Nonbenzodiazepine Receptor Agonists Research Articles

Effect of Lipopolysaccharide on the Duration of Zolpidem-Induced Loss of Righting Reflex in Mice.

Zolpidem, a non-benzodiazepine hypnotic, is primarily used to treat insomnia. In a previous study, pior treatment with non-benzodiazepine receptor agonists was associated with inflammation. The present study aimed to clarify the association between the effects of zolpidem and inflammation in mice treated with lipopolysaccharide (LPS), a known model of inflammation. We assessed the zolpidem-induced loss of righting reflex (LORR) duration 24 h after LPS treatment in mice. Additionally, the expressions of γ-aminobutyric acid (GABA)A receptor subunit and K+-Cl- cotransporter isoform 2 (KCC2) mRNA in the hippocampus and frontal cortex were examined in LPS-treated mice. Pretreatment with LPS was associated with significantly prolonged duration of zolpidem-induced LORR compared to control mice. This effect was significantly attenuated by administering bicuculline, a GABAA receptor antagonist, or flumazenil, a benzodiazepine receptor antagonist, in LPS-treated mice. Compared to controls, LPS-treated mice showed no significant change in the expression of GABAA receptor subunits in the hippocampus or frontal cortex. Bumetanide, an Na+-K+-2Cl- cotransporter isoform 1 blocker, attenuated the extended duration of zolpidem-induced LORR observed in LPS-treated mice. LPS significantly decreased Kcc2 mRNA expression in the hippocampus and the frontal cortex. These findings suggest that inflammation increases zolpidem-induced LORR, possibly through a reduction in KCC2 expression.

The effect of education regarding treatment guidelines for schizophrenia and major depressive disorders on psychiatrists' hypnotic medication prescribing behavior: a multicenter study

BackgroundTo examine whether the "Effectiveness of Guideline for Dissemination and Education in psychiatric treatment (EGIUDE)" project affects the rate of prescriptions of hypnotic medication and the type of hypnotic medications prescribed among psychiatrists, for schizophrenia and major depressive disorder in Japan.MethodsThe EGUIDE project is a nationwide prospective study of evidence-based clinical guidelines for schizophrenia and major depressive disorder in Japan. From 2016 to 2021, clinical and prescribing data from patients discharged from hospitals participating in the EGUIDE project were used to examine hypnotic medication prescriptions The prescribing rate of hypnotics and the prescribing rate of each type of hypnotic (benzodiazepine receptor agonist, nonbenzodiazepine receptor agonist, melatonin receptor agonist, and orexin receptor antagonist) were compared among patients who had been prescribed medication by psychiatrists participating in the EGUIDE project and patients who had been prescribed medication by nonparticipating psychiatrists. Multivariate logistic regression analysis was performed to examine the effect of the EGUIDE project on the prescription of hypnotic medications.ResultsA total of 12,161 patients with schizophrenia and 6,167 patients with major depressive disorder were included. Psychiatrists participating in the EGUIDE project significantly reduced the rate of prescribing hypnotic medication and benzodiazepine receptor agonists for both schizophrenia (P < 0.001) and major depressive disorder (P < 0.001) patients.ConclusionThis is the first study to investigate the educational effects of guidelines for the treatment of psychiatric disorders on psychiatrists in terms of prescribing hypnotic medications to patients. The EGUIDE project may play an important role in reducing hypnotic medication prescription rates, particularly with respect to benzodiazepine receptor agonists. The results suggest that the EGUIDE project may result in improved therapeutic behavior.

Secular Trends in Central Nervous System-Active Polypharmacy Among Serial Cross-Sections of US Adults, 2009-2020.

Data comprehensively examining trends in central nervous system (CNS)-active polypharmacy are limited. The objective of this cross-sectional study was to characterize the composition of and trends in CNS-active medication use in US adults. We included all participants ≥ 18 years old in the National Health and Nutrition Examination Study (NHANES), 2009-2020. The primary outcome was the percent of adults with CNS-active polypharmacy. This was defined as ≥ 3 medications among antidepressants [tricyclic, selective and serotonin-norepinephrine reuptake inhibitors (SSRIs and SNRIs), opioids, antiepileptics, antipsychotics, benzodiazepines, and nonbenzodiazepine receptor agonists ("Z-drugs")]. Secondary outcomes included prevalence of any CNS-active medication and specific medications and classes over time, and their indications. Percentages were weighted according to NHANES's nationally representative sampling frame. log binomial regressions evaluated the relative risk (RR) for each outcome, comparing the last (2017-2020) versus the first (2010-2011) survey cycle. We included 34,189 adults (18.8% at least 65 years old) from five serial cross-sections (survey cycles). The prevalence of CNS-active polypharmacy was 2.1% in 2009-2010 and 2.6% in 2017-2020 [RR 1.18, 95% confidence interval (CI) 0.94-1.47]. The prevalence of CNS-active polypharmacy did not significantly change within any specific age group (e.g., age at least 65 years: RR 1.29, CI 0.74-2.24). The prevalence of any CNS-active medication was 21.0% in 2009 and 24.6% in 2017-2020 (RR] 1.12, 95% CI 1.02-1.25). A substantial increase occurred for antiepileptics (5.1-8.3%), specifically among participants aged 65 years and older (8.3-13.7%). This was largely driven by increasing gabapentin prevalence (1.4-3.6% overall; 3.3-7.9% age 65 years and older). Anticholinergic, SSRIs/SNRIs, antiepileptics, and benzodiazepines were elevated in most cycles for participants at least 65 years old compared with participants less than 65 years, and opioid use was increased in several cycles for older participants as well. Alprazolam was the most common benzodiazepine and third most common medication for anxiety/depression. Gabapentin was the most common CNS-active medication (3.6% of all participants in 2017-2020), followed by sertraline, citalopram, and acetaminophen-hydrocodone (each ~2%). The most common categories were antidepressants (13.7% in 2017-2020), followed by opioids (5.1% in 2017-2020). CNS-active medications are increasingly common, particularly gabapentin, and use of any CNS-active medication increased by 12%. Numerous CNS-active classes also increased in older adults throughout the years. Increasing suboptimal medication use highlight the need for further investigation into causes for potentially inappropriate prescribing, particularly for older adults.

0372 Association between the real-world use of GABA receptor agonists and daytime impairment in US patients with insomnia

Abstract Introduction Currently available data inadequately quantify daytime impairment associated with insomnia disorder and the impact of its treatments in the real-world setting. The objective of this real-world study was to retrospectively examine daytime impairment symptoms before and during pharmacological treatment with non-benzodiazepine receptor agonists (non-BzRAs) and benzodiazepines in US patients with insomnia. Methods Information from HealthVerity was retrieved for patients with insomnia aged ≥ 18 years prescribed non-BzRAs or benzodiazepines as first-line treatment between October 2015 and March 2020. For each patient with data, insurance claims data were extracted alongside physician notes in free-text form. Patient demographics and prescription information were extracted from the claims. Daytime impairment symptoms were extracted and quantified from physician notes using an ontology designed with three domains (i.e., alert/cognition, mood and sleepiness) and 14 items analogous to the Insomnia Daytime Symptoms and Impact Questionnaire (IDSIQ). This ontology extends IDSIQ terms to 109 terms in total to reflect the language of physicians. The annualized rate of daytime impairment measures the frequency of symptoms occurring from 182 days before treatment start to about three months (mean) during treatment. The rate is normalized by one year as the duration before and during treatment is different. A single symptom of a visit is counted maximally once within a specific domain. Results 2361 and 1045 unique patients were prescribed non-BzRAs and benzodiazepines, respectively. Non-BzRAs treatment was associated with a statistically significant 16% overall increase of daytime impairment symptoms during versus before treatment (p=0.003). Statistically significant increase of daytime impairment symptoms with non-BzRA treatment was observed in the alert/cognitive (16%,p=0.019), mood (22%,p=0.002) domains, but only nominal increase in the sleepiness domain (12%,p=0.084). Benzodiazepine treatment was associated with a statistically significant 19% overall increase of daytime impairment symptoms during versus before treatment (p=0.047), with a statistically significant increase seen in the mood domain (26%,p=0.030) but only nominal increases in the alert/cognitive (7%,p=0.76), and sleepiness (21%,p=0.079) domains. Conclusion This study shows that treatment of insomnia with commonly used drugs (i.e. non-BzRA and benzodiazepines) is associated with an overall increase in daytime impairment symptoms in a real-world setting. Support (if any) Idorsia Pharmaceuticals Ltd.

Effects of Obstructive Sleep Apnea and Insomnia on Cognitive Function

Purpose of Review. Obstructive sleep apnea and chronic insomnia are the most common sleep disorders in adults. Both sleep disorders can adversely affect physical and mental well-being. Cognitive function has been extensively studied in relation to chronic insomnia and obstructive sleep apnea. This paper reviews the recent studies investigating the cognitive effects of insomnia and obstructive sleep apnea as well as the potential benefits of treatment. Recent Findings. Recent studies indicate that insomnia is associated with impairments in attention, memory, and executive function. Chronic insomnia may have a moderating role in mild cognitive impairment and Alzheimer’s dementia. Mood and anxiety disorders may moderate the effects of insomnia on cognitive function. Hyperarousal and short sleep time associated with insomnia are risk factors for cognitive impairment. Cognitive behavior therapy for insomnia may improve cognitive function but more studies are needed. Nonbenzodiazepine receptor agonists improve insomnia without causing cognitive impairment. Benzodiazepine use is associated with cognitive impairment. Obstructive sleep apnea is associated with impairments in attention, concentration, memory, and executive function with apnea severity as measured by the apnea hypopnea index and severity of nocturnal hypoxemia being the largest risk factors. Untreated obstructive sleep apnea may have a significant impact on the progression of mild cognitive impairment and Alzheimer’s dementia. The impact of obstructive sleep apnea treatment, particularly with continuous positive airway pressure, appears to mitigate and slow the rate of cognitive decline but more randomized controlled studies are needed. Summary. Standardized cognitive assessments and larger, long-term controlled prospective studies with diverse populations are needed to further elucidate the cognitive impairments associated with chronic insomnia and obstructive sleep apnea. More studies are needed on the benefits of various treatments for obstructive sleep apnea and insomnia.

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.ObjectiveWe aimed to investigate the current pharmacological treatments for insomnia and guide the rational use of drugs.MethodsThe 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.ResultsThe 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.ConclusionsBenzodiazepines 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.

0479 Prescribing Patterns for Hypnotic Medication Among Adults Seeking CBTI Treatment: A Preliminary Report from the RESTING Study

Abstract Introduction Use of prescription hypnotic medications is common among adults with chronic insomnia; however, little is known about prescribing patterns for hypnotic medication in middle-to-older age adults with insomnia disorder who seek to engage in cognitive behavioral therapy for insomnia (CBTI). Methods Participants were 235 adults aged 50 or older with insomnia disorder (mean age 63.1y [SD 7.7y], 73.6% women) enrolled in the ongoing Randomized Controlled Study on Effectiveness of Stepped-Care Sleep Therapy (RESTING). At screening, participants provided information about prescribed medications for sleep, insomnia severity (Insomnia Severity Index), daytime sleepiness (Epworth Sleepiness Scale), chronotype (Composite Morningness Questionnaire), depression (Geriatric Depression Scale) and physical and mental health (PROMIS Global-10, Physical and Mental Health Subscales). Results Of the 235 participants, 95 (40.4%) reported taking at least one medication prescribed to improve sleep. 26.5% were prescribed multiple medications (polypharmacy). Non-benzodiazepine receptor agonists (non-BzRAs) were the most common (prescribed to 51.6% of medication-using sample), followed by benzodiazepines (Bzs; 35.8%) and trazodone (20.0%). 25.2% of participants took a variety of other prescription medications at lower frequencies.Comparing patient characteristics for patients prescribed non-BzRAs, Bzs, and trazodone monotherapies, as well as polypharmacy, there were no significant differences in age, gender, insomnia severity or any other clinical characteristics, outside of modest associations within the PROMIS physical health scale (F[3,81]=2.78, p=.046); participants prescribed trazodone as monotherapy had significantly higher scores (better physical functioning) than participants prescribed non-BzRAs. Bzs were more likely to be prescribed as part of polypharmacy (52.9% of patients prescribed Bz) in the total medication using sample compared to those taking non-BzRAs (34.7%) or trazodone (36.8%; p&amp;lt;.001). Conclusion In this study, a high percentage of adults with insomnia seeking CBTI were also taking medications prescribed for sleep, including medications that are associated with increased risk (benzodiazepines, polypharmacy) or are not FDA-approved for insomnia (trazodone). Increasing prescriber knowledge about CBTI may promote adherence to the American Geriatric Society Beers Criteria for potentially inappropriate medication use in older adults. More research on how prescription patterns may differ among provider specialties could help target educational efforts to increase utilization of CBTI. Support (If Any) 1R01AG057500

Associations of Late-Life Sleep Medication Use With Incident Dementia in the Atherosclerosis Risk in Communities Study.

Sleep medications may contribute to dementia development or indicate sleep disturbances that are markers of or contributors to neurologic disease. The objective of this study was to examine the use of sleep medications and incident dementia in a community-based cohort of older adults. We hypothesize late-life sleep medication use is associated with a greater risk of dementia. The Atherosclerosis Risk in Communities (ARIC) study is an ongoing community-based cohort study. ARIC participants taking barbiturates, benzodiazepines, antidepressants, non-benzodiazepine receptor agonists (Z-drugs), or other hypnotics in 2011-2013 were categorized as sleep medication users. Participants were followed through 2019 for incident dementia. Logistic regression propensity scores were used to match sleep medication users with nonusers (1:2). Cox proportional hazards regression models were used to estimate hazard ratios (HR) for time to dementia diagnosis with adjustment for demographics, lifestyle characteristics, and cardiovascular risk factors. One-quarter of the eligible ARIC participants used sleep medications. In the matched sample (N = 4 197; 69% female; mean age 75.3 + 5.0 years), 632 dementia cases were ascertained over a median follow-up of 6.5 years. In the fully adjusted model, sleep medication use compared to nonuse was associated with a 48% greater risk of dementia (HR: 1.48; 95% confidence interval (CI): 1.26-1.74). To expand on these findings, studies with longer follow-up and earlier assessment of sleep medication use are needed. Furthermore investigation of the potential dose-response association of multiple sleep medications and the potential causal role of sleep medications in the development of dementia may be clinically meaningful.

POSC430 Unmet Needs for Insomnia Patients - Economic Burden in Europe

Insomnia is a prevalent sleep disorder associated with multiple health problems. Prescription sleep medications include among others, benzodiazepines and non-benzodiazepine receptor agonists. This study evaluates the economic burden associated with treated and non-treated chronic insomnia patients in Europe (UK, Germany, France, Spain, Italy), using real world data. Data from the 2020 EU (UK, Germany, France, Italy, Spain; N=62,319) National Health and Wellness Survey (NHWS), which is a patient-reported survey administered yearly to a demographically representative sample of adults (with respect to age, sex, and region), were used. Respondents who self-reported a confirmed diagnosis of insomnia (and no other sleep difficulties) and being on treatment (DT, N=812) were compared to diagnosed but untreated respondents (DUt, N=1601) and to patients self-reporting having experienced insomnia but undiagnosed and untreated (UdUt, N=6221), in respect to work productivity, activity impairment (WPAI), and health care resource (HCRU), using ANOVA tests. Compared with DUt and UdUt, DT patients reported significantly greater overall work productivity impairment (37.63% vs. 36.20% vs. 28.41%), as well as activity impairment (44.16% vs. 40.89% vs. 29.82%). DT patients also reported higher HCRU (past 6 months) with a mean of 0.65 emergency room (ER) visits and 0.23 hospitalizations vs. 0.47 and 0.23, respectively, for DUt and 0.31 ER visits and 0.14 hospitalizations for UdUt patients. Despite treatment for insomnia, this study suggests that the economic burden of insomnia is high, with substantial insomnia-related absenteeism, presenteeism and reduced overall productivity, as well as higher HCRU. There is a significant unmet need for treatments with better outcomes for insomnia patients.

Potentially Inappropriate Medication Use in Older Adults with Alzheimer's Disease and Related Dementias Living in the Community: A Cross-Sectional Analysis.

BackgroundWith the older adult population in the USA increasing, so is the population of those with Alzheimer’s disease and related dementias (ADRD). Older adults are vulnerable to the effects of potentially inappropriate medications as established by the Beers Criteria; however, some medications continue to be prescribed against recommendations.ObjectivesOur objectives were to describe potentially inappropriate medication (PIM) use linked to cognitive impairment or decline (referred to as Cog-PIM) in older adults with and without ADRD and to investigate whether the odds of Cog-PIM report differ by ADRD status in ambulatory care (i.e., outpatient care) in the USA.MethodsA cross-sectional analysis was performed using a nationally representative sample of non-perioperative, office-based ambulatory care visits by adults aged ≥ 65 years in 2016 (n = 218,182,131). Data were collected from the National Ambulatory Medical Care Survey. Cog-PIMs were identified as defined in the 2015 Beers Criteria recommendations for medications that may be potentially inappropriate in older adults with cognitive impairment or dementia. ADRD status was determined by clinician report using free text, the ADRD flag, or the presence of a diagnosis code indicating dementia. Multivariable logistic regressions were used to estimate the odds of Cog-PIM use overall and by medication class.ResultsIn 2016, 2.1% (n = 4,651,563) of outpatient visits were made by older adults with ADRD, 33.2% of which reported at least one Cog-PIM. Anticholinergic Cog-PIMs were noted in 20.5% of ADRD visits compared with 8.1% of non-ADRD visits. Antipsychotic PIMs were noted in 15.5% of ADRD visits compared with 0.8% of non-ADRD visits. Benzodiazepine and non-benzodiazepine receptor agonist hypnotic (Z drug) Cog-PIMs were reported in 10.9% of ADRD visits and 10.7% of non-ADRD visits. ADRD status was a significant predictor of Cog-PIM report overall (adjusted odds ratio [aOR] 2.74 [95% confidence interval {CI} 1.20–6.27]) and for anticholinergics and antipsychotics specifically (aOR 3.35 [95% CI 1.24–9.03] and aOR 22.80 [95% CI 5.80–89.50], respectively).ConclusionThis study demonstrated a high prevalence of Cog-PIM use and increased odds of Cog-PIM use in older adults with ADRD. Future work should investigate opportunities in the ambulatory care setting for safer prescribing and de-escalation of Cog-PIMs.

Preoperative Sedative-hypnotic Medication Use and Adverse Postoperative Outcomes.

To determine the association between preoperative benzodiazepine and nonbenzodiazepine receptor agonist ("Z-drugs") use and adverse outcomes after surgery. Prescriptions for benzodiazepines and Z-drugs have increased over the past decade. Despite this, the association of preoperative benzodiazepines and Z-drug receipt with adverse outcomes after surgery is unknown. Using the Optum Clinformatics Datamart, we performed a retrospective cohort study of adults 18 years or older who underwent any of 10 common surgical procedures between 2010 and 2015. The principal exposure was one or more filled prescriptions for a benzodiazepine or Z-drug in the 90 days before surgery. The primary outcome was any emergency department visit or hospital admission for either (1) a drug related adverse medical event or overdose or (2) a traumatic injury in the 30 days after surgery. Of 785,346 patients meeting inclusion criteria, 94,887 (12.1%) filled a preoperative prescription for a benzodiazepine or Z-drug. From multivariable logistic regression, benzodiazepine or Z-drug use was associated with an increased odds of an adverse postoperative event [odds ratio 1.13; 95% confidence interval: 1.08-1.18). In a separate regression, coprescription of benzodiazepines or Z-drugs with opioids was associated with a 1.45 odds of an adverse postoperative event (95% confidence interval: 1.37-1.53). Preoperative benzodiazepines and Z-drug use is common and associated with increased odds of adverse outcomes after surgery, particularly when coprescribed with opioids. Counseling on appropriate benzodiazepine and Z-drug use in advance of elective surgery may potentially increase the safety of surgical care.

Treating Insomnia in Older Adult Patients: Limiting Benzodiazepine Use

As aging comes, an increased prevalence of medical maladies and chronic pain independently or interactively disrupt sleep, which in turn can exacerbate either one. Furthermore, anxiety about pain can further negatively impact sleep. Fortunately, good quality sleep can improve pain management. Because benzodiazepine receptor agonists (including the “Z” drugs) can reduce anxiety and improve sleep, they seem a convenient choice. However, their use in this population, particularly for more than short-term (guidelines range from 2 to 6 weeks max), is not recommended because of increased likelihood of falls, further disruption of sleep, dependence, and problems with discontinuation (withdrawal). Besides, this population is often likely to take concomitant medication for pain or other central nervous system depressants leading to potentially serious and even life-threatening interactions involving synergistic amplification of respiratory depression (opioids being a particularly dangerous interaction). Therefore, insomnia in older adults should ideally be treated with a non-benzodiazepine receptor agonist; if indicated, they may be used, but should be closely monitored and tapered to avoid long-term adverse problems (direct or from withdrawal). Older adult patients with insomnia may be more optimally treated with sleep aids that do not interact with the GABAA receptor.

Innovations in Insomnia Management: A Review of Current Approaches and Novel Targets Including Orexin Receptor Antagonists

Background: Sleep disturbances are a source of significant challenge to the care of geriatric hospitalized patients. Areas of Uncertainty: Commonly used medications to promote sleep are fraught with side effects especially in the geriatric population. The management of this issue is very important to many patients. Data Sources: We reviewed current data on the effectiveness of current pharmacologic and non-pharmacologic strategies to improve insomnia in elderly patients. Results: Environmental adjustments to the inpatient setting have been shown to improve sleep with no adverse effects. Cognitive behavioral therapy, has also been shown to improve objective and subjective sleep measures in older patients with similar efficacy to medications. Benzodiazepines are still popular medications despite evidence demonstrating adverse outcomes including falls, fractures, and cognitive decline. Nevertheless they have been shown to have a generally small effect on total sleep time. Nonbenzodiazepine receptor agonists have also been demonstrated to pose significant risks of harms to the elderly patient, including delirium and, again, falls and fractures as the price for a small increase in total sleep time. Ramelteon is also shown to have an even smaller effect on sleep time, however, with a more positive side effect profile. Suvorexant is a new agent that works through a novel mechanism inhibiting the orexin activating system. It has been shown to have similar objective efficacy on sleep as other medications mentioned already and was approved by FDA without major warnings. However, more study is required to determine if it will elude the risks of medications already available. Conclusions: Given the lack of adverse consequences, a persuasive case can be made for a comprehensive behavioral approach to sleep promotion before pharmacologic agents are attempted. Studies comparing individual medications are unavailable and thus cannot guide therapy further.

QUALITY OF PHARMACEUTICAL CARE IN DEMENTIA PATIENTS

OBJECTIVES: Use of potentially inappropriate medications (PIM) in dementia patients reflect poor quality of care. The goal of this study was to evaluate quality of pharmaceutical care in dementia patients using the most recent 2015 American Geriatric Society (AGS) Beers criteria. METHODS: This cohort study used the 5% national Medicare data from 2011–2012. The cohort included elderly patients diagnosed with dementia in the baseline year, i.e. 2011. Quality of care, i.e., use of PIMs, was defined in 2012 using the AGS Beers criteria. Predictors were identified in the baseline year based on the Andersen Behavioral Model: predisposing (sociodemographic), enabling (dual eligibility) and need factors (Elixhauser comorbidities, medication use and healthcare utilization). Descriptive statistics was used to determine the prevalence of PIMs. Multivariable logistic regression analysis was used to determine predictors of PIMs in dementia patients. RESULTS: The cohort included 57,469 elderly dementia patients, with mean age of 85 ± 8 years. Overall, 53.1% of dementia patients received PIMs. The prevalence of top seven drugs classes were as follows: antipsychotics (31.3%), H2-receptor antagonists (11.3%), antihistamines (10.3%), antimuscarinic urinary incontinence (9.1%), antiemetics (6.7%), nonbenzodiazepine receptor agonist hypnotics (6.1%), tricyclic antidepressants (5.7%). Mutivariable logistic regression found that females (odds ratio [OR], 1.16), Blacks (OR, 1.18), patients with Elixhauser comorbidities (twelve conditions), emergency room visit (OR, 1.1) and more than five prescription medications (OR, 3.0) were associated with higher likelihood of receiving PIMs. CONCLUSIONS: One out of two dementia patients received at least one PIMs reflecting poor quality of pharmaceutical care in this vulnerable patient population.

Emergency department visits involving benzodiazepines and non-benzodiazepine receptor agonists

ObjectiveSedative-hypnotic medications (e.g., Benzodiazepines [BZDs] and non-benzodiazepine receptor agonists [nBZRAs]) are associated with adverse events, especially in the elderly, that may require emergency department (ED) treatment. This study assessed outcomes from ED visits attributed to BZDs and/or nBZRAs, and variations in these associations by age group. MethodsData came from the 2004–2011 waves of the Drug Abuse Warning Network (DAWN). Visits were categorized as involving: (1) BZDs-only, (2) nBZRAs-only, (3) combination of BZDs and nBZRAs, or (4) any other sedative-hypnotic medication. DAWN also recorded the disposition (i.e., outcome) of the visit. Analyses focused on outcomes indicating a serious disposition defined as hospitalization, patient transfer or death. Using logistic regression, the association of BZD and nBZRA use with visit disposition was assessed after applying sample weights so as to be nationally representative of ED visits in the United States involving medications or illicit substances. ResultsNineteen percent of visits involving other sedative-hypnotics, 28% involving BZDs-only, 20% involving nBZRAs-only and 48% involving a combination of BZDs and nBZRAs resulted in a serious disposition. Compared to visits involving other sedative-hypnotics, visits involving BZDs-only had 66% greater odds (Odds Ratio [OR]=1.66, 95% Confidence Interval [CI]=1.37–2.01), and visits involving a combination of BZDs and nBZRAs had almost four times increased odds of a serious disposition (OR=3.91, 95% CI=2.38–6.41). Results were similar across age groups. ConclusionsFindings highlight the need for clinical and regulatory initiatives to reduce BZD use, especially in combination with nBZRAs, and to promote treatment with safer alternatives to these medications.

A Closer Look at the 2015 Beers Criteria

The Beers Criteria identifies potentially inappropriate medications for patients who are 65 years of age and older. Initially published in 1991, the criteria have been updated multiple times, most recently in 2015. The Beers Criteria is a tool designed to alert health-care providers to the potential harms of specific medications so they may better tailor therapeutic regimens for their elderly patients. The expert panel of the 2015 update made changes to a number of previous recommendations and provided 2 new tables on select drug interactions and select medications requiring renal dose adjustments. The purpose of this review is to provide additional details and rationale behind selected noteworthy changes within the 2015 criteria. Specific information is provided on the changes in recommendations for the use of nitrofurantoin, antiarrhythmics, nonbenzodiazepine receptor agonist hypnotics, antipsychotics, and proton pump inhibitors in the elderly. Additional comparisons are made between the 2012 recommendations and newer recommendations made in the 2015 update, along with rationale for the change. This review will allow practitioners to apply the 2015 Beers Criteria and integrate their clinical judgment when evaluating and selecting drug therapy for elderly patients.

Novel class of medications, orexin receptor antagonists, in the treatment of insomnia - critical appraisal of suvorexant.

Insomnia, a highly prevalent disorder, can be detrimental to patients’ overall health and worsen existing comorbidities. Patients may have acute episodes of insomnia related to a traumatic event, but more commonly insomnia occurs chronically. While proper sleep hygiene and behavioral therapy play important roles in the nonpharmacologic management of short-term and chronic insomnia, medications may also be required. Historically, insomnia has been treated with agents such as benzodiazepines, nonbenzodiazepine receptor agonists, and melatonin agonists. Dual orexin receptor antagonists represent a new class of medications for the treatment of insomnia, which block the binding of wakefulness-promoting neuropeptides orexin A and orexin B to their respective receptor sites. Suvorexant (Belsomra) is the first dual orexin receptor antagonist to be approved in the US and Japan and has demonstrated efficacy in decreasing time to sleep onset and increasing total sleep time. Its unique mechanism of action, data to support efficacy and safety over 12 months of use, and relative lack of withdrawal effects when discontinued may represent an alternative for patients with chronic insomnia who cannot tolerate or do not receive benefit from more traditional sleep agents. Suvorexant is effective and well tolerated, but precautions exist for certain patient populations, including females, obese patients, and those with respiratory disease. Suvorexant has only been studied vs placebo, and hence it is unknown how it directly compares with other medications approved by the US Food and Drug Administration for insomnia. Suvorexant is not likely to replace benzodiazepines or nonbenzodiazepine receptor antagonists as a first-line sleep agent but does represent a novel option for the treatment of patients with chronic insomnia.

Reversal of a Suspected Paradoxical Reaction to Zopiclone with Flumazenil.

We describe the care for an elderly woman who was admitted to the intensive care unit (ICU) to receive noninvasive ventilation for acute exacerbation of chronic obstructive pulmonary disease. After administration of the sleeping pill zopiclone, a nonbenzodiazepine receptor agonist (NBRA), the patient became agitated and was confused, a possible paradoxical reaction to benzodiazepines. These symptoms were immediately resolved after treatment with flumazenil, usually used to reverse the adverse effects of benzodiazepines or NBRAs and to reverse paradoxical reactions to benzodiazepines. This case indicates that zopiclone induced behavioral changes resembling a paradoxical reaction to benzodiazepines and these symptoms may be treated with flumazenil.

Trends in prescribing of sedative-hypnotic medications in the USA: 1993-2010.

Non-benzodiazepine receptor agonists (nBZRAs) were developed as an alternative to benzodiazepines (BZDs) to treat insomnia. Little is known about how the introduction of nBZRAs influenced trends in BZD prescribing. We examined BZD and nBZRA prescribing trends from 1993 to 2010. We used the National Ambulatory Medical Care Survey to examine 516,118 patient visits between 1993 and 2010. We categorized visits as BZD, nBZRA, or BZD + nBZRA visits based on medications prescribed in each visit and applied linear probability regression models to assess trends in visits. Increases were observed in proportions of visits that were BZD (2.6% in 1993 to 4.4% in 2010, p < 0.001) and nBZRA (0% to 1.4%, p < 0.001). Increases in BZD visits were primarily after 2002, with prescribing in the preceding years remaining relatively stable. We also found increases in BZD + nBZRA visits (0% to 0.4%, p < 0.001). Among patients with sleep disorders, there was an increase in nBZRA visits (2.3% to 13.7%, p < 0.001), and decline in BZD visits (23.5% to 10.8%, p = 0.015). Just under a third (30.8%) of any sedative-hypnotic visits were for adults aged 65+ years, among whom increases in BZD, nBZRA, and BZD + nBZRA visits were observed across the study period. There were increases in prescribing of nBZRAs between 1993 and 2010. Increases in prescribing of BZDs were also observed, especially after 2002. The introduction of nBZRAs likely resulted in declines in BZD prescribing among those with a sleep disorder, but not other groups. Delivery of behavioral treatments should be encouraged to avert adverse outcomes associated with sedative-hypnotic use. Copyright © 2015 John Wiley & Sons, Ltd.

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.