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Zolpidem, a nonbenzodiazepine hypnotic, binds to the benzodiazepine binding site on the gammaaminobutyric acid type A (GABA-A) receptors. Many studies have reported efficacy and safety of zolpidem in treatment of insomnia, low abuse, and dependence capability. We present a case of zolpidem dependence in a 33-year-old male to emphasize that clinicians should pay close attention to the potential of zolpidem tolerance, abuse and dependence. Key Word : Zolpidem, Dependence

Background and objectives Zolpidem, a nonbenzodiazepine hypnotic, and trazodone, a sedating antidepressant, are the most common medications used to treat insomnia in the United States. Both drugs have side effect profiles (e.g., drowsiness, dizziness, and cognitive and motor impairment) that can heighten the risk of falls and fractures. Despite widespread zolpidem and trazodone use, little is known about the comparative safety of these medications in patients receiving hemodialysis, a vulnerable population with an exceedingly high fracture rate. Design, setting, participants, & measurements Using data from the United States Renal Data System registry (2013–2016), we conducted a retrospective cohort study to investigate the association between the initiation of zolpidem versus trazodone therapy and the 30-day risk of hospitalized fall-related fractures among Medicare-enrolled patients receiving maintenance hemodialysis. We used an active comparator new-user design and estimated 30-day inverse probability of treatment-weighted hazard ratios and risk differences. We treated death as a competing event. Results A total of 31,055 patients were included: 18,941 zolpidem initiators (61%) and 12,114 trazodone initiators (39%). During the 30-day follow-up period, 101 fall-related fractures occurred. Zolpidem versus trazodone initiation was associated with a higher risk of hospitalized fall-related fracture (weighted hazard ratio, 1.71; 95% confidence interval, 1.11 to 2.63; weighted risk difference, 0.17%; 95% confidence interval, 0.07% to 0.29%). This association was more pronounced among individuals prescribed higher zolpidem doses (hazard ratio, 1.85; 95% confidence interval, 1.10 to 3.01; and risk difference, 0.20%; 95% confidence interval, 0.04% to 0.38% for higher-dose zolpidem versus trazodone; and hazard ratio, 1.60; 95% confidence interval, 1.01 to 2.55 and risk difference, 0.14%; 95% confidence interval, 0.03% to 0.27% for lower-dose zolpidem versus trazodone). Sensitivity analyses using longer follow-up durations yielded similar results. Conclusions Among individuals receiving maintenance hemodialysis, zolpidem initiators had a higher risk of hospitalized fall-related fracture compared with trazodone initiators. Podcast This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2020_12_18_CJN10070620_final.mp3

Aims To estimate prevalence of last 12-month nonmedical use (NMU) of benzodiazepines and Z-drugs (the nonbenzodiazepine hypnotics zaleplon, zolpidem and zopiclone) in the UK. Methods Data were collected using the Non-Medical Use of Prescription Drugs survey with poststratification weighting applied to be representative of the UK population (≥16 years). Participants were questioned about whether they had nonmedically used benzodiazepines and/or Z-drugs in the last 12-months and from where they had obtained the drug (including via a prescription, or illicitly from a friend/family member, a dealer or via the internet). Additional questions were asked about last 12-month use of illicit drugs (cannabis, cocaine, 3,4-methylenedioxymethylamphetamine [MDMA], non-pharmaceutical amphetamine, crack cocaine and/or heroin). Results The study included 10 006 eligible participants representing approximately 52 927 000 UK adults. The estimated prevalence of past 12-month NMU of any benzodiazepine and/or Z-drug was 1.2% (95% confidence interval: 1.0-1.5) corresponding to approximately 635 000 adults; amongst this group only an estimated 4.6% (1.2-8.0) had NMU of both a benzodiazepine and a Z-drug. The highest prevalence of NMU for only Z-drugs was among those who had used heroin in the last 12-months (5.4%, 2.7-10.5), whilst the highest prevalence of NMU for only benzodiazepines was among those who had used illicit stimulants in the last 12-months: cocaine (5.9%, 3.8-8.9), amphetamine (5.6%, 3.1-10.0) and MDMA (5.2%, 3.1-8.8). The drug non-medically used was more commonly acquired without than with a prescription for both only benzodiazepines (70.2%, 59.4-81.1 compared to 51.3%, 41.5-64.6) and only Z-drugs (75.6%, 61.6-89.7 compared to 33.9%, 16.9-51.0). Conclusion There is little overlap between benzodiazepine and Z-drug NMU suggesting distinct nonmedical use of the drugs; future studies need to explore whether this relates to personal preference, drug availability or other factors. A significant proportion are acquiring these drugs for NMU without a prescription, so without guidance and monitoring from a medical practitioner. While the dangers of mixing benzodiazepines and heroin/other opioids are well documented, there is a paucity of data regarding concomitant NMU of benzodiazepines and stimulant drugs, or NMU of Z-drugs and opioids, and, given the prevalence of these combinations, this requires further investigation.

Sleep plays an important role in the recovery of critically ill patients. However, patients in the intensive care unit (ICU) often suffer sleep disturbances and abnormal circadian rhythms, which may increase delirium and lengthen ICU stay. Nonpharmacologic strategies for preventing and treating sleep disturbances and delirium, such as overnight eye masks and ear plugs, are usually employed first, given the lack of adverse effects. However, a multimodal approach to care including pharmacotherapy may be necessary. Despite the limited available data supporting their use, medications such as melatonin, ramelteon, suvorexant, and dexmedetomidine may promote sleep and improve a variety of patient-centric outcomes such as delirium. This narrative review focuses on these nonbenzodiazepine agents used for sleep in the ICU. Practical application of each of these agents is described for when providers choose to utilize one of these pharmacotherapies to promote sleep or prevent delirium.

Studies on psychotropic medications decrease, discontinuation, or switch have uncovered withdrawal syndromes. The present overview aimed at analyzing the literature to illustrate withdrawal after decrease, discontinuation, or switch of psychotropic medications based on the drug class (i.e., benzodiazepines, nonbenzodiazepine benzodiazepine receptor agonists, antidepressants, ketamine, antipsychotics, lithium, mood stabilizers) according to the diagnostic criteria of Chouinard and Chouinard [Psychother Psychosom. 2015;84(2):63–71], which encompass new withdrawal symptoms, rebound symptoms, and persistent post-withdrawal disorders. All these drugs may induce withdrawal syndromes and rebound upon discontinuation, even with slow tapering. However, only selective serotonin reuptake inhibitors, serotonin noradrenaline reuptake inhibitors, and antipsychotics were consistently also associated with persistent post-withdrawal disorders and potential high severity of symptoms, including alterations of clinical course, whereas the distress associated with benzodiazepines discontinuation appears to be short-lived. As a result, the common belief that benzodiazepines should be substituted by medications that cause less dependence such as antidepressants and antipsychotics runs counter the available literature. Ketamine, and probably its derivatives, may be classified as at high risk for dependence and addiction. Because of the lag phase that has taken place between the introduction of a drug into the market and the description of withdrawal symptoms, caution is needed with the use of newer antidepressants and antipsychotics. Within medication classes, alprazolam, lorazepam, triazolam, paroxetine, venlafaxine, fluphenazine, perphenazine, clozapine, and quetiapine are more likely to induce withdrawal. The likelihood of withdrawal manifestations that may be severe and persistent should thus be taken into account in clinical practice and also in children and adolescents.

Background: Being a nonbenzodiazepine, zolpidem is believed to have a favorable side-effect profile and is widely prescribed for insomnia. However, in the past few years, numerous neuropsychiatric adverse reactions, particularly complex sleep behaviors (CSBs), have been reported with zolpidem. Objective: To conduct a systematic review of zolpidem-associated CSBs. Data Sources: An electronic search was conducted using MEDLINE, Embase, PubMed, and Cochrane database of systematic reviews to extract relevant articles till July 2020. Study Eligibility Criteria: Any type of literature article (case report, case series, and observational or interventional study) reporting CSBs associated with zolpidem. Results: In this review, we present aggregate summarized data from 148 patients presenting with zolpidem-induced CSBs (79 patients from 23 case reports and 5 case series; 69 patients out of 1454 taking zolpidem [4.7%] from three observational clinical studies). Various types of CSBs associated with zolpidem were reported, most common being sleepwalking/somnambulism and sleep-related eating disorder. On causality assessment, around 88% of cases were found to have a probable association with zolpidem. Limitations: Extraction of data from observational studies and spontaneous reports, due to nonavailability of any randomized controlled trials relevant to the study objective. Conclusion and Implication of Key Findings: Zolpidem-induced CSBs, although not very common, may develop when the drug is used at therapeutic doses for insomnia. Doctors need to be alert to monitor such adverse effects of zolpidem and exercise caution while prescribing it.

Objective Receipt of concurrent psychotropic prescription medications from both US Department of Veterans Affairs (VA) and non-VA healthcare providers may increase risk of adverse opioid-related outcomes among veterans with traumatic brain injury (TBI). Little is known about patterns of dual-system opioid or sedative-hypnotic prescription receipt in this population. We estimated the prevalence and patterns of, and risk factors for, VA/non-VA prescription overlap among post-9/11 veterans with TBI receiving opioids from VA providers in Oregon. Setting Oregon VA and non-VA outpatient care. Participants Post-9/11 veterans in Oregon with TBI who received an opioid prescription from VA providers between the years of 2014 and 2019. Design Historical cohort study. Main measures Prescription overlap of VA opioids and non-VA opioids or sedative-hypnotics; proportions of veterans who received VA or non-VA opioid, benzodiazepine, and nonbenzodiazepine sedative-hypnotic prescriptions were also examined by year and by veteran characteristics. Results Among 1036 veterans with TBI receiving opioids from the VA, 210 (20.3%) received an overlapping opioid prescription from a non-VA provider; 5.3% received overlapping benzodiazepines; and none received overlapping nonbenzodiazepine sedative-hypnotics. Proportions of veterans with prescription overlap tended to decrease over time. Veterans with other than urban versus urban addresses (OR = 1.4; 95% CI, 1.0-1.8), high versus medium average annual VA visits (OR = 1.7; 95% CI, 1.1-2.6), and VA service connection of 50% or more versus none/0% to 40% (OR = 4.3; 95% CI, 1.3-14.0) were more likely to have concurrent VA/non-VA prescriptions in bivariable analyses; other than urban remained associated with overlap in multivariable models. Similarly, veterans with comorbid posttraumatic stress disorder diagnoses were more likely to have concurrent VA/non-VA prescriptions in both bivariable and multivariable (OR = 2.1; 95% CI, 1.0-4.1) models. Conclusion Among post-9/11 veterans with TBI receiving VA opioids, a considerable proportion had overlapping non-VA prescription medications. Providers and healthcare systems should consider all sources of psychotropic prescriptions, and risk factors for overlapping medications, to help mitigate potentially unsafe medication use among veterans with TBI.

Background Clinical guidelines and black boxed warnings caution on the serious risks, including death, associated with concomitant use of prescription opioids and benzodiazepines. Objective This study aimed to characterize the co-utilization of a similar class of medications – non-benzodiazepine sedative ‘Z’-drugs – with opioids at ambulatory care visits in the United States. Methods A cross-sectional analysis of the National Ambulatory Medical Care Survey (NAMCS) from 2006 to 2016 characterized the trends in co-utilization of opioids and Z-drugs. Visits involving adult patients with an opioid prescription were included in the analysis. The weighted annual prevalence of concomitant use of an opioid medication and a Z-drug (zolpidem, eszopiclone, zaleplon) was evaluated. The analysis was stratified by patient demographics and the status of the prescriptions (i.e., new initiation or continued use). Results The authors analyzed 564,090,296 visits (weighted from a sample of 28,773) with a reported opioid prescription. Co-utilization of opioids with Z-drugs fluctuated during the study period beginning at 4.0% in 2006 (95%CI 2.2% to 5.7%), 6.3% in 2012 (95%CI 3.7% to 8.9%), and 4.7% in 2016 (95%CI 2.8% to 6.5%). Among all opioid visits in the study period, co-utilization with a Z-drug was not significantly different among female patients compared to male patients (5.26% vs. 4.63%, p = 0.26). Among visits with concomitant opioid and Z-drugs, 7.0% reported new initiation of both medications in the same visit. Conclusion At ambulatory care visits between 2006 and 2016, co-utilization of opioids and Z-drugs fluctuated with some differences by sex. Major regulatory advisories and policy changes during this period may have contributed to these varying rates of utilization. Additional work is needed to identify predictors of co-utilization and downstream consequences more widely.

Background The concurrent use of opioids with benzodiazepines (BZD) or nonbenzodiazepine sedatives (S) recently was found to be associated with an increased risk of overdose death compared with the use of opioids alone. In the current study, the authors examined the frequency and trend of concurrent opioid/BZD-S use and its associated risk factors among patients with cancer. Methods Data regarding the frequency and trend of concurrent opioid/BZD-S use were extracted for 1500 randomly selected patients referred to the outpatient palliative care clinic at The University of Texas MD Anderson Cancer Center between the calendar years of 2011 and 2016. To explore associated risk factors, the authors compared the demographic and clinical predictors of 418 patients each in the concurrent opioid/BZD-S group and opioids-only group. Results In 2011, at the time of referral to the palliative care clinic, 96 of 221 patients with cancer (43%) were prescribed concurrent opioids/BZD-S. This rate progressively declined to 67 of 217 patients (31%) by 2016 (P = .0008). Patients in the concurrent opioid/BZD-S group had a higher percentage of females (233 individuals; 55% [P = .007]) and whites (323 individuals; 77% [P = .002]), and patients reported higher scores regarding depression (P = .0001), anxiety (P ≤ .0001), drowsiness (P = .048), and worst feeling of well-being (P = .001). The morphine equivalent daily dose was significantly higher in concurrent opioid/BZD-S group (median of 67.5 mg/day [interquartile range (IQR), 30-135 mg/day] vs 60 mg/day [IQR, 30-105 mg/day]; P = .034). Multivariate analysis demonstrated that anxiety (P ≤ .0001), white race (P = .0092), and poor Eastern Cooperative Oncology Group performance status (P = .0017) were significantly associated with concurrent use. Conclusions The concurrent use of opioids with BZD-S has declined but continues to be frequent among patients with cancer. Anxiety, white race, and poor Eastern Cooperative Oncology Group performance status were associated with its use. More research is needed to explore which medications can replace these agents.

OBJECTIVE: To determine the association between preoperative benzodiazepine and nonbenzodiazepine receptor agonist (“Z-drugs”) use and adverse outcomes after surgery. BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Background The opioid epidemic continues to worsen with a concomitant increase in opioid-related mortality. In response, the Department of Defense and Veterans Health Agency recommended against the use of long-acting opioids (LAOs) and concurrent use of opioids with benzodiazepines. Subsequently, we eliminated benzodiazepines and LAOs from our postoperative pain control regimen. Objective To evaluate the impact of removing benzodiazepines and LAOs on postoperative pain in single-level transforaminal lumbar interbody fusion (TLIF) patients. Methods A retrospective cohort study of single-level TLIF patients from February 2016-March 2018 was performed. Postoperative pain control in the + benzodiazepine cohort included scheduled diazepam with or without LAOs. These medications were replaced with nonbenzodiazepine, opioid-sparing adjuncts in the -benzodiazepine cohort. Pain scores, length of hospitalization, trigger medication use, and opioid use and duration were compared. Results Among 77 patients, there was no difference between inpatient pain scores, but the -benzodiazepine cohort experienced a faster rate of morphine equivalent reduction (-18.7%, 95% CI [-1.22%, -36.10%]), used less trigger medications (-1.55, 95% CI [-0.43, -2.67]), and discharged earlier (0.6 d; 95% CI [0.01, 1.11 d]). As outpatients, the -benzodiazepine cohort was less likely to receive opioid refills at 2 wk (29.2% vs 55.8%, P = .021) and 6 mo postoperatively (0% vs 13.2%, P = .039), and was less likely to be using opioids by 3 mo postoperatively (13.3% vs 34.2%, P = .048). Conclusion Replacement of benzodiazepines and LAOs in the pain control regimen for single-level TLIFs did not affect pain scores and was associated with decreased opioid use, a reduction in trigger medications, and shorter hospitalizations.

Objective To assess the change in prescribing of nonbenzodiazepine and benzodiazepine receptor agonist hypnotics (Z-drugs) prescribed to adults after U.S. Food and Drug Administration safety warnings. Setting Five clinical sites as part of a Federally Qualified Health Center (FQHC). Practice description Virginia Garcia Memorial Health Center is an FQHC consisting of 5 patient centered medical homes. Practice innovation Examine Z-drug use in a vulnerable adult population to confirm appropriate prescribing and quality care. Evaluation The primary measure was to determine the percentage of Z-drugs prescribed to patients age 18 years or older during the study period of September 1, 2016, to August 31, 2017. Patients were identified using the electronic health record. Z-drugs included zolpidem, zaleplon, and eszopiclone. Secondary measures included percentage of Z-drug prescribing to adults age 65 years and older, percentage of female patients prescribed zolpidem doses greater than 5 mg, prior behavioral health encounter, and prior pharmacotherapy for insomnia. Results Of 22,733 adults age 18 years and older, 282 patients (1.3%) received a Z-drug prescription during the study period. Forty-nine (28.9%) female patients received 10 mg of zolpidem nightly, a zolpidem dose higher than the recommended 5 mg nightly. In addition, of 2239 patients age 65 years and older, 34 patients (1.5%) received a prescription for a Z-drug. Conclusion Prescribing rates of zolpidem in 10-mg doses to female patients were high, indicating that providers could benefit from further education on this topic. In the population, and in adults age 65 years and older, Z-drug prescribing in an FQHC was low compared with available prescribing rates.

Background: Obstructive Sleep Apnea (OSA) is the most common form of sleep disordered breathing and represents a major public health problem. It is caused by repetitive collapse of a narrow upper airway during sleep with periodic cessation of breathing (for more than 10 seconds). These events usually result in fragmented sleep, intermittent hypoxia and lead to excessive daytime sleepiness.Aim of Study: We aimed to evaluate the effect of sedatives, as a method to improve over night continuous positive airway pressure titration, short-term therapy compliance, and outcomes in patients with newly diagnosed obstructive sleep apnea.Patients and Methods: 40 Subjects in this randomized, double-blind, placebo-controlled trial were divided to group I received 3mg eszopiclone and group II received placebo within 60min prior to the start of CPAP titration (at lights out) and, for 2 weeks as a combined therapy with CPAP before sleep, we compared the quality of CPAP titrations and Adher-ence to CPAP (primary outcome) during the first 4 weeks of therapy between the two groups, and evaluated improvements in symptoms (secondary outcomes) after 2 and 4 weeks of therapy.Results: Eszopiclone significantly improved sleep titration quality (increased sleep efficiency, increased total sleep time, decreased total arousal index, decreased CPAP pressure, decreased AHI at the highest CPAP pressure) and significantly & rapidly improved short term compliance (% of night CPAP used, mean hours/nights CPAP used, % of nights CPAP used >4 hours) and functional and behavioral outcomes, compared with placebo group.Conclusion: Nonbenzodiazepine hypnotics (eszopiclone) are safe and relatively inexpensive and have the potential to improve the quality of polysomnograms or prevent studies from needing to be repeated. A short course of nonbenzodi-azepines is a simple option that may facilitate better CPAP tolerance, improve therapeutic adherence, and reduce the rate of self-discontinuation of therapy. Good CPAP adherence lead to better functional outcomes.

OBJECTIVES: Insomnia is an important clinical problem affecting the elderly. We examined trends in insomnia diagnosis and treatment among Medicare beneficiaries over an eight-year period. DESIGN: Time series SETTING AND PARTICIPANTS: 5% sample of Medicare administrative data for years 2006–2013 Measurements: Insomnia was defined as the presence of at least one claim containing International Classification of Disease, Version 9, Clinical Modification (ICD-9-CM) codes 307.41, 307.42, 307.49, 327.00, 327.01, 327.09, 780.52, V69.4 in any given year. Insomnia medications were identified by searching the Part D prescription drug files in each year for barbiturates, benzodiazepines, chloral hydrate, hydroxyzine, non-benzodiazepine sedative hypnotics, and sedating antidepressants. RESULTS: Prevalence of physician-assigned insomnia diagnoses increased from 3.9% in 2006 to 6.2% in 2013. Prevalence of any insomnia medication use ranged from 21.0% in 2006 to 29.6% in 2013 but remained steady. A sharp increase in use of benzodiazepines from 2012–2013 (1.1% to 17.6%) drove up total insomnia medication use for 2013. Prevalence of both insomnia diagnosis and medication use ranged from 3.5% in 2006 to 5.5% in 2013, while prevalence of either insomnia diagnosis or medication use ranged from 22.7% in 2006 to 31.0% in 2013. CONCLUSIONS: In this large national analysis of Medicare beneficiaries, prevalence of physician-assigned insomnia diagnoses was low but increased over time. Prevalence of insomnia medication use was up to four-times higher than insomnia diagnoses and remained steady over time. Notably, prevalence of benzodiazepine use increased dramatically from 2012–2013 after these medications were included in the Medicare Part D formulary.

Benzodiazepines (BZDs) are CNS depressant drugs with sedative, hypnotic, anticonvulsant, and muscle relaxant properties. BZDs replaced barbiturates and other hypnotics in the late 1950s and became the most prescribed medications in 1977. Generally considered effective and safe for short-term use, long-term BZD use beyond 6 weeks is controversial due to loss of efficacy and cognitive adverse outcomes. Side effects include alteration of sleep architecture, nightmares, agitation, amnesia, cognitive impairment, confusion, depression, and dementia. BZD-induced psychomotor impairments lead to increased risks of falls and motor vehicle accidents. Abrupt BZD discontinuation may lead to rebound of the symptoms for which they were prescribed and withdrawal symptoms. The mortality risk of BZD use disorder is of special concern in vulnerable populations given the current opioid overdose epidemic, as BZDs use by patients with opioid use disorders (OUD) contributes significantly to an increase in opioid-related death. In the early 1990s, nonbenzodiazepine GABAA receptor agonists at the BZD receptor site, the Z-drugs (zaleplon, zolpidem, zopiclone, and eszopiclone), were introduced for treatment of insomnia. Z-drugs have been promoted as safer than traditional BZDs and rapidly gained wide acceptance with the public and practitioners. However, given their similar mechanism of action, their risks and side effects are similar. Given the risks, prescription of sedatives should be avoided or, if necessary, should be limited to short-term use for acute issues. Studies demonstrate that BZD discontinuation after long-term use is associated with improved quality of life once the withdrawal syndrome has been overcome.

Up to 10% of the US adult population will experience chronic insomnia, with women and elderly individuals at particularly high risk. Cognitive behavioral therapy is the core treatment for insomnia. When cognitive behavioral therapy is not enough, medications can help patients overcome the barriers and learned behaviors that prevent a good night's sleep. Benzodiazepines and nonbenzodiazepine GABA-A receptor agonists are the traditional medications used to treat insomnia. More recently, orexin inhibitors have been introduced that may have fewer adverse effects, including the development of dependence. To date, only suvorexant and lemborexant have been approved for the treatment of insomnia. However, several other agents are in later stages of development. This article will review the available pharmacotherapeutic options for treating insomnia.

The present paper is describing a case of persistent genital arousal disorder that developed to a 55-year-old woman, shortly after the initiation of zolpidem. Persistent genital arousal disorder (PGAD) is a clinical entity that appears with a relatively low frequency in women, and is characterized by persistent or recurrent, unwanted and bothersome feelings of genital arousal, which often do not resolve with orgasm and are not associated with sexual desire (sexual interest, thoughts or fantasies). Women who experience PGAD often have feelings of shame, guilt and distress. Although its exact etiology remains unclear, various etiological factors have been proposed, central or peripheral, which may be psychological, vascular, dietary, pharmacological or neurological. Additionally, its presence has been associated to restless legs syndrome and overactive bladder syndrome. Likewise, multiple therapeutic interventions have been proposed and tried in patients with PGAD, either pharmacological (SSRIs, SNRIs, antiandrogens, benzodiazepines, antipsychotics, anticonvulsive agents) or other (ECT, physiotherapy, psychotherapy, nerve stimulation). Zolpidem is a nonbenzodiazepine indirect GABA A receptor agonist, which has lately been used as a therapeutic agent for PGAD in some cases. Nevertheless, in our patient, receiving zolpidem for insomnia seemed to be timely connected to the onset of PGAD symptomatology. The aim of the present paper is to highlight the need for more research into the possible factors that may contribute to PGAD.

Background Venous thromboembolism (VTE) is a life-threatening disease, and some studies reported that benzodiazepine receptor agonist (BZRA) use could increase the risk of VTE, but this association lacks population-based evidence. Objectives To investigate the association between BZRA use and the risk of VTE. Patients/methods A nested case-control study analyzing Taiwan's claims database was conducted of patients with at least one new BZRA prescription on record from January 1, 2002, to December 31, 2012. We included new users who did not have any BZRA prescriptions in the preceding 2 years and identified cases with VTE and disease risk score matched control subjects. We used a logistic regression model to investigate the association between BZRA exposure and the risk of VTE. The exposure duration, dose, and classes of BZRAs were comprehensively evaluated. Results We identified 2800 VTE cases and 2800 matched controls. Current BZRA prescription (≤90 days) was associated with VTE occurrence (adjusted odds ratio [aOR]: 1.83; 95% confidence interval [CI], 1.62-2.06). The point estimates of benzodiazepine hypnotics (aOR: 2.00; 95% CI, 1.45-2.76) had a marginally higher risk of VTE than nonbenzodiazepine hypnotics (aOR: 1.39; 95% CI, 1.07-1.81). The VTE risk was increased with combination BZRA use, number of BZRA used, and a higher dose of BZRA. On examination of individual BZRA, the risk of VTE was higher with flunitrazepam use (aOR: 2.99; 95% CI, 1.43-6.28) than other BZRAs. Conclusions This study presents that current BZRA use may increase the risk of VTE. Also, benzodiazepine hypnotics, especially flunitrazepam, have a higher risk of VTE.

The sedative, hypnotic, and anxiolytic class of medication includes benzodiazepines, barbiturates, and the nonbenzodiazepine “Z-drugs.” Tolerance, dependence, and withdrawal can occur with any of these medications when misused or used for treatment. Benzodiazepines are of concern with their use contributing to opioid overdoses. It is important to recognize and treat, as well as prevent, sedative, hypnotic, and anxiolytic use disorders. Cessation, especially abrupt withdrawal, of any of these medications can lead to a clinically significant withdrawal syndrome, which must be immediately recognized by providers and treated as a medical emergency. Benzodiazepines, barbiturates, and the nonbenzodiazepine “Z-drugs” have distinct, though variably overlapping, clinical manifestations of intoxication and withdrawal, which are described. Treatment of sedative-hypnotic use disorders, including pharmacological, therapeutic, and psychosocial, will be covered elsewhere in this book.

Background Anxiety associated with pediatric surgery can be stressful. Midazolam is a well-accepted anxiolytic in this setting. However, there are cases in which this medication is not effective. Zolpidem is a short-acting nonbenzodiazepine hypnotic drug that is administered orally and has quick onset of action (~15 minutes), and 2-3 hour duration. Aims Based on the theory that impaired perception following oral zolpidem administration would suppress the development of anxiety, we sought to compare zolpidem to midazolam for pediatric preoperative anxiety. Methods This prospective randomized double-blinded clinical trial was designed to compare the effectiveness of oral midazolam and zolpidem for anxiety premedication. Eighty ASA class I-II pediatric patients between 2 and 9 years old, surgery >2 hours, and at least 23 hours postoperative admission were included in the study. Randomization was done with 0.5 mg/kg midazolam or 0.25 mg/kg zolpidem administered orally. The primary outcome measure was between group difference in patient anxiety at the time of separation using the Modified Yale Preoperative Anxiety Scale. Secondary outcomes included emergence delirium and mask acceptance at induction. Results There was no significant difference in Modified Yale Preoperative Anxiety Scale scores at separation between midazolam (median/interquartile range = 26.7/23.3-36.6) and zolpidem (median/interquartile range = 30.0/23.3-56.6) groups, difference 0.01 (95% CI -3E-5 , 3E-2 ; P = 0.07). Mask acceptance score was significantly better in the midazolam group. There was no significant difference in emergence delirium scores between groups. Conclusion This study demonstrates that zolpidem, as dosed, was similar to midazolam with regard to anxiety scoring, and inferior with regard to mask acceptance scores.

Objective The objective of the study was to determine electrical status epilepticus in sleep (ESES) outcome in children with very high spike–wave index (SWI; ≥ 85%), and assess treatment pattern. Methods Medical records of children 1–17 years old with ESES were reviewed. In this study, ESES is defined as SWI in non-rapid eye movement (non-REM) sleep of ≥ 85%. Electrical status epilepticus in sleep resolution is defined as reduction of SWI to Results Complete data were available in 33 children. Age at ESES diagnosis ranged from 32 to 165 months, median 76 months. The median duration of follow-up was 33 months. Two-thirds of the children were on one or more antiepileptic drugs (AED) at ESES diagnosis. Antiepileptic drugs were used as first treatment for ESES in 24/33 (73%). Electrical status epilepticus in sleep initially resolved in 76%, but 56% had subsequent relapse. The relapse rate was higher for steroids (89%) and benzodiazepines (60%) as compared with nonbenzodiazepine AEDs (29%). At last follow-up, ESES resolved in 21 children (64%). Electrical status epilepticus in sleep resolution was associated with seizure freedom (Fisher's exact, p Significance Using electroencephalogram (EEG) criteria, ESES resolved in 64%. We found high failure rate of first-line AEDs in preventing ESES, and high relapse rate. Standardization of ESES management is urgently needed.

This article provides a short history of the creation of hypnotics, examines their mechanisms of action, and conducts a comparative analysis of the main groups of hypnotics such as barbiturates, benzodiazepines, «nonbenzodiazepine» benzodiazepine receptor agonists, melatonin receptor agonists, orexin receptor antagonists, histamine H 1 -receptor antagonists.

Objective:Clinical guidelines suggest that benzodiazepines (BZDs) and non-BZD hypnotics (NBHs) be used on a short-term basis. The authors examined trends in long-term BZD and NBH use from 1999 to 2...

Background The relationship between the use of benzodiazepine-receptor agonists (BZRAs) and the risk of hospitalization for pneumonia remains inconclusive. This study aimed to explore the association between BZRA use and hospitalization for pneumonia in a general population. Methods This population-based nested case-control study used Taiwan's National Health Insurance Research Database between 2002 and 2012. We included only new users who did not have any BZRA prescriptions on record in the preceding 2 years and identified 12,002 subjects who were hospitalized for pneumonia (International Classification of Diseases, Ninth Revision codes 480-486, and 507) and 12,002 disease risk score-matched control subjects. A logistic regression model was used to determine the association of BZRA use and hospitalization for pneumonia. The exposure date, dose-response relationship, and class of BZRAs were comprehensively assessed. Results Current BZRA exposure was associated with hospitalization for pneumonia (adjusted OR [aOR],1.86; 95% CI, 1.75-1.97). Benzodiazepine hypnotic agents (aOR, 2.42; 95% CI, 2.16-2.71) had a higher risk of pneumonia than did benzodiazepine anxiolytic agents (aOR, 1.53; 95% CI, 1.44-1.63) or nonbenzodiazepine hypnotic agents (aOR, 1.60; 95% CI, 1.46-1.76). The pneumonia risk was increased with ultrashort-acting and short- to intermediate-acting agents, a higher defined daily dose, and the number of BZRAs used. Among individual BZRAs examined, midazolam had a higher risk (aOR, 5.77; 95% CI, 4.31-7.73) of hospitalization for pneumonia than did the others. Conclusions This study suggests that there is a dose-response relationship between current BZRA use and the risk of hospitalization for pneumonia. In addition, benzodiazepine hypnotic agents, especially midazolam, present a greater risk of hospitalization for pneumonia. These findings reinforce the importance of a careful analysis of the benefits vs the risks of BZRA use.

During status epilepticus (SE), synaptic γ-aminobutyric acid A receptors (GABAA Rs) become internalized and inactive, whereas spare N-methyl-d-aspartate receptors (NMDARs) assemble, move to the membrane, and become synaptically active. When treatment of SE is delayed, the number of synaptic GABAA Rs is drastically reduced, and a GABAA agonist cannot fully restore inhibition. We used a combination of low-dose diazepam (to stimulate the remaining GABAA Rs), ketamine (to mitigate the effect of the NMDAR increase), and valproate (to enhance inhibition at a nonbenzodiazepine site) to treat seizures in a model of severe cholinergic SE. High doses of diazepam failed to stop electrographic SE, showing that benzodiazepine pharmacoresistance had developed. The diazepam-ketamine-valproate combination was far more effective in stopping SE than triple-dose monotherapy using the same individual drugs. Isobolograms showed that this drug combination's therapeutic actions were synergistic, with positive cooperativity between drugs, whereas drug toxicity was simply additive, without positive or negative cooperativity. As a result, the therapeutic index was improved by this drug combination compared to monotherapy. These results suggest that synergistic drug combinations that target receptor changes can control benzodiazepine-refractory SE.

Several major medical and psychiatric organizations, including the American Geriatrics Society, advise against using benzodiazepines or nonbenzodiazepine hypnotics in older adults. Despite these recommendations, benzodiazepines continue to be massively prescribed to a group with the highest risk of serious adverse effects from these medications. This article summarizes legitimate reasons for prescribing benzodiazepines in the elderly, serious associated risks of prescribing them, particularly when not indicated, barriers physicians encounter in changing their prescription patterns, and evidence-based strategies on how to discontinue benzodiazepines in older patients. Although more research is needed, we propose several alternatives for treating insomnia and anxiety in older adults in primary care settings. These include nonpharmacological approaches such as sleep restriction-sleep compression therapy and cognitive behavioral therapy for anxiety or insomnia, and as well as alternative pharmacological agents.

Purpose Insomnia is problematic for older adults. After behavioral modifications fail to show adequate response, pharmacologic options are used. The pharmacokinetics of agents used to treat insomnia may be altered. This review focuses on the safety and efficacy of medications used to treat insomnia. Methods A literature search of Medline, PubMed, and Embase was conducted (January 1966–June 2016). It included systematic reviews, randomized controlled trials, observational studies, and case series that had an emphasis on insomnia in an older population. Search terms included medications approved by the US Food and Drug Administration for insomnia: benzodiazepines (triazolam, estazolam, temazepam, flurazepam, and quazepam), nonbenzodiazepine receptor agonists (non-BzRAs; zaleplon, zolpidem, and eszopiclone), suvorexant, ramelteon, doxepin and trazodone. Off-label drugs such as other antidepressants, antihistamines, antipsychotics, gabapentin, pramipexole, tiagabine, valerian, and melatonin were also included. Findings Cognitive behavioral therapy and sleep hygiene are considered initial therapy for insomnia. Benzodiazepines are discouraged in the geriatric population, especially for long-term use. Although non-BzRAs have improved safety profiles compared with benzodiazepines, their side effects include dementia, serious injury, and fractures, which should limit their use. Ramelteon has a minimal adverse effect profile and is effective for sleep-onset latency and increased total sleep time, making it a valuable first-line option. Although the data on suvorexant are limited, this drug improves sleep maintenance and has mild adverse effects, including somnolence; residual daytime sedation has been reported, however. Sedating low-dose antidepressants should only be used for insomnia when the patient has comorbid depression. Antipsychotic agents, pramipexole, and tiagabine have all been used for insomnia, but none has been extensively studied in an older population, and all have considerable adverse effects. Gabapentin may be useful in patients with restless leg syndrome or chronic neuropathic pain and insomnia. Diphenhydramine should be avoided in the elderly. Valerian and melatonin are unregulated products that have a small impact on sleep latency and can produce residual sedation. Implications An ideal treatment for insomnia should help to improve sleep latency and sleep duration with limited awakenings and be without significant adverse effects such as daytime somnolence or decreased alertness. Cognitive behavioral therapy should always be first line treatment. Clinical inertia regarding previous prominent use of benzodiazepines and non-BzRAs will be a significant challenge for patients accustomed to their issuance. The future direction of insomnia treatment should have an emphasis on nonpharmacologic interventions, treating comorbid conditions, and focusing therapy on using benzodiazepines and non-BzRAs as last resorts.

Zolpidem is an imidazopyridine nonbenzodiazepine hypnotic drug with a high affinity to the α1 subunit of the gamma amino butyric acid A receptor It is the first pharmacological option in the short-term management of sleep-onset insomnia. Initially considered a safer drug compared to benzodiazepines because of lower liability for abuse and dependence, recently, an increasing body of reports has questioned zolpidem's proneness to misuse. In this report, we describe a case of serious zolpidem abuse requiring pharmacological washout during hospitalization because of previous withdrawal seizures in a patient with chronic sleep-onset and maintenance insomnia.

Multiple etiologies contribute to sleep disturbance in atopic dermatitis (AD) patients, including learned scratching behavior and increased monoamines, cutaneous blood flow, inflammatory cell activities, and cytokines, as well as decreased melatonin, anti-inflammatory cytokines, and skin barrier function. Insomnia impairs cognitive development in children with AD, leading to behavioral problems and learning disabilities. Insomnia in adults with AD impedes work productivity. In this article, we discuss pearls on improving insomnia through both nonpharmacologic modalities, such as environmental adjustments and massage therapy, and pharmaceutical approaches including melatonin, antihistamines, tricyclic antidepressants, mirtazapine, and benzodiazepine and nonbenzodiazepine sedatives. Future investigations should further delineate the mechanistic link between insomnia and AD exacerbation and identify strategies to combat sleep-related disease burden.

OBJECTIVES/HYPOTHESIS In this study, we tested the use of repetitive transcranial magnetic stimulation (rTMS) to reduce depression and anxiety in patients using or not using benzodiazepines. We hypothesized that rTMS would concurrently reduce symptoms in both depression and anxiety and that these reductions would correlate with patients using benzodiazepines. MATERIALS AND METHODS This retrospective study screened for patients treated in a TMS clinic within a five-year period. Each patient had received high-frequency (10 or 20 Hz) rTMS over the left dorsolateral prefrontal cortex and completed pre- and posttreatment Beck Depression Inventory and Visual Analog Scale-Anxiety ratings. Fifty-eight patients (37 women) met these criteria and 37 (63.8%) took benzodiazepines. We used two mixed analysis of variance analyses to separately evaluate the effects of rTMS on depression and anxiety. We additionally directly evaluated the relationship between reductions in depression and anxiety by computing three linear correlations (all patients, benzodiazepine users, nonbenzodiazepine users). RESULTS rTMS was an effective treatment of depression for all patients (p

Chronic neuropathic pain may be caused, in part, by loss of inhibition in spinal pain processing pathways due to attenuation of local GABAergic tone. Nociception and nocifensive behaviors are reduced after enhancement of tonically activated extrasynaptic GABA(A)R mediated currents by agonist ligands for δ subunit-containing GABA(A)Rs. However, typical ligands that target δ subunit-containing GABA(A)Rs are limited due to sedative effects at higher doses. We used the spinal nerve ligation (SNL) and gp120 models of experimental neuropathic pain to evaluate compound 2–261, a non-benzodiazepine (BZ) site positive allosteric modulator (PAM) of α(4)β(3)δ GABA(A)Rs optimized to be non-sedative by selective activation of β(2/3) subunit-containing GABA(A)Rs over receptor subtypes incorporating β(1) subunits. Similar levels of 2–261 were detected in the brain and plasma following intraperitoneal administration. While systemic 2–261 did not alter sensory thresholds in sham-operated animals, it significantly reversed SNL-induced thermal and tactile hypersensitivity in a GABA(A)R dependent fashion. Intrathecal 2–261 produced conditioned place preference (CPP) and elevated dopamine levels in the nucleus accumbens of nerve-injured, but not sham-operated rats. Additionally, systemic pretreatment with 2–261 blocked CPP from spinal clonidine in SNL rats. Moreover, 2–261 reversed thermal hyperalgesia and partially reversed tactile allodynia in the gp120 model of HIV-related neuropathic pain. The effects of 2–261 likely required interaction with the α(4)β(3)δ GABA(A)R since 2–301, a close structural analog of 2–261 with limited extrasynaptic receptor efficacy, was not active. Thus, 2–261 may produce pain relief with diminished side-effects through selective modulation of β(2/3) subunit-containing extrasynaptic GABA(A)Rs.

The criminal use of drugs to render a victim susceptible to nonconsensual acts (known as drug-facilitated crime) is not a new phenomenon. Drugs used for this purpose are often rapidly acting central nervous system depressants that may additionally possess amnestic (impairment of memory) and/or immobilizing properties. Drug development in the last 50 years has greatly expanded the pharmaceuticals that have been used for drug-facilitated crimes. This chapter will focus on drugs implicated in drug-facilitated sexual assault that can present analytical challenges: γ-hydroxybutyric acid and its analogs, ketamine, methylenedioxymethamphetamine, flunitrazepam, and the nonbenzodiazepine sedative-hypnotics.

Benzodiazepines (BZDs) have been widely used in neurological disorders such as insomnia, anxiety, and epilepsy. The use of classical BZDs, e.g., diazepam, has been limited due to adverse effects such as interaction with alcohol, ataxia, amnesia, psychological and physical dependence, and tolerance. In the quest for new benzodiazepine agonists with more selectivity and low adverse effects, novel derivatives of 4,6-diphenylpyrimidin-2-ol were designed, synthesized, and evaluated. In this series, compound 2, 4-(2-(benzyloxy)phenyl)-6-(4-fluorophenyl)pyrimidin-2-ol, was the most potent analogue in radioligand binding assay with an IC50 value of 19 nM compared to zolpidem (IC50 = 48 nM), a nonbenzodiazepine central BZD receptor (CBR) agonist. Some compounds with a variety of affinities in radioligand receptor binding assay were selected for in vivo evaluations. Compound 3 (IC50 = 25 nM), which possessed chlorine instead of fluorine in position 4 of the phenyl ring, exhibited an excellent ED50 value in most in vivo tests. Proper sedative-hypnotic effects, potent anticonvulsant activity, appropriate antianxiety effect, and no memory impairment probably served compound 3, a desirable candidate as a benzodiazepine agonist. The pharmacological effects of compound 3 were antagonized by flumazenil, a selective BZD receptor antagonist, confirming the BZD receptors’ involvement in the biological effects of the novel ligand.

In “Association of guideline publication and delays to treatment in pediatric status epilepticus,” Fernandez et al. reported that despite publication of evidence of delays in treatment of refractory status epilepticus (SE) in the Pediatric Status Epilepticus Research Group (pSERG) at the end of 2014, there was no difference in time to initiation of benzodiazepines, nonbenzodiazepine antiepileptic drugs (AEDs), and continuous infusions to patients with refractory SE in pSERG in the hospital between 2011–2014 and 2015–2019. The authors identified a number of proposed actions to overcome potential barriers to the timely initiation of AEDs. Albuja et al. commented that they improved the time to administration of second-line AEDs at their institution by creating a SE alert system to contact neurology, pharmacy, the rapid response team, and the bed manager simultaneously when an inpatient is suspected to be in SE. Amengual-Gual et al. applauded them for implementing this initiative. It is imperative to continue to identify quality improvement measures to identify SE and ensure that AEDs are given in a timely fashion to patients with SE because it becomes more resistant over time, which may lead to increased morbidity and mortality.[1][1],[2][2] In “Association of guideline publication and delays to treatment in pediatric status epilepticus,” Fernandez et al. reported that despite publication of evidence of delays in treatment of refractory status epilepticus (SE) in the Pediatric Status Epilepticus Research Group (pSERG) at the end of 2014, there was no difference in time to initiation of benzodiazepines, nonbenzodiazepine antiepileptic drugs (AEDs), and continuous infusions to patients with refractory SE in pSERG in the hospital between 2011–2014 and 2015–2019. The authors identified a number of proposed actions to overcome potential barriers to the timely initiation of AEDs. Albuja et al. commented that they improved the time to administration of second-line AEDs at their institution by creating a SE alert system to contact neurology, pharmacy, the rapid response team, and the bed manager simultaneously when an inpatient is suspected to be in SE. Amengual-Gual et al. applauded them for implementing this initiative. It is imperative to continue to identify quality improvement measures to identify SE and ensure that AEDs are given in a timely fashion to patients with SE because it becomes more resistant over time, which may lead to increased morbidity and mortality.1,2 [1]: #ref-1 [2]: #ref-2

STUDY OBJECTIVES: The objective of this study was to test the hypothesis that use of zolpidem, eszopiclone, and zaleplon would be associated with increased risk of traumatic brain injury (TBI) and hip fracture. METHODS: We conducted a case-crossover study on a 5% random sample of Medicare beneficiaries age 65 y or older hospitalized with either TBI (n = 15,031) or hip fracture (n = 37,833) during 2007-2009. Use of zolpidem, eszopiclone, or zaleplon during the 30-day period prior to injury hospitalization was compared to use during four control periods at 3, 6, 9, and 12 mo prior to injury. The primary outcome was hospitalization for TBI or hip fracture. RESULTS: Zolpidem use during the month prior to injury was associated with increased risk of TBI (odds ratio [OR] 1.87; 95% confidence interval [CI] 1.56, 2.25); however, eszopiclone use during the same period was not associated with increased risk (OR 0.67; 95% CI 0.40, 1.13). Zolpidem use during the month prior to injury was associated with increased risk of hip fracture (OR 1.59; 95% CI 1.41, 1.79); however, eszopiclone use during the same period was not associated with increased risk (OR 1.12; 95% CI 0.83, 1.50). Analysis of zaleplon use in the month prior to injury was limited by low drug utilization but was not associated with increased risk of TBI (OR 0.85; 95% CI 0.21, 3.34) or hip fracture (OR 0.92; 95% CI 0.40, 2.13) in this study. CONCLUSIONS: For the treatment of insomnia in older adults, eszopiclone may present a safer alternative to zolpidem, in terms of fall-related injuries. Language: en

Patients admitted to the intensive care unit (ICU) commonly develop pain and agitation. Such symptoms are associated with adverse clinical outcomes, as they can cause delirium, self-removal of life-sustaining devices, difficulty in use of ventilatory supports, hemody namic instability, intracranial hypertension, posttraumatic stress disorder, etc. Thus, prompt recognition and treatment of pain and agitation are imperative. Identification of possible causes of pain and agitation and nonpharmacological managements should be attempted initially. However, administration of analgesics and sedatives is necessary in many cases. Preemptive interventions prior to procedures to relieve pain are recommended. Intravenous opioids are considered as the first-line drug to treat pain in critically ill patients, especially in those who require mechanical ventilation. For most patients in the ICU, a light level of sedation is associated with improved clinical outcomes. However, patients with unstable medical conditions including severe acute respiratory distress syndrome, hemodynamic instability, refractory status epilepticus, and intracranial hypertension may require a deep level of sedation. Sedation strategies using nonbenzodiazepine sedatives may be preferred over sedation with benzodiazepines in mechanically ventilated patients to shorten the duration of mechanical ventilation, length of ICU stay, and days with delirium. Often, ensuring that critically ill patients are free from pain and agitation may conflict with other clinical management goals. Therefore, provision of comprehensive care based on the patients’ condition cannot be overemphasized in the ICU. The purpose of this review is to address pain and agitation management strategies and introduce pharmacological characteristics of sedatives and analgesics commonly used in the ICU. J Neurocrit Care 2015;8(2):53-65

Managing sedative and analgesic medications is an essential part of critical care medicine. There is a shift toward favoring the use of nonbenzodiazepine agents because of their side effects. There is an increasing interest in using ketamine as an analgo-sedative in the intensive care unit because of its unique pharmacologic properties. A comprehensive literature search was performed to capture all the studies involving ketamine use in critical care. We searched PubMed, EMBASE, and Cochrane databases. We also extracted the references from major review articles and recent guidelines. In this review, we present the most up-to-date studies done on this topic. We also present the proposal for a future multicenter randomized trial through the Saudi Critical Care Trials Group.

The transition from single seizures to status epilepticus (SE) is associated with malaptive trafficking of synaptic gamma-aminobutyric acid (GABAA) and glutamate receptors. The receptor trafficking hypothesis proposes that these changes are key events in the development of pharmacoresistance to antiepileptic drugs (AEDs) during SE, and that blocking their expression will help control drug-refractory SE (RSE). We tested this hypothesis in a model of SE induced by very high-dose lithium and pilocarpine (RSE), and in a model of SE induced by sc soman. Both models are refractory to benzodiazepines when treated 40 min after seizure onset. Our treatments aimed to correct the loss of inhibition because of SE-associated internalization of synaptic GABAA receptors (GABAAR), using an allosteric GABAAR modulator, sometimes supplemented by an AED acting at a nonbenzodiazepine site. At the same time, we reduced excitation because of increased synaptic localization of NMDA and AMPA (?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-D-aspartate) receptors (NMDAR, AMPAR (?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, N-methyl-D-aspartate receptors)) with an NMDAR channel blocker, since AMPAR changes are NMDAR-dependent. Treatment of RSE with combinations of the GABAAR allosteric modulators midazolam or diazepam and the NMDAR antagonists dizocilpine or ketamine terminated RSE unresponsive to high-dose monotherapy. It also reduced RSE-associated neuronal injury, spatial memory deficits, and the occurrence of spontaneous recurrent seizures (SRS), tested several weeks after SE. Treatment of soman-induced SE also reduced seizures, behavioral deficits, and epileptogenesis. Addition of an AED further improved seizure outcome in both models. Three-dimensional isobolograms demonstrated positive cooperativity between midazolam, ketamine, and valproate, without any interaction between the toxicity of these drugs, so that the therapeutic index was increased by combination therapy. The midazolam-ketamine-valproate combination based on the receptor trafficking hypothesis was far more effective in stopping RSE than the midazolam-fosphenytoin-valproate combination inspired from clinical guidelines for the treatment of SE. Furthermore, sequential administration of midazolam, ketamine, and valproate was far less effective than simultaneous treatment with the same drugs at the same dose. These data suggest that treatment of RSE should be based at least in part on its pathophysiology. The search for a better treatment should focus on the cause of pharmacoresistance, which is loss of synaptic GABAAR and gain of synaptic glutamate receptors. Both need to be treated. Monotherapy addresses only half the problem. Improved pharmacokinetics will not help pharmacoresistance because of loss of receptors. Waiting for one drug to fail before giving the second drugs gives pharmacoresistance time to develop. Future clinical trials should consider treating both the failure of inhibition and the runaway excitation which characterize RSE, and should include an early polytherapy arm. This article is part of the Special Issue "Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures".

INTRODUCTION Zolpidem is a short-acting nonbenzodiazepine hypnotic that has been approved by the Republic of Singapore Air Force (RSAF) for aircrew sleep management since 2005. Prior to consuming zolpidem for operational reasons, each RSAF aircrew member is required to undergo a ground test to exclude operationally relevant adverse drug effects. This study describes the RSAF's zolpidem ground testing outcomes over a 12.5-yr period. METHODS This is a retrospective case series of 578 RSAF aircrew members who underwent zolpidem test dosing from 1 January 2005 to 30 June 2017. RESULTS The median age was 29 yr (range, 19-54 yr) and the mean age was 30.1 yr ± 6.3 yr. Of the aircrew members, 568 (98.3%) were men and all were of Asian origin; 558 (96.5%) were medically cleared for the operational use of zolpidem. Among the 20 (3.5%) who failed zolpidem ground testing, next-day drowsiness (cumulative incidence, 1.04%), headache (cumulative incidence, 0.87%), and dizziness (cumulative incidence, 0.35%) were the most common causes of failure. None of the aircrew members reported abnormal sleep behaviors or major adverse drug events from zolpidem ingestion. DISCUSSION Our results suggest a low occurrence of adverse effects among military aircrew members who undergo zolpidem test dosing prior to using the drug operationally. To our knowledge, this is the single largest published case series of zolpidem ground testing outcomes among Asian military aviators.Kew GS, See B. Zolpidem as a sleep aid for military aviators. Aerosp Med Hum Perform. 2018; 89(4):406-408.

To ascertain the degree to which a general medical condition or substance is a causative factor of a patient’s anxiety, the clinician should know whether the medical condition or substance has been closely associated with the anxiety symptoms in the literature. Assessment of anxiety in the medically ill requires examining biologic as well as psychosocial factors. In particular, clinicians should address the major psychologic issues, such as isolation, dependency, loss of bodily integrity, and dying that are known to be commonly associated with anxiety in the medically ill. Management of the physical disease-induced anxiety should be preceded by treatment of the physical diseases. The primary treatment of substance-induced anxiety disorder is the removal of the causally involved substance. However, any successful intervention for these patients should be a biopsychosocial approach that includes psychopharmacological and psychosocial treatment. Benzodiazepine or nonbenzodiazepine anxiolytics and antidepressants may be helpful in decreasing anxiety symptoms in the medically ill. Psychosocial treatment includes providing accurate medical information (e.g., diagnosis and prognosis), explaining the role and meaning of the monitoring equipment, providing emotional support and reassurance, and reinforcing the appropriate use of denial. For patients with persistent anxiety symptoms, cognitive and behavioral strategies can be used.

Objective: To describe the time elapsed from onset of pediatric convulsive status epilepticus (SE) to administration of antiepileptic drug (AED). Methods: This was a prospective observational cohort study performed from June 2011 to June 2013. Pediatric patients (1 month–21 years) with convulsive SE were enrolled. In order to study timing of AED administration during all stages of SE, we restricted our study population to patients who failed 2 or more AED classes or needed continuous infusions to terminate convulsive SE. Results: We enrolled 81 patients (44 male) with a median age of 3.6 years. The first, second, and third AED doses were administered at a median (p 25 –p 75 ) time of 28 (6–67) minutes, 40 (20–85) minutes, and 59 (30–120) minutes after SE onset. Considering AED classes, the initial AED was a benzodiazepine in 78 (96.3%) patients and 2 (2–3) doses of benzodiazepines were administered before switching to nonbenzodiazepine AEDs. The first and second doses of nonbenzodiazepine AEDs were administered at 69 (40–120) minutes and 120 (75–296) minutes. In the 64 patients with out-of-hospital SE onset, 40 (62.5%) patients did not receive any AED before hospital arrival. In the hospital setting, the first and second in-hospital AED doses were given at 8 (5–15) minutes and 16 (10–40) minutes after SE onset (for patients with in-hospital SE onset) or after hospital arrival (for patients with out-of-hospital SE onset). Conclusions: The time elapsed from SE onset to AED administration and escalation from one class of AED to another is delayed, both in the prehospital and in-hospital settings.

Background This study examined the relationship between depression, benzodiazepine (BZD)/nonbenzodiazepine hypnotics (non-BZD), and other risk factors in a national sample of Taiwan's elderly diabetic patients. Methods Data were drawn from the 2005 Taiwan National Health Interview Survey and adults aged 65 years and older. A total of 1331 subjects were included in this study. The Chinese version of Center for Epidemiologic Studies Depression Scale was used to evaluate patients' depression symptoms. Results The rates of depression in the diabetes mellitus (DM) and non-DM groups were 13.5% (39/288) and 9.8% (102/1043) and the average ages were 73.7 and 73.4 years, respectively. In multivariate regression, the odds ratio of depression was 1.66-fold higher among BZD/non-BZD users (95% confidence interval: 1.10–2.51, model 2) than among those without BZD/non-BZD use. In addition, hyperlipidaemia, poor physical function, and antidepressant use were associated with a higher risk of depressive symptoms. Meanwhile, a monthly household income of NT$30 000–NT$49 999, exercise, and betel chewing were associated with a lower risk of depression. We performed an additional logistic analysis for which the odds ratio of depression significantly increased to 1.52 in non-DM elderly patients (95% confidence interval: 1.06–2.19) who were prescribed BZD/non-BZD. In contrast, there was no significant difference in the odds ratio of depression in the DM elderly regardless of BZD/non-BZD use, although there was a slight tendency for depression among those who used BZD/non-BZD. Conclusion Depression in non-DM Taiwanese elderly patients was found to be associated with BZD/non-BZD use, whereas depression in DM Taiwanese elderly patients was not found to be associated with BZD/non-BZD use.

The purpose of this study was to assess the classes and types of psychotropic medication reported by borderline patients and axis II comparison subjects over 16 years of prospective follow-up. Medication use was assessed at baseline using a semistructured interview of proven reliability and validity as well as its follow-up analog at eight contiguous two-year follow-up periods. A significantly higher percentage of borderline patients than axis II comparison subjects reported taking an antidepressant, an anxiolytic, an antipsychotic, and a mood stabilizer over time. They also reported more commonly taking seven of the ten more specific types of medication studied (i.e., all but tricyclic antidepressants, monoamine oxidase inhibitor antidepressants [MAOIs], and atypical antipsychotics). The rates over time of taking antipsychotics and mood stabilizers were stable, while there was a significant decline in the rates of antidepressants and anxiolytics from baseline to eight-year follow-up (but not from eight to 16-year follow-up) reported by those in both study groups. In terms of specific medications, rates of atypical antidepressants and anticonvulsants were the most stable. In contrast, nonbenzodiazepine anxiolytics declined the most steadily over time, while rates of atypical antipsychotics increased significantly over the 16 years of prospective follow-up. Taken together, the results of this study suggest that a substantial percentage of borderline patients continue to use the major classes of medication over time. They also suggest that the declining rates of use tend to stabilize less than a decade after index admission.

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.

High rates of controlled prescription drugs are associated with cognitive impairment, falls, and misuse and dependence. Little is known about the prevalence of these medications among older adults receiving home healthcare. The purpose of this study was to determine the frequency of, and the factors related to, opioid analgesics, benzodiazepines (BNZ), and nonbenzodiazepine (NBNZH) hypnotics among a large sample of older adults entering home healthcare services. The data came from administrative records of 133 Certified Home healthcare Agencies located across 32 states. Patients (age ≥ 65) receiving Medicare home healthcare services and who received a start-of-care Medicare OASIS assessment between January 1, 2013, and December 31, 2014, were included in the study (n = 87,780). Rates of controlled medication use were compared across patient-level sociodemographic, clinical, functional, and environmental variables. The prevalence of controlled medication was high, with 58% prescribed at least one class of controlled drug, 44% were prescribed an opioid, 19% were prescribed a BNZ, and almost 7% were prescribed a NBZDH. Factors independently associated with higher levels of controlled medication usage include younger-old age, white race, postsurgical status, injuries, referral from inpatient settings, and rural location. Home healthcare clinicians are well positioned to review and reconcile medication, oversee referrals and follow-up care, and provide ongoing assessment of risk regarding the use of opioids, BNZ, and hypnotics among home healthcare patients.

Objectives To determine patterns of and trends in contributions to central nervous system (CNS) polypharmacy, defined by the Beers Criteria as three or more CNS-active medications of each medication class, of adults aged 65 and older seen in U.S. outpatient medical practices. Design National Ambulatory Medical Care Survey (2004–2013). Setting U.S. outpatient medical care. Participants Visits by older adults to outpatient physicians (N = 97,910). Measurements Visits including three or more CNS medications including antipsychotics, benzodiazepines, nonbenzodiazepine benzodiazepine receptor agonist hypnotics (NBRAs), tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and opioids. The proportion of CNS polypharmacy that each medication class contributed during 2011 to 2013 was determined, and then logistic regression was used to determine trends from 2004 to 2013 in the contribution of individual medication classes to such polypharmacy. Results Of recent CNS polypharmacy visits, 76.2% included an opioid, and 61.8% included a benzodiazepine; 66.0% of the polypharmacy visits with benzodiazepines included opioids, and 53.3% of the polypharmacy visits with opioids included benzodiazepines. Between 2011 and 2013, opioid and benzodiazepine co-prescribing occurred at approximately 1.50 million visits (95% confidence interval (CI) = 1.23–1.78 million) annually. From 2004 (reference) to 2013, the proportion of polypharmacy visits with opioids rose from 69.6% to 76.2% (adjusted odds ratio = 2.15, 95% CI = 1.19–3.91, P = .01), and the corresponding proportion that included benzodiazepines fell. Of the polypharmacy visits, the odds of SSRI, NBRA, and antipsychotic use were unchanged, and that of TCAs decreased. Conclusion In older adults, opioid use appears to be largely driving the recent national increase in CNS polypharmacy. Although concomitant use of opioids and benzodiazepines is associated with greater mortality, they are the most common contributors to CNS polypharmacy in older adults.

Geriatric patients often experience insomnia because of physiological and neurological changes that occur during the aging process. Use of benzodiazepines, nonbenzodiazepine hypnotics, and diphenhydramine for the treatment of insomnia pose an increased risk of cognitive impairment, falls, and fractures in this patient population. Therapeutic alternatives approved by the Food and Drug Administration include suvorexant, doxepin, ramelteon, and tasimelteon, which have shown efficacy and safety in various studies. This paper explores and outlines the available safety and efficacy data associated with these medications and reviews their potential place in therapy in treating insomnia in the geriatric population.

The mechanism of action and the pharmacokinetics of hypnotic drugs are key determinants of their clinical effects in patients with primary or comorbid insomnia. Accordingly, the sedation and sleep-promoting properties of drugs acting as positive allosteric modulators of the GABA A receptor depend upon their selective binding to the α 1 receptor subtype. The additional binding to other receptor subtypes conditions the occurrence of adverse events. The absorption rate has been emphasized as a determinant of onset of action, and the elimination half-life ( t 1/2 ) and distribution as key factors of duration of action of hypnotic drugs in clinical use. Benzodiazepine and nonbenzodiazepine hypnotics improve sleep induction, and depending on their t 1/2 and presence of active metabolites, they improve sleep maintenance. In this respect, the pyrazolopyrimidine derivative zaleplon does not affect total sleep time. On the other hand, the increase of total sleep time that follows the administration of the benzodiazepine and imidazopyridine derivatives midazolam, triazolam, and zolpidem immediate-release, is limited to the first half of the night. In order to circumvent this limitation, a zolpidem extended-release preparation has been made available. The benzodiazepine hypnotics, temazepam, flunitrazepam, and flurazepam, and the cyclopyrrolone derivatives, zopiclone and eszopiclone, increase total sleep time beyond the first half of the night. The effect of the melatonin agonist ramelteon on sleep variables is limited to a decrease of the latency to sleep onset. The benzodiazepine derivatives induce a further reduction of slow-wave sleep (SWS) and rapid eye movement (REM) sleep in patients with an insomnia complaint. Furthermore, during the administration of the nonbenzodiazepine derivatives, zaleplon, zolpidem, zopiclone, and eszopiclone, and the melatonin agonist ramelteon, SWS and REM sleep do not regain normal levels or can even be further suppressed.

Anxiety is a common neuropsychiatric disorder which affects both physical and mental health. Complex neurobiological mechanisms are involved in the genesis of anxiety, and the drugs used to date, though effective, are not free from shortcomings. Conventional agents like the classical benzodiazepines and the atypical nonbenzodiazepine agents like buspirone have their own limitations. There is thus need to explore newer neurochemical pathways to develop efficacious and safer drugs for the disorder. Nitric oxide (NO) is a unique neuromodulator substance, with the ability to influence and modulate several other conventional messengers which play an important role in anxiety. The currently available experimental and clinical data indicate that NO may be involved in the regulation of anxiety-like behavior induced by a variety of stimuli. These studies have explored the pharmacological and biochemical basis of nitrergic mechanisms in anxiety, and the data available are equivocal. This chapter reviews the research data available in this specific area and suggests that in view of the nature of the existing data, there is considerable scope for future research in this field.

Zolpidem is a nonbenzodiazepine sedative hypnotic drug used for the short-term treatment of insomnia. While quite effective in producing sedation, zolpidem has potentially hazardous side effects when put in the context of complex tasks. Therefore, to more fully understand the postmortem concentrations of zolpidem, our laboratory has developed a sensitive method for the quantitation of zolpidem in biological specimens. Additionally, we have evaluated the distribution of zolpidem in various postmortem tissues and fluids from 10 aviation fatalities. This method incorporated a modified acetonitrile 'crash and shoot' extraction and a Waters Xevo TQ-S with an Acquity ultra-performance liquid chromatograph. The linear dynamic range was 0.4-800 ng/mL. The extraction efficiencies ranged from 78 to 87%, depending on the concentration. Postmortem blood zolpidem concentrations in these 10 cases ranged from 7.6 to 76.5 ng/mL. The highest concentrations of zolpidem present in each victim were found in the liver, spleen, lung and kidney tissues. Distribution coefficients for zolpidem were determined for each of the specimen types analyzed. These coefficients are expressed relative to the blood concentration in each case. This method proved to be simple, accurate and robust for the identification and quantitation of zolpidem in postmortem fluids and tissues.