide Population-Based Nested Case-Control Study.

Obstructive sleep apnea (OSA) is characterized by recurrent upper airway collapse. Benzodiazepine receptor agonists (BZRAs) are associated with pharyngeal muscle relaxation, increased apnea duration, and hypoxia, which might worsen OSA. This study aimed to examine the association between the use of BZRAs and the risk of OSA. The study was conducted using data from the National Health Insurance Database of Taiwan between 2002 and 2011. We only included new users who were never exposed to any BZRAs and identified 1848 participants with OSA, and 1848 matched controls. A logistic regression model was used to determine the association between the use of BZRAs and the development of OSA. BZRA exposure was divided into usage patterns, dosage, duration, and pharmacokinetic class. We found an increased risk of OSA in current users and recent past users compared with distant past users. Patients with a higher cumulative dose of BZRAs were more likely to develop OSA compared to those with a lower cumulative dose. We found an increased risk of OSA in patients treated with BZRAs, especially for current users and those with higher cumulative doses. A reduced risk of OSA was found in Z-drug users compared with benzodiazepine users.

Effectiveness of Benzodiazepine Receptor Agonists in the Treatment of Insomnia: An Examination of Response and Remission Rates.

Study objectives: To examine the real-world effectiveness of benzodiazepine receptor agonists (BzRAs) by quantifying response and remission rates in a clinical sample receiving chronic BzRA treatment for insomnia. Methods: Participants were outpatients (N = 193; 72% female; 55.2 ± 11.1 year) who had an insomnia diagnosis per medical records, and who were taking a therapeutic dose of BzRA for their insomnia. Endpoints were nocturnal sleep disturbance and Insomnia Severity Index (ISI) scores. A reduction meeting the criterion for the minimally important difference in ISI scores (change ≥ 6) constituted "response"; "remission" was inferred when symptoms fell below the clinical cutoff (ISI < 11). Results: Most participants (71%) used BzRAs at least 5 nights per week. Mean ISI scores were significantly lower (t = 22.31; p < .01) while on BzRAs than when untreated, but remained in the clinical range (mean = 11.0; standard deviation = 5.7). Although 76.7% responded to treatment, only 47.7% remitted. The majority (68.9%) of participants had a sleep-onset latency > 30 minutes and/or wake-time after sleep onset > 60 minutes while on BzRAs. After controlling for gender and insomnia severity when untreated, odds of insomnia persistence despite BzRA use were 2 times higher in patients with comorbid medical [odds ratio (OR) = 2.39; 95% confidence interval (CI) = 1.20% to 4.77%; p < .05] and psychiatric disorders (OR = 2.24; 95% CI = 1.21% to 4.13%; p < .05). Conclusions: This is the first study to distinguish between response and remission in insomnia patients taking BzRAs. Findings suggest that while many insomnia patients respond to chronic BzRA treatment, most do not remit. Remission rates are particularly low for comorbid insomnia, the most prevalent phenotype of the disorder.

Non-Benzodiazepine Receptor Agonists for Insomnia.

Because of proven efficacy, reduced side effects, and less concern about addiction, non-benzodiazepine receptor agonists (non-BzRA) have become the most commonly prescribed hypnotic agents to treat onset and maintenance insomnia. First-line treatment is cognitive-behavioral therapy. When pharmacologic treatment is indicated, non-BzRA are first-line agents for the short-term and long-term management of transient and chronic insomnia related to adjustment, psychophysiologic, primary, and secondary causation. In this article, the benefits and risks of non-BzRA are reviewed, and the selection of a hypnotic agent is defined, based on efficacy, pharmacologic profile, and adverse events.

The Use of Benzodiazepine Receptor Agonists and Risk of Respiratory Failure in Patients with Chronic Obstructive Pulmonary Disease: A Nationwide Population-Based Case-Control Study.

STUDY OBJECTIVES: Insomnia is prevalent in patients with chronic obstructive pulmonary disease (COPD), and benzodiazepine receptor agonists (BZRAs) are the most commonly used drugs despite their adverse effects on respiratory function. The aim of this study was to investigate whether the use of BZRAs was associated with an increased risk of respiratory failure (RF) in COPD patients. DESIGN: Matched case-control study. SETTING: National Health Insurance Research Database (NHIRD) in Taiwan. PARTICIPANTS: The case group consisted of 2,434 COPD patients with RF, and the control group consisted of 2,434 COPD patients without RF, matched for age, sex, and date of enrollment. MEASUREMENTS AND RESULTS: Exposure to BZRAs during the 180-day period preceding the index date was analyzed and compared in the case and control groups. Conditional logistic regression was performed, and the use of BZRAs was associated with an increased risk of RF (adjusted odds ratio [aOR] 1.56, 95% confidence interval [CI] 1.14-2.13). In subgroup analysis, we found that the benzodiazepine (BZD) users had a higher risk of RF (aOR 1.58, 95% CI 1.14-2.20), whereas the risk in non-benzodiazepine (non-BZD) users was insignificant (aOR 0.85, 95% CI 0.51-1.44). A greater than 2-fold increase in risk was found in those who received two or more kinds of BZRAs and those using a combination of BZD and non-BZD medications. CONCLUSIONS: The use of benzodiazepine receptor agonists was a significant risk factor for respiratory failure in patients with chronic obstructive pulmonary disease (COPD). Compared to benzodiazepine, the prescription of non-benzodiazepine may be safer for the management of insomnia in COPD patients.

Patient Background Factors Affecting the Therapeutic Outcomes in Response to Eszopiclone in Adult Patients with Chronic Insomnia: A Post Hoc Analysis of a Double-Blind Phase III Study in Japan.

STUDY OBJECTIVE: To identify whether baseline demographic factors or subjective sleep variables are associated with the outcomes following treatment with eszopiclone using data from a recent randomized controlled trial of 78 Japanese subjects with insomnia who were treated with 2 mg eszopiclone per day. METHODS: We performed a post hoc analysis of factors including sleep latency (SL), wake time after sleep onset (WASO) (both assessed via sleep diaries), and several demographic variables. Subjects with a SL or WASO > 30 min at baseline and with evaluable SL/WASO data at Week 4 were included in SL and WASO remitter analyses, respectively; those with a SL or WASO ≤ 30 min at Week 4 were defined as SL or WASO remitters, respectively. Threshold baseline SL and WASO values for identification of remitters were determined. RESULTS: No relationships between subjectively assessed therapeutic outcomes and demographic factors were identified. Patients with shorter SL and lower WASO values at baseline showed better outcomes following treatment with eszopiclone in terms of SL and WASO changes, respectively. Baseline SL of 75 min and baseline WASO of 80 min were selected as arbitrary cutoff values for determination of SL and WASO remitters/non-remitters, respectively. CONCLUSION: These findings may help clinicians to predict their patients' outcomes in response to standard doses of eszopiclone in clinical practice.

Restless nocturnal eating: a common feature of Willis-Ekbom Syndrome (RLS).

STUDY OBJECTIVES: To determine the frequency of nocturnal eating (NE) and sleep related eating disorder (SRED) in restless legs syndrome (RLS) versus psychophysiological insomnia (INS), and the relationship of these conditions with dopaminergic and sedative-hypnotic medications. DESIGN: Prospective case series. SETTING: Sleep disorders center. PATIENTS: Newly diagnosed RLS or INS. INTERVENTION: RLS or INS pharmacotherapy with systematic follow up interview for NE/SRED. MEASUREMENTS AND RESULTS: Patients presenting with RLS (n = 88) or INS (n = 42) were queried for the presence of NE and SRED. RLS patients described nocturnal eating (61%) and SRED (36%) more frequently than INS patients (12% and 0%; both p < 0.0001). These findings were not due to arousal frequency, as INS patients were more likely to have prolonged nightly awakenings (93%) than RLS patients (64%; p = 0.003). Among patients on sedative-hypnotics, amnestic SRED and sleepwalking were more common in the setting of RLS (80%) than INS (8%; p < 0.0001). Further, NE and SRED in RLS were not secondary to dopaminergic therapy, as RLS patients demonstrated a substantial drop (68% to 34%; p = 0.0026) in the frequency of NE after dopamine agents were initiated, and there were no cases of dopaminergic agents inducing novel NE or SRED. CONCLUSION: NE is common in RLS and not due to frequent nocturnal awakenings or dopaminergic agents. Amnestic SRED occurs predominantly in the setting of RLS mistreatment with sedating agents. In light of previous reports, these findings suggest that nocturnal eating is a non-motor manifestation of RLS with several clinical implications discussed here.