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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.

Status epilepticus (SE) is a life-threatening neurologic condition that requires immediate assessment and intervention. Over the past few decades, the duration of seizure required to define status epilepticus has shortened, reflecting the need to start therapy without the slightest delay. The focus of this review is on the management of convulsive and nonconvulsive status epilepticus in critically ill patients. Initial treatment of both forms of status epilepticus includes immediate assessment and stabilization, and administration of rapidly acting benzodiazepine therapy followed by nonbenzodiazepine antiepileptic drug. Refractory and super-refractory status epilepticus (RSE and SRSE) pose a lot of therapeutic problems, necessitating the administration of continuous infusion of high doses of anesthetic agents, and carry a high risk of debilitating morbidity as well as mortality.

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.

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.

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.

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.

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.

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

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.

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".

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.

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.

Sleep disorders (somnipathies) are conditions characterized by disruptions of sleep quality or of sleep pattern. They can involve difficulty falling asleep (prolonged sleep onset latency), difficulty staying asleep (disturbance of sleep maintenance), sleep of poor quality (unrefreshing), or combinations of these and can lead to poor health and quality of life problems. A subtype of sleep-maintenance insomnia is middle-of-the-night wakefulness, a relatively common occurrence. Zolpidem, a nonbenzodiazepine benzodiazepine receptor agonist, allosterically modulates an ion channel and increases the influx of Cl−, thereby dampening the effect of excitatory (sleep disrupting) input. Recently, product label changes to some zolpidem containing products have been implemented by the FDA in order to reduce the risk associated with their morning after residual side effects. A new formulation of zolpidem tartrate (Intermezzo) sublingual tablet, an approved product indicated exclusively for the treatment of middle-of-the-night wakefulness and difficulty returning to sleep, did not have its label changed. We present a short summary of its basic science and clinical attributes in light of the recent regulatory changes for zolpidem products.

Introduction: Benzodiazepines are prescribed inappropriately in up to 40% of outpatients. The purpose of this study is to describe a collaborative team-based care model in which clinical pharmacists work with primary care providers (PCPs) to improve the safe use of benzodiazepines for anxiety and sleep disorders and to assess the preliminary results of the impact of the clinical service on patient outcomes. Methods: Adult patients were eligible if they received care from the academic primary care clinic, were prescribed a benzodiazepine chronically, and were not pregnant or managed by psychiatry. Outcomes included baseline PCP confidence and knowledge of appropriate benzodiazepine use, patient symptom severity, and medication changes. Results: Twenty-five of 57 PCPs responded to the survey. PCPs reported greater confidence in diagnosing and treating generalized anxiety and panic disorders than sleep disorder and had variable knowledge of appropriate benzodiazepine prescribing. Twenty-nine patients had at least 1 visit. Over 44 total patient visits, 59% resulted in the addition or optimization of a nonbenzodiazepine medication and 46% resulted in the discontinuation or optimization of a benzodiazepine. Generalized anxiety symptom severity scores significantly improved (−2.0; 95% confidence interval (CI): −3.57 to −0.43). Conclusion: Collaborative team-based models that include clinical pharmacists in primary care can assist in optimizing high-risk benzodiazepine use. Although these findings suggest improvements in safe medication use and symptoms, additional studies are needed to confirm these preliminary results.

Introduction: Zolpidem is a nonbenzodiazepine sedative-hypnotic agent which binds selectively to the benzodiazepine ω1-receptor subtype in the central nervous system. Case Presentation: This is case of 56-year old woman suffering from Breathing Pattern Disorder. Her symptoms of insomnia as well as her craving for anxiolytic effect of zolpidem, that helped her to cope with everyday activities, transformed her into a zolpidem abuser. The patient discontinued zolpidem use and respiratory function improved. Treatment with antidepressant improved her psychosocial state. Discussion: Zolpidem is an interesting alternative to benzodiazepines in the treatment of insomnia under a range of cautious medical supervision and prescription.

Numerous medical disorders can cause insomnia. Soporific agents are drugs that facilitate the development and normalization of sleep. However, the sleep that is induced by the majority of drugs differs from natural sleep. There are many known compounds of various chemical classes that can be classified as hypnotics and sedative drugs, which are capable of causing various degrees of central nervous system depression, relieving anxiety, and causing sleep. From the chemical point of view, soporific, sedative, and hypnotic drugs are classified as barbiturates, histamine H1 receptor antagonists, benzodiazepine hypnotics, which became available in the 1970s, nonbenzodiazepine hypnotics, so-called Z-drugs, melatonin receptor agonists, 5-HT2A and 5-HT2C antagonists/inverse agonists, NK1 receptor agonists, melatonergic (MT1/MT2) agonists, orexin receptor (OX1/OX2) antagonists, and so on. This chapter describes the syntheses of soporific drugs that are included in the list of Top 200 Drugs by sales for the 2010s.

Background JM-1232(-), (-)-3-[2-(4-methyl-1-piperazinyl)-2-oxoethyl]-2-phenyl-3,5,6,7-tetrahydrocyclopenta [f]isoindol-1(2H)-one, molecular formula, C(24)H(27)N(3)O(2); molecular weight, 389.49, is a novel isoindoline water-soluble benzodiazepine receptor agonist with favorable anesthetic/sedative properties in animals. MR04A3 is a 1% aqueous presentation of JM-1232(-). Methods In Step 1, healthy male volunteers received 10-min infusions of MR04A3, 0.05, 0.1, 0.2, 0.4, and 0.8 mg/kg, with three MR04A3 subjects and one placebo subject per dose concentration. In Step 2, doses were 0.025, 0.05, 0.075, 0.1, 0.2, 0.3, and 0.4 mg/kg over 1 min with six MR04A3 subjects and one placebo subject per dose concentration. Results Hypnotic effects of MR04A3 were seen at all dose concentrations in Step 1 and at doses of 0.075 mg/kg or more in Step 2. Central nervous system effect was seen at all dose concentrations with larger doses of MR04A3 producing a deeper and longer reduction in bispectral index. Ramsay sedation scores were increased with higher doses causing sedation and then unresponsiveness. The adverse event profile of subjects receiving MR04A3 was similar to that of subjects given placebo except that some subjects receiving MR04A3 developed upper airway obstruction while sedated. This responded to simple maneuvers (i.e., chin lift). Changes in systolic arterial blood pressure and heart rate were minimal. Conclusions MR04A3 is hypnotic in man with a satisfactory hemodynamic and safety profile.

Alon Y Avidan1, Liisa A Palmer2, Justin F Doan3, Robert W Baran31UCLA Department of Neurology, Los Angeles, CA, USA; 2Thomson Reuters, Washington, DC, USA; 3Takeda Global Research and Development Center, Deerfield, IL, USAObjective: This study examined the risk of accidental events in older adults prescribed a sedating antidepressant, long-acting benzodiazepine, short-acting benzodiazepine, and nonbenzodiazepine, relative to a reference group (selective melatonin receptor agonist).Methods: This was a retrospective cohort analysis of older adults (≥65 years) with newly initiated pharmacological treatment of insomnia. Data were collected from the Thomson MarketScan® Medicare Supplemental and Coordination of Benefits databases (January 1, 2000, through June 30, 2006). Probit models were used to evaluate the probability of an accidental event.Results: Data were analyzed for 445,329 patients. Patients taking a long-acting benzodiazepine (1.21 odds ratio [OR]), short-acting benzodiazepine (1.16 OR), or nonbenzodiazepine (1.12 OR) had a significantly higher probability of experiencing an accidental event during the first month following treatment initiation compared with patients taking the reference medication (P < 0.05 for all). A significantly higher probability of experiencing an accidental event was also observed during the 3-month period following the initiation of treatment (1.62 long-acting benzodiazepine, 1.60 short-acting benzodiazepine, 1.48 nonbenzodiazepine, and 1.56 sedating antidepressant; P < 0.05).Conclusions: Older adults taking an SAD or any of the benzodiazepine receptor agonists appear to have a greater risk of an accidental event compared with a reference group taking an MR.Keywords: insomnia, accidental events, benzodiazepine receptor agonist, melatonin receptor agonist, older adults

OBJECTIVES: To identify factors associated with sustained benzodiazepine use in older adults. DESIGN: Twelve-year cohort study. SETTING: Community-based epidemiological survey. PARTICIPANTS: One thousand three hundred forty-two individuals aged 65 and older. MEASUREMENTS: Demographics, medication use, depressive symptoms, sleep complaints, alcohol use, and smoking assessed at 2-year intervals; descriptive analysis to characterize benzodiazepine users and identify factors associated with sustained benzodiazepine use (use at two consecutive waves); and longitudinal lag-time analysis to determine characteristics that predicted sustained use. RESULTS: Initially, 5.5% of men and 9.8% of women were using benzodiazepines. Users were significantly more likely than nonusers to be female and less educated, report more depressive and anxiety symptoms, use more prescription medications, have lower self-rated health, have difficulty maintaining sleep, and be less likely to consume alcohol. Approximately 50%, 44%, and 25% of these users aged 65 to 74, 75 to 84, and 85 and older, respectively, were sustained users at follow-up. Being female, using two or more nonbenzodiazepine prescription medications, and smoking were independently associated with subsequent sustained benzodiazepine use. CONCLUSION: At the population level, women, smokers, and users of at least two prescription drugs have higher probabilities of sustaining benzodiazepine use once started. This information can facilitate risk assessment and counseling of older adults before prescribing benzodiazepines.

Sleep disturbances occur more often in the elderly than in patients in any other age category. Traditional treatment regimens for insomnia in older patients have emphasized benzodiazepines. The useful anxiolytic and hypnotic properties of these agents have made them the most widely prescribed class of drugs in the world. Concern has been expressed however about the significant side effect profile associated with these agents. There is now considerable evidence that all benzodiazepines show significant dose-dependent impaired daytime performance on a variety of memory, cognitive and psychomotor tests. In addition, the risk of falls, hip fractures, and traffic accidents is significantly increased in patients who are treated with benzodiazepines. There is little evidence that benzodiazepine hypnotics are still effective after chronic use. On the other hand, several impairments persist when using these hypnotics over long time. Recently, the nonbenzodiazepine drugs zolpidem and zaleplon have been introduced and are claimed to be relatively safe (i.e. less daytime sedation) when compared to benzodiazepines. Zopiclone, a non-benzodiazepine hypnotic, shows no advantages over benzodiazepines with respect to daytime performance. Several factors may interact with the effects of hypnotics on daytime functioning, including normal cognitive decline during aging, the effects of insomnia itself on daytime functioning, the presence or absence of co-morbid disorders, and pharmacokinetic changes accompanying aging. The impact of hypnotics on daytime performance further depends on various drug-related factors including the administered dose, half-life, time between intake and performance, duration of treatment, gender, and individual differences. In contrast, zolpidem and zaleplon do not significantly impair daytime performance when administered at bedtime at the recommended dose. Although further studies of drug effects in elderly insomniacs are necessary, the available evidence suggests that these short acting and relatively safer non-benzodiazepine hypnotics are a preferred alternative therapy for treating insomnia in the elderly.

The benzodiazepine binding site on the GABA A receptor is the target for the majority of hypnotics, including the nonbenzodiazepine ‘Z drugs' (zaleplon, zolpidem, zopiclone and eszopiclone). Concerns still exist over long-term benzodiazepine use, and efforts are, therefore, being made to search for new hypnotic agents and alternative receptor target sites, with novel mechanisms of action. Clinically useful compounds, including GABA mimetics and GABA-uptake inhibitors, have been found by developing structurally rigid analogs of GABA. The GABA-site agonist 4,5,6,7-tetra hydroisoxazolo[5,4-c]pyridin-3-ol (THIP) shows high potency for extrasynaptic GABA A receptor subtypes, which are not primary targets for classical benzodiazepines or the Z drugs. Hence, THIP targets a novel set of GABA A receptors. The antiepileptic drug, tiagabine, is a specific blocker of the GAT-1 GABA-transporter, increasing GABA levels following synaptic GABA release. It is proposed that this promotes extrasynaptic GABA A receptor activity. In contrast, two other GABA analogs, pregabalin and gabapentin, are not GABA mimetics but appear to act at calcium channels responsible for neurotransmitter release, rather than at the GABA receptors. All of these GABA analogs modify sleep behaviors and so are potentially effective hypnotic drugs that provide an alternative to the benzodiazepine binding site of the GABA A receptor.

Eszopiclone, the active S(+)-enantiomer of zopiclone [(R,S)-zopiclone], was approved by the Food and Drug Administration (FDA) in 2004 for the treatment of insomnia in adult patients ≥18 years of age, and in 2005 became the first sedative hypnotic approved by the FDA for the long-term treatment of chronic insomnia. It is classified by the FDA as a Schedule IV drug under the Controlled Substances Act and is available in the United States as the brand Lunesta® in dosages of 1, 2, and 3 mg. Eszopiclone 2 and 3 mg consistently demonstrated significant improvements of the primary variable, latency to persistent sleep, assessed subjectively or objectively, in short- and long-term clinical trials. Additionally, improvements in sleep maintenance, sleep quality, and daytime functioning have also been observed. Eszopiclone 3 mg has been shown to improve insomnia associated with comorbid conditions. Tolerance with eszopiclone was not apparent in any of the sleep parameters for up to 12 months treatment duration and rebound insomnia, where documented, tends to be transient and limited to the first night of withdrawal. Eszopiclone is generally well tolerated and the most frequent adverse event is unpleasant bitter taste. Both eszopiclone and its racemic compound, zopiclone, are nonbenzodiazepine hypnotic agents that are derivatives of the cyclopyrrolone class, with eszopiclone exhibiting greater affinity than the R(−)-enantiomer for the GABAA/benzodiazepine receptor complex; hence the sedative hypnotic effects of the racemate are primarily linked to the S(+)-enantiomer rather than the R(−)-enantiomer. The racemate zopiclone is available as 3.75, 5, and 7.5 mg tablets; the latter contains 3.75 mg of S(+)-zopiclone, which is more than the highest dose (3 mg) available in the United States. Eszopiclone is not marketed in the European Union, as it was too similar to the racemate to be considered a patentable product.

Benzodiazepine receptor ligands are suggested to play a role in the pathogenesis of hepatic encephalopathy (HE). Accumulation of these ligands in brain was suggested to explain in part the notion of"increased GABAergic tone," the rational for which arose initially from reports of a beneficial effect of the selective benzodiazepine antagonist flumazenil in HE patients. It was suggested on the basis of the effect of flumazenil in human HE that liver failure may result in alterations of the density and/or affinity of the benzodiazepine-associated GABA-A receptor site. Subsequent controlled-clinical trials showed that fumazenil had a transient beneficial effect in only a subpopulation of HE patients. In contrast to the antagonists, partial inverse agonists of the benzodiazepine receptor have unequivocal beneficial effects on behavioral and electro-physiological performance in all experimental models of HE studied so far. Benzodiazepine-associated GABA-A receptors have consistently been demonstrated to be unaltered in both human and experimental HE. Contrary to initial reports, the so-called "endogenous benzodiazepines" do not appear to be significantly related to the pathogenesis of HE. On the other hand, nonbenzodiazepine GABA-A receptor complex modulators, such as neuro-steroids, recently identified in brain in human and experimental HE, may provide a new mechanistic basis for this disorder and lead to novel treatments for human HE.

Sleep-related complaints are common in the general population. Prevalence rates are significantly higher among women and the older age groups. In addition, a substantial number of those experiencing insomnia state that the complaint is chronic. The management of chronic primary insomnia combines nonpharmacological measures and pharmacotherapy. In patients with chronic secondary insomnia, hypnotic medication may be beneficial as an adjunct to treatment of the primary disorder. Presently available hypnotic drugs include the benzodiazepines and the nonbenzodiazepine derivatives zopiclone, eszopiclone, zolpidem and zaleplon. The finding that the sedative/hypnotic effect of benzodiazepine and nonbenzodiazepine compounds is mediated through GABAA receptors containing the α1 subunit presents new possibilities for designing more effective and safe hypnotic drugs. Imidazopyridinone, imidazolyl-methyl-imidazole, ring-fused-imidazole, imidazolyl-methyl-pyridazine, imidazolyl-methyl-pyrimidine, imidazolyl-methyl-pyri...

It has been suggested that alterations of GABAergic neurotransmission are implicated in the pathophysiology of hepatic encephalopathy (HE). Increased concentrations of endogenous benzodiazepines with positive allosteric modulatory properties at the GABA-A receptor complex were proposed as a pathophysiological mechanism to explain increased GABAergic tone in HE. However, results of controlled trials with benzodiazepine receptor antagonists have yielded equivocal results and increases in benzodiazepine levels in body fluids of cirrhotic patients were suggested to be largely accounted for by previous pharmaceutical benzodiazepine intake. In the present study the issue of benzodiazepine receptor ligands in brains of cirrhotic patients, and their contribution to alterations of GABA-A receptor complex in HE are addressed. "Benzodiazepine-like" ligands were present in trace amounts in autopsied brain tissue from control subjects (0.2 +/- 0.2 ng/g tissue), and from cirrhotic patients not previously exposed to benzodiazepine medication (0.8 +/- 0.4 ng/g tissue). In contrast, these ligands accumulate in brain extracts from cirrhotic patients previously exposed to benzodiazepines by up to 200-fold (161.5 +/- 93.2 DE ng/g tissue). Brain extracts from cirrhotic patients increased the binding of the GABA-A receptor agonist [3H]muscimol. This increase was minimal with brain extracts from controls (6.8 +/- 2.8%), but was significant with brain extracts from cirrhotic patients without (29.4 +/- 2.7%), or with (55.1 +/- 7.6%) previous exposure to benzodiazepines. Addition of flumazenil, a selective benzodiazepine receptor antagonist did not significantly modify the increase of [3H]muscimol binding by brain extracts from patients without prior exposure to benzodiazepines and only partially inhibited the increase of [3H]muscimol binding in presence of brain extracts from cirrhotic patients previously exposed to benzodiazepines. These findings suggest the presence of nonbenzodiazepine substances (possibly neurosteroids) with positive allosteric modulatory properties at the GABA-A receptor complex in brain in hepatic encephalopathy.

Sleep disorders are a frequent but under-addressed complication of burn injuries. Burn injuries can potentially disrupt sleep for a variety of reasons, including the physiological effects of trauma as well as ramifications of treatment (ie, intensive care unit environment, pain, itching, medications). The literature on sleep disorders and burn injuries is reviewed, and suggestions for treatment are provided. Treatment is divided into two major types: nonpharmacologic and pharmacologic. Nonpharmacologic treatment, also referred to as behavioral techniques, may include any one or combination of the following: sleep hygiene, stimulus control, sleep restriction, relaxation techniques, cognitive, and light therapy. Pharmacologic therapies may include hypnotics (benzodiazepine, nonbenzodiazepine, or benzodiazepine receptor agonists), antidepressants, over-the-counter preparations, hormone replacement therapy, herbs, and melatonin.

Study objectives Obesity alters the therapeutic window of sedative/hypnotic drugs and increases the probability of respiratory complications. The current experiments used an established rodent model of obesity to test the hypothesis that the sedative/hypnotic drugs eszopiclone and dexmedetomidine alter ventilation differentially in obese rats compared with lean/fit rats. Design This study used a within-groups/between-groups experimental design. Setting University of Michigan. Participants Experiments were conducted using lean/fit rats (n = 21) and obese rats (n = 21) that have features of metabolic syndrome. Interventions Breathing was measured with whole-body plethysmography after systemic administration of vehicle (control), the nonbenzodiazepine, benzodiazepine site agonist eszopiclone, or the alpha-2 adrenergic receptor agonist dexmedetomidine. Measurements and results Data were analyzed using two-way analysis of variance and appropriate post hoc comparisons. At baseline, the obese/metabolic syndrome rats had increased respiratory rates (21.6%), lower tidal volumes/body weight (-24.1%), and no differences in minute ventilation compared to lean/fit rats. In the obese rats, respiratory rate was decreased by dexmedetomidine (-29%), but not eszopiclone. In the lean and the obese rats, eszopiclone decreased tidal volume (-12%). Both sedative/hypnotic drugs caused a greater decrease in minute ventilation in the obese (-26.3%) than lean (-18%) rats. Inspiratory flow rate (VT / TI) of the obese rats was decreased by dexmedetomidine (-10.6%) and eszopiclone (-18%). Duty cycle (TI / TTOT) in both rat lines was decreased by dexmedetomidine (-16.5%) but not by eszopiclone. Conclusions Dexmedetomidine, in contrast to eszopiclone, decreased minute ventilation in the obese/metabolic syndrome rats by depressing both duty cycle and inspiratory flow rate. The results show for the first time that the obese phenotype differentially modulates the respiratory effects of eszopiclone and dexmedetomidine. These differences in breathing are consistent with previously documented differences in sleep between lean/fit and obese rats. These findings also encourage future studies of obese/metabolic syndrome rats that quantify the effect of sedative/hypnotic drugs on respiratory mechanics as well as hypoxic and hypercapnic ventilatory responses. Continued findings of favorable homology between obese humans and rodents will support the interpretation that these obese rats offer a unique animal model for mechanistic studies.

Endozepines are nonbenzodiazepine, nonprotein molecules, which may play a role in modulating γ-aminobutyric acid-A (GABA-A) transmission in the central nervous system. For causes unknown, reports of patients, mostly from Italy, with recurrent stupor and coma have been shown to exhibit massively elevated serum and cerebrospinal fluid endozepine-4 levels. The clinical syndrome closely resembles benzodiazepine intoxication with fatigue, ataxia, and dysarthria somnolence. Patients can have multiple attacks, and the condition has been coined recurrent endozepine stupor. EEG findings are identical to benzodiazepine overuse; however, biochemical assays and other investigations fail to disclose either exogenous benzodiazepines or other causes of metabolic encephalopathy. Both clinical and EEG resolutions are achieved with treatment with flumazanil. This article will discuss this unusual clinical entity with some attention paid to the controversy that exists regarding the validity of this recurrent encephalopathic syndrome.

Besides benzodiazepine, antidepressant and neuroleptic agents, all of which have established roles in supportive care, other psychotropic drugs deserve consideration in selected conditions affecting patients with advanced cancer. This article briefly reviews relevant aspects of miscellaneous psychotropics available for second-line treatment, including nonbenzodiazepine sedative, hypnotic and anxiolytic drugs, anaesthetic agents, stimulants, and analgesic adjuvants acting on the central nervous system. The proper use of such subsidiary psychotropic agents requires that both their specificities and the particular characteristics of palliative care patients are taken into account.

Insomnia is the subjective complaint of poor sleep or an inadequate amount of sleep that adversely affects daily functioning. For the past 4 decades, treatment of insomnia has shifted away from the use of barbiturates toward the use of hypnotic agents of the benzodiazepine class. However, problems associated with the latter (eg, next-day sedation, rebound insomnia, dependence, and tolerance) have prompted development of other agents.This review describes the recently approved nonbenzodiazepine agent, zaleplon.Studies of zaleplon were identified through a search of English-language articles listed in MEDLINE and International Pharmaceutical Abstracts, with no limitation on year. These were supplemented by educational materials from conferences.The efficacy and tolerability of zaleplon have been documented in the literature. Zaleplon has been shown to improve sleep variables in comparison with placebo. Like most hypnotic agents, zaleplon can be used for problems of sleep initiation at the beginning of the night, but its short duration of clinical effect may also allow patients to take it later in the night without residual effects the next morning. Zaleplon can be takenor = 2 hours before awakening without "hangover" effects. It is generally well tolerated, with headache being the most commonly reported adverse event in clinical trials (15%-18%). Compared with flurazepam, a long-acting benzodiazepine sedative-hypnotic agent, zaleplon causes significantly less psychomotor and cognitive impairment (P0.001). Zaleplon has not been studied in pregnant women or children. The dose of zaleplon should be individualized; the recommended daily dose for most adults is 10 mg.Insomnia has a substantial impact on daily functioning. If pharmacologic treatment is indicated for insomnia, the choice of an agent should be guided by individual patient characteristics.

Drugs such as benzodiazepines, which enhance the effects of inhibitory neurotransmitter gamma-amino butyric acid (GABA), are known to modulate the mesocorticolimbic dopaminergic system, which is considered to mediate the rewarding effects of psychostimulants. The effects of diazepam, a benzodiazepine that binds unspecifically to omega 1- (omega1-) and omega2-receptors, and zolpidem, a nonbenzodiazepine drug that binds preferentially to omega1-receptors, on cocaine- and amphetamine-induced place preference were evaluated in Wistar rats. In tests using the counterbalanced method, neither diazepam (0.2, 1, and 5 mg/kg) nor zolpidem (2.5, 5, and 10 mg/kg) alone induced place preference or place aversion. Diazepam pretreatment prevented both cocaine- and amphetamine-induced (15 and 9 mg/kg, respectively) place preference; however, at doses that were earlier shown to cause sedation and amnesia, zolpidem failed to prevent either cocaine- or amphetamine-induced place preference. These results suggest that diazepam interferes with the rewarding properties of the psychostimulants, whereas zolpidem is less effective in this respect, possibly due to differential distribution of omega1- and omega2-receptors in the brain.

▴ Zaleplon is a nonbenzodiazepine sedative-hypnotic which acts as a selective agonist at the benzodiazepine ω1 (type 1) receptor.

Quantitative structure–activity relationship (QSAR) studies are made on some nonbenzodiazepine ligands of benzodiazepine receptor (BZR), namely a series of 6-arylpyrrolo[2,1-d][1,5]benzo-thiazepines, a series of pyrido[1,2-a]benzimidazoles, and a series of some fused imidazopyridines. A Fujita-Ban approach adopted for the first series led to the suggestion that the most advantageous substituents in the series were only 4-Cl and 7-OCON(CH3)2. All other substituents were found to have negative contributions to the binding of the compounds with the BZR. In the case of pyrido[1,2-a]benzimidazoles, the 8-CONHR group was found to play an important role in the binding. The activity was found to be significantly correlated with the hydrophobic property of the R moiety and the electron-withdrawing ability of the ortho substituents in it. In the case of imidazopyridines, the Fujita-Ban approach revealed only the negative effects of the substituents that really mattered. By Hansch analysis these negative effects were accounted for by steric parameters.

The main inhibitory neurotransmitter receptor of the brain, the gamma-aminobutyric acid type A receptor (GABA[A]), mediates the actions of several classes of clinically important drugs, such as benzodiazepines, barbiturates and general anaesthetics. This review summarizes the current knowledge on how classical benzodiazepines and novel nonbenzodiazepine compounds act on the benzodiazepine site of GABA(A) receptors and on their clinical pharmacology related to anxiolytic, sedative, hypnotic and cognitive effects or side-effects. Partial agonism, receptor subtype selectivity and novel binding sites are discussed as possible strategies to develop new drugs with fewer adverse effects than are seen in the clinical use of benzodiazepines.

Use of dexmedetomidine or propofol rather than a benzodiazepine sedation strategy may improve ICU outcomes. We reviewed randomized trials comparing a benzodiazepine and nonbenzodiazepine regimen in mechanically ventilated adult ICU patients to determine if differences exist between these sedation strategies with respect to ICU length of stay, time on the ventilator, delirium prevalence, and short-term mortality.We searched CINAHL, MEDLINE, the Cochrane databases, and the American College of Critical Care Medicine's Pain, Agitation, Delirium Management Guidelines' literature database from 1996 to 2013. Citations were screened for randomized trials that enrolled critically ill, mechanically ventilated adults comparing an IV benzodiazepine-based to a nonbenzodiazepine-based sedative regimen and reported duration of ICU length of stay, duration of mechanical ventilation, delirium prevalence, and/or short-term mortality. Trial characteristics and results were abstracted in duplicate and independently, and the Cochrane risk of bias tool was used for quality assessment. We performed random effects model meta-analyses where possible.We included six trials enrolling 1,235 patients: midazolam versus dexmedetomidine (n = 3), lorazepam versus dexmedetomidine (n = 1), midazolam versus propofol (n = 1), and lorazepam versus propofol (n = 1). Compared to a benzodiazepine sedative strategy, a nonbenzodiazepine sedative strategy was associated with a shorter ICU length of stay (n = 6 studies; difference = 1.62 d; 95% CI, 0.68-2.55; I = 0%; p = 0.0007) and duration of mechanical ventilation (n = 4 studies; difference = 1.9 d; 95% CI, 1.70-2.09; I2 = 0%; p0.00001) but a similar prevalence of delirium (n = 2; risk ratio = 0.83; 95% CI, 0.61-1.11; I2 = 84%; p = 0.19) and short-term mortality rate (n = 4; risk ratio = 0.98; 95% CI, 0.76-1.27; I2 = 30%; p = 0.88).Current controlled data suggest that use of a dexmedetomidine- or propofol-based sedation regimen rather than a benzodiazepine-based sedation regimen in critically ill adults may reduce ICU length of stay and duration of mechanical ventilation. Larger controlled studies are needed to further define the impact of nonbenzodiazepine sedative regimens on delirium and short-term mortality.

1. Physical dependence and cross-physical dependence on barbital of the benzodiazepine receptor partial agonist S-(+)-DN-2327 and the benzodiazepine receptor full agonist diazepam were compared in male Fischer 344 rats. 2. In the physical dependence study, rats were treated with S-(+)-DN-2327 (30, 100, 300 and 1000 mg/kg/day) or diazepam (30, 100 and 300 mg/kg/day) for 4 weeks by the drug admixed with food method. After stopping the treatment, the body weight and food consumption in the diazepam 100 and 300 mg/kg groups tended to decrease or decreased to values lower than those in the control group, whereas these parameters in the S-(+)-DN-2327 30, 100 and 300 mg/kg groups were comparable to the control group values. 3. In the cross-dependence study, rats were treated with increasing doses of barbital by admixing the drug with food for 4 weeks, after which the diet admixed with barbital was replaced by basal diet alone or admixed with S-(+)-DN-2327 or diazepam (target doses: 100 and 300 mg/kg/day for each compound). During the substitution period, the decreases in body weight and food consumption in both S-(+)-DN-2327 and both diazepam groups were suppressed compared with those in the basal diet group. 4. These results suggest that S-(+)-DN-2327 possesses minimal physical dependence-producing liability, but shows cross-dependence on barbital, as do benzodiazepine receptor full agonists.

Objectives To assess the efficacy, usefulness, safety, and dosages of flumazenil required when flumazenil is used in the diagnosis of benzodiazepine-induced coma (vs. other drug-induced coma), and to reverse or prevent the recurrence of unconsciousness. Design A two-phase study: a controlled, randomized, doubleblind study followed by a prospective, open study. Setting An 800-bed, teaching, university-affiliated hospital. Patients Unconscious patients (n equals 110) suspected of benzodiazepine overdose, graded 2 to 4 on the Matthew and Lawson coma scale, were treated with flumazenil, the specific benzodiazepine receptor antagonist. The first 31 patients were studied in a double-blind fashion, while the rest of the patients were given flumazenil according to an open protocol. Interventions All patients received supplemental oxygen; endotracheal intubation was performed, and synchronized intermittent mandatory ventilation was initiated whenever it was deemed necessary. A peripheral intravenous cannula was inserted, as were indwelling arterial and urinary bladder catheters. Blood pressure, electrocardiogram, respiratory rate, end-tidal CO2, and core temperature were continuously monitored. The first 31 double-blind patients received either intravenous flumazenil (to a maximum of 1 mg) or saline, while the rest of the patients were given flumazenil until either regaining consciousness or a maximum of 2.5 mg was injected. Patients remaining unconscious among double-blind patients or those patients relapsing into coma after the first dose were later treated in the open phase of the study. Treatment continued by boluses or infusion as long as efficacious. Measurements and Main Results Fourteen of 17 double-blind, flumazenil-treated patients woke after a mean of 0.8 plus minus 0.3 (SD) mg vs. one of 14 placebo patients (p less than .001). Seventy-five percent of the aggregated controlled and uncontrolled patients awoke from coma scores of 3.1 plus minus 0.6 to 0.4 plus minus 0.5 (p less than .01) after the injection of 0.7 plus minus 0.3 mg of flumazenil. These patients had high benzodiazepine serum blood concentrations. Twenty-five percent of the patients did not regain consciousness. These patients had very high serum concentrations of nonbenzodiazepine drugs. Sixty percent of the responders who had primarily ingested benzodiazepines remained awake for 72 plus minus 37 mins after flumazenil administration; 40% relapsed into coma after 18 plus minus 7 mins and various central nervous system depressant drugs were detected in their blood in addition to benzodiazepines. Seventy-one percent of the patients had ingested tricyclic antidepressants. Seventy-eight percent of the responders were continually and efficaciously treated for less than equals 8 days. Fourteen (25%) of the intubated patients were extubated safely while 12 patients, who had shown increased respiratory insufficiency, resumed satisfactory respiration after flumazenil injection. Five cases of transient increase in blood pressure and heart rate were encountered. There were 27 mildly unpleasant ``waking'' episodes, such as anxiety, restlessness, and aggression, but no patient had benzodiazepine withdrawal signs, convulsions, or dysrhythmia, most noticeably absent in tricyclic antidepressant-intoxicated patients. Conclusions Flumazenil is a valid diagnostic tool for distinguishing pure benzodiazepine from mixed-drug intoxication or nondrug-induced coma. Flumazenil is effective in preventing recurrence of benzodiazepine-induced coma. Respiratory insufficiency is reversed after its administration. Flumazenil is safe when administered cautiously, even in patients with coma caused by a mixed overdose of benzodiazepine plus tricyclic antidepressants.

Insomnia, especially when chronic, is associated with disturbances in daytime well-being and performance, resulting in a poor quality of life for those affected. Zopiclone has been proven as a drug that favourably balances sleep induction and maintenance as well as an improvement in daytime well-being (efficacy) with a low potential for adverse effects (safety) in the symptomatic treatment of insomnia. Management of chronic insomnia with zopiclone needs a multidimensional approach involving the proper diagnosis of possible underlying causes, and combined use of causal treatment, general sleep hygiene measures, basic elements of psychological treatment and adjunctive medication. It is recommended that therapy with the nonbenzodiazepine hypnotic zopiclone should conform to the guidelines for the use of hypnotics, which are valid for all benzodiazepine receptor agonists.

Quantitative structure - activity relationship (QSAR) studies have been performed on some non-benzodiazepine series of benzodiazepine receptor (BZR) ligands, namely a series of thienylpyrazologuinolines and a series of imidazoquinoxalines. Studies reveal the merits and demerits of the substituents and their physicochemical properties in each case, in addition to the essential requirements for the binding for each type of ligand.

In previous studies we have reported that the benzodiazepine hypnotic triazolam and the nonbenzodiazepine zolpidem increase the likelihood that insomniacs will report having been asleep when awakened by an electronic tone of progressive intensity. It has not been known, however, whether this occurs with normal sleepers. In the present study we have administered placebo, flurazepam 30 mg and zolpidem 10 mg to 15 normal sleepers and awakened them with an electronic tone at five points across the night. In contrast to previous reports with insomniacs, both compounds made only modest improvements in sleep. When all time points were combined, subjects reported having been asleep in 40.3, 42.9 and 47.9% of the trials on placebo, flurazepam and zolpidem, respectively (ns). Subjects were accurate in their estimate of total time asleep, and this accuracy was not influenced by the drugs. Similarly, there were no effects on a variety of questions related to dreaming and other cognitive activity during sleep. These results suggest that the effects of these hypnotics, which have been described previously in insomniacs, are not found in normals. Further studies will be necessary to clarify whether such effects in insomniacs are related to the clinical efficacy of hypnotics.

Introduction: Over the last few years, hypnotic and anxiolytic medications have had their clinical efficacy questioned in the context of concerns regarding dependence, tolerance alongside other adverse effects. It remains unclear how these concerns have impacted clinical prescribing practice. Materials and Methods: This is a study reviewing community-dispensed prescribing data for patients on the East Practice Medical Center list in Arbroath, Scotland, in 2007, 2011 and 2015. Anxiolytic and hypnotic medications were defined in accordance with the British National Formulary chapter 4.1.1 and chapter 4.1.2. All patients receiving a drug within this class in any of the study years were collated and anonymized using primary care prescribing data. The patients’ age, gender, name of the prescribed drug(s), and total number of prescriptions in this class over the year were extracted. Results: The proportion of patients prescribed a benzodiazepine medication decreased between 2007 and 2015: 83.8% (n = 109) in 2007, 70.5% (n = 122) in 2011, and 51.7% (n = 138) in 2015 (P = 0.006). The proportion of these patients prescribed a nonbenzodiazepine drug increased between 2007 and 2015: 30% (n = 39) in 2007, 46.2% (n = 80) in 2011, and 52.4% (n = 140) in 2015 (P = 0.001). There was a significant increase in the number of patients prescribed melatonin (P = 0.020). Discussion: This study reports a reduction in benzodiazepine prescriptions in primary care alongside increases in nonbenzodiazepine and melatonin prescribing, with an increase in prescribing rates of this drug class overall. Conclusion: Changes in this prescribing practice may reflect the medicalization of insomnia, local changes in prescribing practice and alongside national recommendations.

Objectives: To evaluate the effect of the Medicare benzodiazepine coverage exclusion on psychotropic use of benzodiazepine users. Design: Pre�post design with concurrent control group. Setting: General community. Participants: Intervention and comparison cohorts of individuals drawn from the same insurer who were prescribed benzodiazepines through the end of 2005. Intervention participants (n = 19,339) were elderly adults from a large, national Medicare Advantage plan subject to benzodiazepine exclusion as a result of the Medicare Modernization Act (MMA). Comparison participants (n = 3,488) were near-elderly individuals enrolled in a managed care plan not subject to the MMA benzodiazepine exclusion. Measurements: Any psychotropic drug use and expenditures. Results: In the intervention cohort, benzodiazepine use and expenditures significantly declined from 100% and $134 in 2005 to 74.8% and $59, respectively, in 2007. Nonbenzodiazepine psychotropic drug use and expenditures significantly increased from 35.8% and $163 in 2005 to 39.5% and $207, respectively, in 2007. In the comparison cohort, benzodiazepine use and expenditures also significantly declined from 100% and $173 in 2005 to 57.5% and $105, respectively, in 2007, but nonbenzodiazepine psychotropic drug use and expenditures significantly declined from 55.4% and $647 in 2005 to 45.1% and $572, respectively, in 2007. Changes in antidepressant and anxiolytic use were the primary cause of changes in nonbenzodiazepine psychotropic drugs in both cohorts. Conclusion: Use of benzodiazepines continued in elderly adults despite negative financial incentives, possibly because of the low costs of such medications. Although some substitution occurred with antidepressants and anxiolytics, the magnitude of this increase did not fully offset the reduction in benzodiazepine use.

Isolated from their mother, rat pups respond with changes in ultrasound vocalization (USV), a paradigm that can be used as a test for a large range of anxiolytics. Because the relation between corticosterone (CORT) and putative stress responses like USV is not clear, we examined the effects of the benzodiazepine drugs chlordiazepoxide and diazepam vs. the nonbenzodiazepine drugs buspirone and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) on USV and plasma CORT concentrations. All drugs caused a dose-related decrease in USV, but only buspirone and 8-OH-DPAT induced a dose-related increase in CORT. We suggest that the seemingly paradoxical effects of buspirone and 8-OH-DPAT, that is, the decrease in USV and the concomitant increase in plasma CORT, are due to the fact that these two drugs act as full agonists at both pre- and postsynaptic 5-HT1A receptors. Our results indicate that, when measured as an increase in the activity of the pituitary adrenocortical axis, the stress response can be interpreted in markedly different ways, depending on whether the increased activity is elicited by an environmental stressor or by pharmacological manipulation.