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STUDY OBJECTIVES An uncomfortable environment or continuous positive airway pressure (CPAP) intolerance may cause poor sleep efficiency during polysomnography and result in a poor-quality study. Unsatisfactory polysomnograms often must be repeated. Nonbenzodiazepine hypnotics may improve sleep efficiency without disruption of sleep architecture. We hypothesized that premedication with zolpidem improves polysomnogram quality and decreases the need to restudy. METHODS We retrospectively reviewed 200 consecutive polysomnograms. Zolpidem premedication was not standardized and was prescribed at the discretion of consulting sleep physicians, who were unaware of this study. We compared the quality of polysomnograms between patients who received zolpidem 10 mg prior to polysomnography and those who did not. A poor-quality polysomnogram was defined as having insufficient sleep time to allow for diagnosis, incomplete CPAP titration with a resulting apnea-hypopnea index > 10 on the highest level of CPAP achieved, or complete CPAP intolerance. RESULTS Of 200 records reviewed, 54 patients (27%) received zolpidem. Demographics did not differ between groups. Premedication with zolpidem resulted in improved sleep latency (11.8 +/- 9.5 minutes vs 26.0 +/- 19.9 minutes, p = .002) and sleep efficiency (89.5% +/- 5.6% vs 78.8 +/- 12.3, p < .0001). Zolpidem premedication resulted in significantly fewer studies meeting criteria for poor quality (7.4% vs 33.6%, p = .005). Of the 49 studies meeting criteria for poor quality, 21 were repeated using zolpidem, showing significant improvements in sleep latency (10.8 +/- 7.1 minutes vs 42.8 +/- 30.5 minutes, p = .0004) and sleep efficiency (89.5% +/- 4.9% vs 61.8% +/- 13.7%, p < .0001). No study repeated with zolpidem met criteria for poor quality. CONCLUSIONS Pretreatment with zolpidem significantly improved polysomnographic quality and may decrease the need to repeat polysomnograms.

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.

BACKGROUND Benzodiazepines are used to treat alcohol withdrawal (AW) but cause cognitive impairment, sedation, and ataxia, and interact with alcohol. Nonbenzodiazepine anticonvulsants are promising and possibly safer alternatives for the treatment of AW. OBJECTIVE To compare follow-up measures of Epworth Sleepiness Scale (ESS), Penn Alcohol Craving Scale (PACS), ataxia rating, and Clinical Institute Withdrawal Assessment for Alcohol revised (CIWA-Ar) symptoms between alcohol-dependent individuals randomized to treatment with gabapentin or chlordiazepoxide. METHODS A randomized, double-blind study was conducted in US veterans with alcohol withdrawal (DSM-IV criteria). Subjects requiring hospitalization or taking benzodiazepines or nonbenzodiazepine anticonvulsants were excluded. Twenty-six participants were randomized: 17 received gabapentin and 9 received chlordiazepoxide. Gabapentin doses were 1200 mg orally for 3 days, followed by 900 mg, 600 mg, and 300 mg for 1 day each. Chlordiazepoxide doses were 100 mg orally for 3 days, followed by 75 mg, 50 mg, and 25 mg for 1 day each. CIWA-Ar, ESS, PACS scales and evaluation for ataxia were administered daily. RESULTS Follow-up mean ESS and PACS scores did not differ significantly between treatment groups in the early treatment period (days 1–4) but were lower (mean difference −3.70; 95% CI −7.21 to −0.19; p = 0.04) and (mean difference −6.05; 95% CI −12.82 to 0.72; p = 0.08), respectively, at the end of the treatment period (days 5–7) in gabapentin-treated subjects. CIWA-Ar scores were reduced similarly in both groups. Ataxia was not observed. No significant adverse events were noted. Limitations include our small sample size and 35% loss to follow-up at the end of the treatment period. CONCLUSIONS In ambulatory veterans with symptoms of alcohol withdrawal, gabapentin treatment resulted in significantly greater reduction in sedation (ESS) and a trend to reduced alcohol craving (PACS) by the end of treatment compared to chlordiazepoxide treatment. Although limited by the small sample size, the suggestion of reduction in sleepiness and less craving warrants replication of the study with a larger sample.

Insomnia is rife. Acutely, almost every individual has experienced a poor night’s sleep, and many short-term remedies for insomnia are tried, including over-the-counter sleep aids and alcohol. Chronic insomnia is the most common sleep disorder, affecting nearly 40 million Americans and accounting for nearly one-third of adults. The annual cost associated with this disorder in the US is estimated at over $15 billion1 and over $100 billion for indirect costs, such as costs of self-medication, health care-related costs due to exacerbations of comorbid conditions, and costs of reduced productivity.2 Degradations of sleep quantity and sleep quality in insomnia have been associated with deleterious long-term effects, including cardiovascular, endocrine, psychological, and immune system complications. Despite these facts, chronic insomnia is not always perceived as a treatable and important medical condition. Symptoms are not always proffered by patients, and diagnoses can be ignored by physicians, partly because insomnia is so common that it is considered somewhat normal, particularly in elderly individuals. These days, recognized treatments for insomnia include pharmacological therapies and the more recently accepted behavioral therapies, including stimulus control, relaxation, and cognitive and behavioral therapy. Research to evaluate and formulate treatments for insomnia is often beset by the problem that insomnia is usually of multifactorial etiology among individuals. Thus, complex and important questions remain, eg, which types of insomnia can be cured, which therapy is best in each situation and in each patient, and why do so many untreated or suboptimally treated individuals with insomnia exist? There is also a clear need to examine the long-term effects of treatment on diverse cultures, ages, and races and in those with comorbid disorders, using randomized clinical trials of sufficient duration. In the first full year of publication, the Nature and Science of Sleep (NSS) has published a set of articles that begins to examine the advantages and limitations of a number of relatively novel pharmacological and behavioral therapies for insomnia. These papers ought to help clinicians appraise new therapies, better manage insomnia, and identify important gaps in our knowledge and promising future approaches. A number of papers in NSS review new pharmacological strategies for insomnia therapy, including the use of nonbenzodiazepine gamma-aminobutyric acid receptor agonists such as zolpidem, zaleplon, and eszopiclone (Z-drugs), which potentially have reduced adverse effects with improved safety and tolerance compared with older benzodiazepines;9 the melatonin receptor agonist ramelteon;12 serotonin receptor antagonists;6 and therapies with novel routes of administration, such as oral spray and sublingual tablets.7,11 For instance, administration of zolpidem via a rapid-absorption oral spray or a sublingual tablet can have advantages due to faster onset of action, lower dose requirement, better patient compliance and convenience, and increased bioavailability. Because the Z-drugs are rapid action, they could be used for short-term insomnia, with the precaution that fast-acting drugs could have potentially faster side effects and pose an increased risk for accidental overdose or abuse of the drugs. Moreover, further studies are needed to establish safety, particularly in terms of the carryover of excessive sleepiness into the daytime.11 Sleep patterns change with increasing age. Typically, sleep is lighter, more fragmented, and shorter,9 and the presence of comorbid conditions that interfere with sleep, such as chronic pain, depression, chronic obstructive pulmonary disease (COPD), and congestive heart failure, also lead to a higher prevalence of insomnia in the elderly. An article in NSS highlights the fact that insomnia is associated with an increased risk of hypertension and cardiovascular disease.13 This interrelationship between insomnia and disease can precipitate a vicious circle whereby insomnia can exacerbate disease, which can further exacerbate insomnia. Moreover, interpretation of clinical trials in the elderly becomes challenging due to confounding effects of medications for these comorbid conditions, and decreased clearance of sleep medications. To solve this challenging question, a paper in NSS specifically reviews pharmacotherapy for insomnia in the elderly4 and concludes that eszopiclone is well suited, improving quality of life without the development of drug tolerance and without rebound insomnia after discontinuation. Similarly, some promise was suggested for the use of 5-hydroxytryptamine 2A (5-HT2A) antagonists in treating sleep maintenance insomnia.6 Ramelteon was helpful in sleep onset insomnia and circadian rhythm disorder, with no rebound insomnia and reportedly no abuse potential. Ramelteon also did not exacerbate respiratory disorders such as sleep apnea and COPD, which is a concern for other sedative medications that can depress ventilation or arousal responses.12 Understanding the molecular and receptor mechanisms involved in promoting sleep in varied disorders could provide future approaches in new drug development. In the long term, more randomized controlled trials are needed to assess both short-term and long-term effects of these medications and their efficacy in comorbid diseases that affect sleep quality or quantity. In search of a better therapeutic approach for insomnia there is an emerging debate about using pharmacotherapy and behavioral therapy to manage insomnia. One of the first studies to formally address this debate using a randomized placebo-controlled trial was published in 1999 and demonstrated that a combined pharmacological and cognitive behavioral therapy for insomnia (CBT-I) was very effective, particularly in terms of duration of effect. Although this was the largest clinical trial in the field at that time, the sample size was relatively small (n = 78), included only elderly people, and the pharmacotherapy included one medication, temazepam. Thus, this result cannot be generalized to a wider population or other drugs.3 In this regard, recent papers in NSS have begun to examine CBT-I in varied populations. For instance, a pilot randomized controlled crossover study in breast cancer survivor patients suggested that individualized CBT-I therapy sessions continued to improve sleep quality.10 Furthermore, two studies examined the efficacy of CBT-I in pediatric populations and showed promising results.14,15 Novel multimodal controlled therapies in children aged 5–10 years combined with training sessions with their parents revealed better efficacy and improved compliance.14 This novel age-appropriate treatment program was also very effective in improving sleep efficiency in children aged 11–17 years, possibly reflecting better acceptance in this age group.15 CBT-I contains components such as psychotherapy, sleep restriction, paradoxical intention, stimulus control, sleep hygiene, relaxation training, and biofeedback. These techniques can be effective in many patients, but a common problem is accessibility to CBT-I.5 Also, the relative efficacy of individual psychological therapeutic techniques within the components of CBT-I still needs to be evaluated in appropriately controlled studies. Additional individual novel therapies for insomnia are reviewed in NSS, such as Internet-based interventions, bright light treatments, intensive sleep retraining, mindfulness meditation, and acupuncture, and these are assessed for comparative effectiveness with the goal of improved outcomes, reduced costs, and/or improved compliance. Many of these approaches have encouraging findings but still require further research, including randomized placebo-controlled trials, to establish their effectiveness.8 Finally, due to the importance of adequate insomnia management, in its first full year, NSS has published numerous original articles that highlight the relative efficacy of specific therapies over others and in specific patient populations. Specifically, NSS has published 12 articles on novel pharmacological and cognitive behavioral therapeutic methods for relieving insomnia in varied populations, including children, adolescents, adults, and the elderly. Additionally, NSS has published focused reviews on insomnia with comorbid conditions, as well as other novel therapeutic options. These informative reviews point out that there is a need for future long-term clinical trials. As mentioned previously, due to the complexity and multifactorial etiology of insomnia, many questions remain unanswered. We encourage you to continue your research to provide tailored approaches to managing insomnia in specific populations or individuals, to publish your research in NSS, and to help put insomnia to sleep.

Evaluation of: Berry SD, Lee Y, Cai S, Dore DD. Nonbenzodiazepine sleep medication use and hip fractures in nursing home residents. JAMA Intern. Med. 173(9), 754–761 (2013). Sleep disturbances and complaints about poor sleep are common among residents of aged care facilities. Nonbenzodiazepine (non-BZD) hypnotics are often prescribed to older individuals in preference to benzodiazepines. To establish whether the use of non-BZD hypnotics is associated with an increased risk of hip fracture, Berry et al. conducted a case-crossover study among 15,528 long-stay US nursing home residents with a hip fracture. Medicare hospitalization and pharmacy claims data were used for determining hip fractures and medication use, and the minimum data set was used to ascertain resident characteristics. Odds ratios (ORs) for hip fracture were estimated by comparing the use of non-BZD hypnotics 0–29 days before hip fracture (hazard period) with use of non-BZD hypnotics 60–89 days and 120–149 days before hip fracture (control periods). During the 18-month study period, non-BZD hypnotics were dispensed to 11% (n = 1715) of the residents with hip fracture. There was an increased risk of hip fracture within 30 days of using a non-BZD hypnotic (OR: 1.66; 95% CI: 1.45–1.90). The risk of hip fracture was higher among new users of non-BZD hypnotics (OR: 2.20; 95% CI: 1.76– 2.74) and in those requiring supervision or limited assistance to transfer, compared with those requiring full assistance to transfer (OR: 2.02 vs 1.43; p = 0.02). The present study did not directly compare the risk of hip fracture associated with non-BZD hypnotics and benzodiazepines. However, the results suggest that clinicians should continue to exercise caution when prescribing non-BZD hypnotics to residents of aged care facilities.

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.

Zolpidem (Ambien), a relatively new nonbenzodiazepine sedative-hypnotic, was involved in the death of a 39-year-old obese male who was being treated for depression and insomnia. The identification and quantitation procedures of zolpidem in postmortem tissues included dual-column gas chromatography (GC) with nitrogen-phosphorus detection and GC-mass spectrometry. Zolpidem was present at concentrations of 2.91, 1.40, and 2.13 microg/mL in the heart blood, peripheral blood, and urine, respectively. The liver had zolpidem present at a concentration of 4.74 microg/g, and the gastric contents had a total of 172 mg zolpidem. Additional drugs present included hydrocodone and morphine (nonconjugated) at 0.16 and 0.04 microg/mL, respectively. The cause of death was determined to be multiple drug intoxication. This report describes the analytical techniques and significance of the zolpidem findings.

This report describes the first evaluation in humans of Ro 41-3696. Based on its preclinical profile, Ro 41-3696, a nonbenzodiazepine partial agonist at the benzodiazepine receptor, offers promising perspectives as an innovative hypnotic drug in that it does not exhibit most of the disadvantages associated with full agonists. Single oral doses of 0.1, 0.3, 1.0, 3.0, 10, and 30 mg were administered sequentially to six groups of six healthy male volunteers in a placebo-controlled, double-blind design. Tolerability was assessed and pharmacokinetic and pharmacodynamic measurements were conducted during a period of 28 hours after drug intake. Ro 41-3696 was well tolerated at all doses, causing no clinically relevant changes in vital signs or laboratory parameters. At doses of 10 and 30 mg there were signs of unsteady gait, indicating a central nervous system depressant effect. Pharmacokinetic analyses revealed that Ro 41-3696 was absorbed and eliminated rapidly (tmax = approximately 1 hour; t1/2 = approximately 4 hours). At all times plasma levels of Ro 41-3290, the desethylated derivative of Ro 41-3696, were higher than those of the parent drug (tmax and t1/2 values = approximately 2 and 8 hours, respectively). Area under the curve (AUC) data indicated dose-proportional pharmacokinetics for both Ro 41-3696 and Ro 41-3290. Performance in both a tracking and a memory search test was significantly affected by doses of 10 and 30 mg, and long-term memory, as assessed by a word learning and recall test, was slightly impaired at these doses. The results of this study support the initiation of therapeutic efficacy studies with Ro 41-3696 in doses up to approximately 5 mg and further exploration of the characteristics of Ro 41-3290.

The psychopharmacology of clobazam, specifically its effects on CNS arousal, cognitive and memory functions and psychomotor performance, is reviewed. Compared with the 1,4-benzodiazepine tranquillizers, clobazam is characterized by a lack of sedative and amnestic effects and no impairment of psychomotor skills including car driving, both in volunteer and clinically anxious patient populations. Clobazam also compares favourably with buspirone, a nonbenzodiazepine anxiolytic agent. Differentiation of the psychopharmacological profile of clobazam from the 1,4-benzodiazepines suggests important pharmacodynamic differences between the two groups. These in turn represent significant advantages for the clinical use of clobazam in the management of ambulant patients with anxiety.

We have shown previously that the benzodiazepine hypnotic triazolam alters the perception of being awake or asleep in insomniacs, making it more likely that they will report having been asleep when awakened by an electronic tone at various times of the night. In the present study, we examined the question as to whether this is also true for other benzodiazepines as well as for nonbenzodiazepine hypnotics. Ten insomniacs were given placebo, flurazepam 30 mg and zolpidem 10 mg and were awakened at five times during subsequent sleep in a random-sequence repeated-measures study. Across all five awakenings following placebo, insomniacs reported being asleep with a frequency of 30.9%. This rose to 40.4% (ns) and 54.7% (p < 0.03) on flurazepam and zolpidem, respectively. Subjects were also more likely to report having been dreaming during the awakening 5 minutes after "lights out" after receiving zolpidem. A number of polygraphic measures of sleep, including sleep latency, total sleep and sleep efficiency, improved significantly on both drugs, and there was similar improvement in some global measures of quality of sleep. Neither drug altered the subjective sense of duration of time. These findings suggest that drug-induced alterations in the perception of being awake or asleep are not unique to benzodiazepines, but occur with the nonbenzodiazepine zolpidem as well.

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.

Several agents are known to improve sleep induction and/or maintenance in patients with insomnia disorder. These include the benzodiazepine (BZD) and non-BZD receptor allosteric modulators, the melatonin receptor agonist ramelteon, low-dose doxepin, and suvorexant. One of the drawbacks of the BZDs is their known reduction in both N3 sleep [also known as slow wave sleep or delta sleep and characterized by the occurrence of slow high amplitude delta (0.5–2 Hz) waves] and rapid eye movement (REM) sleep. Low-dose doxepin has shown similar association with decrease in REM sleep. By contrast, suvorexant increases REM sleep. The available evidence tends to indicate that irrespective of their mechanisms of action, the selective serotonin 5-HT2A receptor antagonists and inverse agonists, including volinanserin, pruvanserin, and nelotanserin, when given in isolated administration, increases slow wave sleep in laboratory animals. Wakefulness and REM sleep were decreased in some studies. Moreover, subjects with normal sleep showed significant increase in N3 sleep following the administration of eplivanserin, nelotanerin, and pimavanserin. Nelotanserin has also been shown to augment N3 sleep in patients with chronic insomnia disorder. N2 sleep tended to decrease in most of these studies, while REM sleep showed no significant changes. Taken together, these evidences suggest that the coadministration of a selective 5-HT2A receptor antagonist or inverse agonist with a hypnotic drug could be a valid clinical strategy for normalizing sleep induction and maintenance and for promoting N3 sleep in patients with insomnia disorder. Additionally, the 5-HT2A receptor agents may have a potential value for improving the cognition and memory deficits in patients with a chronic insomnia disorder as well as elderly patients who show reductions in N3 sleep.

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.

Zopiclone, zolpidem and zaleplon (Z-drugs) are nonbenzodiazepine hypnotic drugs that are used for the treatment of insomnia. These drugs were developed with the intent to overcome some disadvantages of benzodiazepines, such as dependence and next day sedation. In general, the nonbenzodiazepine hypnotic drugs are administered in oral doses daily and are widely biotransformed in the body. A large number of analytical methods based on chromatographic and electrophoretic techniques for the quantification of Z-drugs and their metabolites in biological matrices have been reported. In this review, the bioanalytical methods for Z-drugs were reviewed with the focus placed on sample preparation procedures and the separation techniques used. Furthermore, as these drugs are also reported as drugs of abuse or in drug-facilitated crime, screening methods that simultaneously cover these drugs and also other drugs of abuse were included in this review.

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.

We examined the effects of the nonbenzodiazepine hypnotic zopiclone and the benzodiazepine hypnotics triazolam and nitrazepam on standing steadiness. Eight healthy volunteers received placebo, zopiclone (7.5 mg), triazolam (0.25 mg), and nitrazepam (5 mg) in a random-order, double-blind crossover design. Postural sway was assessed before and 1 and 2 h after drug administration using a stabilometer connected to a microcomputer. Triazolam significantly impaired standing steadiness. Zopiclone also impaired standing steadiness but the degree of impairment seemed to be less marked. Nitrazepam 5 mg had no significant effects on postural sway. Triazolam 0.25 mg, zopiclone 7.5 mg, and nitrazepam 5 mg, which are reported to be equipotent to each other as hypnotics, are not equipotent with respect to their effects on postural sway.

To the Editor: Spinocerebellar ataxia (SCA) is an inherited disorder of brain function characterized by progressive incoordination of gait and is often associated with poor coordination of hands, speech, and eye movements. It is a slowly progressive disease that gradually worsens over a period of years. Zolpidem is a nonbenzodiazepine sedative in the imidazopyridine class and is chemically distinct from other sedatives. It is a short-acting hypnotic with a selective agonist effect for γ-aminobutyric acid (GABA) type A receptors in the brain. It was considered originally by physicians as almost devoid of abuse and dependence potential. Intriguingly, aside from its hypnotic effect, zolpidem has been shown to improve catatonia,1 aphasia,2 Parkinson's disease,3 and ataxia.4 However, reports of zolpidem abuse or dependence are increasing,5,6 and more attention should be paid in terms of zolpidem withdrawal. We report a patient with SCA who took zolpidem for movement difficulties initially, developed dependence on high-dose zolpidem treatment, and encountered serious withdrawal symptoms. We also review the literature on the possible mechanism for the effect of zolpidem on SCA. Case report. Ms A, a 40-year-old married woman, was referred in 2009 for psychiatric consultation due to high-dose zolpidem use. She was diagnosed with SCA type IV at age 35 years with initial symptoms of unsteady gait and mild slurred speech. Her father and brother were also afflicted with SCA. This time, she was admitted via emergency department to our neurology department because of loss of consciousness. Generalized seizure lasted for 1 minute at home, and initial management at the emergency department with phenytoin intravenous drip terminated further progression. Toxicology testing detected no plasma alcohol, whereas plasma benzodiazepine level was 64.80 ng/mL. She claimed she had abused triazolam and alcohol during early adulthood due to insomnia. Other illicit substance use was denied. She had started taking zolpidem 3 years earlier for insomnia, and, paradoxically, zolpidem relieved her ataxia and spasticity. She recalled being able to move her arms and turn her trunk more easily, although the improvement lasted only around 1 hour after taking zolpidem. The dose of zolpidem was gradually escalated by the patient to reach optimal effect. The dose usually amounted to 1,000 mg/d for the past year. Nausea, palpitation, jitters, hand tremor, and perspiration were noted if she did not take enough zolpidem. She was bedridden due to SCA and was cared for by her husband. Although she consumed high doses of zolpidem, her husband tried to cater to all her needs out of sympathy. Zolpidem had been prescribed from different physicians. Withdrawal seizures were noted several times if her supply of zolpidem fell short. Ms A was detoxified by taper of zolpidem gradually over 2 weeks. We prescribed trazodone 100 mg before sleep and diazepam 20 mg/d and propranolol 30 mg/d for anxiety. No seizure attack was noted during hospitalization. After this 2-week hospitalization, she was referred to the psychiatric clinic for further management. The imidazopyridine hypnotic zolpidem binds preferably to the α1 subtype of the benzodiazepine receptor, which is part of GABAA receptor complex. This highly accounts for its sedative effect, whereas the anxiolytic action of benzodiazepines appears to be mediated by receptors that contain the α2 subunit.7 Zolpidem at high doses might lose its selectivity on α1 subunits and bind to lower-affinity α2 units, leading to an anxiolytic effect. Thus, high-dose zolpidem may have a paradoxical effect for alleviating anxiety, and abrupt discontinuation would produce withdrawal symptoms such as palpitation, anxiety, tremor, or seizure similar to those seen with benzodiazepine withdrawal. There is no definite treatment that can prevent or slow the progression of SCA. Clauss et al4 reported transient improvement of SCA with zolpidem in 4 cases. Single photon emission computed tomography demonstrated that GABAergic function may be decreased in the cerebral cortex, thalamus, striatum, and cerebellum in patients with SCA.8 Zolpidem has been shown to mildly improve catatonia, aphasia, and Parkinson's disease.9 Such motor improvement may be due to selective inhibition by zolpidem of GABAergic inhibitory neurons in the internal globus pallidus and substantia nigra pars reticulata, resulting in activation of the thalamus and cerebral cortex.9 Positron emission tomography imaging also has shown normalized tracer uptake in the left thalamus and cerebellum after treatment with zolpidem.4 Our case further corroborates that zolpidem has a mode of action apart from hypnotic properties. To our knowledge, this is the first case report concerning high-dose zolpidem withdrawal seizure in a patient with SCA. We should be more cautious in prescribing zolpidem to patients with past drug abuse or dependence to prevent unwanted consequence. Further investigation of the pharmacologic efficacy of zolpidem in SCA might be needed.

Objective To review the literature for the management of insomnia. Data source MEDLINE/PUBMED searches (January 1950-June 2010) were conducted to identify pertinent English-language studies. Study selection and data extraction All studies evaluating aspects of the treatment of insomnia. Data synthesis Insomnia is a major public health problem requiring effective diagnosis and treatment. Treatment options include cognitive behavioral therapy as well as pharmacologic therapy. Benzodiazepine receptor-agonist modulators are considered first-line therapy in the treatment of chronic insomnia. A nonbenzodiazepine receptor-modulator option to improve sleep latency is ramelteon. Low-dose sedative antidepressants, such as quetiapine or olanzapine, may be used in the treatment of comorbid insomnia. Over-the-counter and herbal agents are not recommended. Conclusion Numerous medications being used in the management of insomnia have side effects that can limit their use and have a potential for drug interactions. Furthermore, some medications used in the treatment of insomnia do not have clinical trial data to support their use. Future studies are warranted to define second- and third-line agents in the management of insomnia.

Insomnia is a highly prevalent condition, and due to ongoing demand from patients suffering with this condition, new pharmacological treatments are actively being sought. As our neurophysiological understanding of insomnia grows, so too do the available treatment options. A significant advance in the treatment of insomnia came with the development of the nonbenzodiazepine hypnotic medications, zolpidem, zaleplon and eszopiclone. These medications have shorter durations of action than many traditional benzodiazepines and may be associated with less risk of tolerance and abuse. They have also been demonstrated to be helpful in cases in which insomnia is comorbid with depression or anxiety, leading to beneficial effects not only with sleep but also with mood and anxiety symptoms. Melatonin, a naturally-occurring substance intimately involved in the regulation of the circadian rhythm, has also been explored as a hypnotic. Little data to date support its use; however, there is evidence that ramelteon, a melatonin agonist, may be helpful for sleep initiation difficulties. Tri-cyclic antidepressants have long been used for insomnia, but use has been limited by unwanted anticholinergic side effects. Low-dose doxepin, at doses of 3 and 6mg, has been demonstrated to have the unique property among its class of being free of anticholinergic effects at those doses. In addition, it seems to have particular efficacy for sleep maintenance insomnia, exhibiting the most robust effects in the latter third of the night. The hypocretin/orexin system has been identified as a possible target. Almorexant, a hypocretin/orexin antagonist displayed evidence of efficacy during Phase III clinical trials but these trials were recently discontinued due to its side effect profile. Another hypocretin/orexin antagonist with a different mechanism of action, MK-4035, is presently in clinical trials. Serotonin antagonists and inverse agonists have been investigated; however, a recent trial with APD125 was discontinued due to lack of efficacy. Sodium oxybate has been used off-label for insomnia by some providers, although data supporting its use are limited. While the sleep-promoting effects of GABA(A) (nonbenzodiazepines and benzodiazepines) enhancement is well-established, newer research examining other mechanisms of action suggest that agents which modulate the histaminergic, serotonergic, melontonergic, and hypocretin/orexin and perhaps GABA-B systems show promise.

Publisher Summary This chapter describes the current knowledge about the medications used for promotion of sleep, beginning with the benzodiazepines and nonbenzodiazepine agents acting as agonists at the γ-aminobutyric acid type A (GABA A) receptor complex. The chapter focuses on the medications which have a sedating effect, including antidepressants, antihistamines, antipsychotics, and others. The available efficacy data support the use of benzodiazepine receptor agonists (BzRAs), and to a lesser extent ramelteon, for the pharmacological treatment of insomnia. Clinicians are using a wide variety of sedating antidepressants, antihistamines, antipsychotics, and other sedative drugs, despite the absence of supportive data and the presence of known safety concerns. A number of sedating medications, including melatonin, gabapentin, tiagabine, gaboxadol, and valerian, are being investigated as potential hypnotics, but compelling support for their use is lacking and further work is needed to establish the role they might play in the management of insomnia.

A fatality due to ingestion of zolpidem, a recently developed nonbenzodiazepine hypnotic, and acepromazine, a phenothiazine sedative used in veterinary practice, is reported. Both drugs were identified and quantified using high-performance liquid chromatography with diode-array detection. Zolpidem and acepromazine blood concentrations were 3.29 and 2.40 micrograms/ml, respectively. It is the first report of a death involving either of these two drugs. The results are discussed in the light of the existing literature and may suggest a reciprocal potentiation of the toxic effects of zolpidem and phenothiazines.

Within horseracing, the detection of prohibited substance doping often requires urine analysis; hence, it is necessary to understand the metabolism of the drugs in question. Here, the previously unknown equine metabolism of eight sedatives is reported in order to provide information on target metabolites for use in doping control. Phase I metabolite information was provided by incubation with equine liver S9 fraction. In vitro techniques were chosen in order to reduce the ethical and financial issues surrounding the study of so many compounds, none of which are licensed for use in horses in the UK. Several metabolites of each drug were identified using liquid chromatography-high resolution mass spectrometric (LC-HRMS) analysis on an LTQ-Orbitrap. Further structural information was obtained by tandem mass spectrometry (MS/MS) analysis; allowing postulation of the structure of some of the most abundant in vitro metabolites. The most abundant metabolites of alpidem, etifoxine, indiplon, tiletamine, zaleplon, zolazepam, zolpidem, and zopiclone related to hydroxylation/N-oxidation, deethylation, demethylation, deethylation, hydroxylation/N-oxidation, demethylation, hydroxylation/N-oxidation and hydroxylation/N-oxidation, respectively. In many cases, further work would be required to fully elucidate the precise positioning of the functional groups involved. The results of this study provide metabolite information that can be used to enhance equine anti-doping screening methods. However, the in vitro metabolites identified are at present only a prediction of those that may occur in vivo. In the future, any positive findings of these drugs and/or their metabolites in horse urine samples could help validate these findings and/or refine the choice of target metabolites.

Eszopiclone (Lunesta™) is the first hypnotic to receive US FDA approval for the long-term treatment of chronic insomnia. This novel nonbenzodiazepine hypnotic provides another option for patients with sleep disorders by inducing rapid-sleep onset and sleep maintenance. The drug is effective and well tolerated in adult patients with insomnia. Eszopiclone is more expensive than some other nonbenzodiazepine hypnotics (zaleplon, immediate release zolpidem) and benzodiazepine hypnotics, and much less expensive than controlled-release zolpidem. It is unclear whether or not the cost of eszopiclone will be offset owing to its side-effect profile and tolerability, since pharmacoeconomic studies are lacking.

Background Insomnia in patients with bipolar disorder (BD) can cause distress, daytime dysfunction, cognitive impairment, worsening of hypomanic/manic symptoms and increased suicide risk. Physicians often prescribe hypnotics for BD patients with insomnia although no hypnotic has a specific FDA indication for this use. In this study, the patterns of use, efficacy and safety of five nonbenzodiazepine hypnotics (NBZHs) were assessed in a large group of outpatients with BD. Method A chart review was performed for all older adolescents and adult BD outpatients in a private outpatient clinic. Clinical data was collected for any patient who had ever been prescribed a NBZH for insomnia and included successful current use, past unsuccessful treatments, side effects, duration of use, concurrent psychiatric medications, and absence or presence of untoward events often associated with chronic use of hypnotics. Results A significant number of BD patients take NBZHs as needed or on a daily basis. Four NBZHs had adequate success rates; ramelteon was limited in efficacy. Some patients experienced satisfactory results from a NBZH after unsuccessful trials with one or more other NBZHs. About half of the current NBZH users are taking them on a daily long-term basis, and none of these patients have experienced unacceptable untoward events. About three quarters of the chronic NBZH users are taking antimanic medications concurrently, and less than half of the chronic users are taking antidepressants. Limitations The results may not be generalizable to other BD populations. A control group was not included in the design. Chronic users of NBZHs were not asked to discontinue their NBZH in order to confirm indication for long-term use. Conclusions Most NBZHs can be effective and safe agents for selected BD outpatients with episodic or chronic insomnia. Failure to respond to one or more NBZH does not preclude a satisfactory response to a different NBZH. Some BD patients who take maintenance antimanic agents also require NBZH treatment. Overactivation from antidepressant treatment does not contribute to chronic NBZH use in most BD patients.

Several classes of nonbenzodiazepine compounds, including imidazopyridines such as alpidem and zolpidem and cyclopyrrolones, e.g., zopiclone, have effects similar to benzodiazepines and may act at the benzodiazepine receptor in brain. We characterized the binding of these compounds to the benzodiazepine site in three brain regions using specific uptake of the high-affinity ligand [3H]Ro15-1788 (flumazenil). For alpidem, benzodiazepine binding was decreased in cortex and hippocampus with increasing drug dose. For zolpidem, receptor binding was reduced in cortex without a dose-response effect and no effect was observed on cerebellar binding. Zopiclone did not alter binding except for a decrease in binding at the lowest dose evaluated and an increase in binding above control at the highest dose. These data corroborate prior studies indicating that the imidazopyridines appear to act at the benzodiazepine receptor, but do not support receptor subtype selectivity of zolpidem. The limited effect of zopiclone except for increased binding at high doses is also consistent with prior studies suggesting that zopiclone acts at a site distinct from the benzodiazepine receptor.

The diagnosis, course, and therapeutic management of the benzodiazepine withdrawal syndrome is still a debated question. The correct method for clinical trials in this indication is also not yet codified. A large sample of patients is required, so the trial must be conducted on a multicenter basis. The present paper describes the main features of a protocol aimed at investigating the ability of a new nonbenzodiazepine anxiolytic drug, alpidem, in preventing or treating the benzodiazepine withdrawal syndrome. A pretrial to standardize the diagnostic and evaluation criteria to be used in the multicenter trial is described.

Anxiety disorders appear to be among the most common psychiatric illnesses of the elderly. Although systematic studies of the phenomenology and treatment of anxiety disorders in the elderly are rather scant, inferences based on studies of younger patients combined with careful clinical observations can be very helpful for both diagnostic and treatment purposes. Several medical conditions can mimic anxiety disorders and suggest a need to consider a possible underlying organic condition during the process of evaluation. Clinical evaluation should be complemented by rating scales and laboratory tests where appropriate. Anxiety disorders occurring for the first time in late life appear to be milder in symptomatology than early-onset disorders. Most anxiety disorders can be well managed using the available treatments. It appears that short-acting benzodiazepines, such as oxazepam and lorazepam, are the treatment of choice for short-term symptoms of geriatric anxiety. For anxiety of longer durations (e.g., greater than 6 months), a nonbenzodiazepine such as buspirone seems preferable. Antidepressants seem effective in cases of mixed anxiety-depression or panic disorder. There is clearly a need, however, to perform more controlled clinical trials of these medications to establish empirically derived guidelines for safety, efficacy, and specificity of these drugs for the elderly population. Finally, nonpharmacologic methods such as cognitive-behavioral treatments can be very effective for the management of certain anxiety disorders, particularly phobias.

No abstract available. Article truncated after first page. What is the estimated prevalence of insomnia symptoms in patients with obstructive sleep apnea? 1. Less than 1% 2. 5%-10% 3. 20-30% 4. 40%-60% 5. Greater than 80%

Insomnia is a common and underdiagnosed condition that can result in significant economic and clinical consequences. Despite numerous behavioral and pharmacotherapeutic treatment options available for insomnia, few receive adequate treatment, and sleep maintenance (staying asleep) remains a significant problem. To date, available sedative-hypnotic agents have limitations that have lead to inadequate treatment of insomnia. This review provides an overview of eszopiclone and its role in the treatment of insomnia. Electronic databases (MEDLINE, EMBASE, International Pharmaceutical Abstracts) were searched for applicable primary literature and review articles. Mechanisms of action at the gammaamino butyric acid (GABA) receptor sites and pharmacologic and pharmacokinetic characteristics are presented. Eszopiclone, a nonbenzodiazepine S-enantiomer of racemic zopiclone, is highlighted as the first sedative-hypnotic agent to be approved by the United States Food and Drug Administration for the treatment of sleep onset latency and sleep maintenance insomnia with no short-term restrictions. Recently, the European Medicines Agency recommended marketing authorization of eszopiclone. Eszopiclone has been shown to be an efficacious and cost-effective option for the treatment of transient and chronic insomnia in adults.

Pierre A GuertinNeuroscience Unit, Laval University Medical Center (CHUL), Quebec City, CanadaAbstract: Recent findings in animal models of paraplegia suggest that specific nonbenzodiazepine anxiolytics may temporarily restore locomotor functions after spinal cord injury (SCI). Experiments using in vitro models have revealed, indeed, that selective serotonin receptor (5-HTR) ligands such as 5-HTR1A agonists, known as relatively safe anxiolytics, can acutely elicit episodes of rhythmic neuronal activity refered to as fictive locomotion in isolated spinal cord preparations. Along the same line, in vivo studies have recently shown that this subclass of anxiolytics can induce, shortly after systemic administration (eg, orally or subcutaneously), some locomotor-like hindlimb movements during 45–60 minutes in completely spinal cord-transected (Tx) rodents. Using ‘knock-out’ mice (eg, 5-HTR7-/-) and selective antagonists, it has been clearly established that both 5-HTR1A and 5-HTR7 were critically involved in mediating the pro-locomotor effects induced by 8-OH-DPAT (typically referred to as a 5-HTR1A agonist) in Tx animals. Taken together, these in vitro and in vivo data strongly support the idea that 5-HTR1A agonists may eventually become constitutive elements of a novel first-in-class combinatorial treatment aimed at periodically inducing short episodes of treadmill stepping in SCI patients.Keywords: 5-HT agonists, anxiolytics, locomotion, SCI

A number of news items and case reports describing complex behaviours (e.g. sleep driving, sleep cooking, sleep eating, sleep conversations, sleep sex) associated with the use of hypnosedative medications have recently received considerable attention. Regulatory agencies examining these reports have subsequently issued warnings regarding the potential of hypnosedative agents to produce complex behaviours. Despite these warnings, little is known about the likelihood, presentation, treatment or prevention of hypnosedative-induced complex behaviours. The purpose of this review is to evaluate the published evidence regarding the clinical presentation, incidence, mechanism and management of sleep-related behaviours induced by nonbenzodiazepine receptor agonists (NBRAs).Review of the literature identified ten published case reports of NBRA-induced complex behaviours involving 17 unique patients. Fifteen of the 17 patients described in the case reports had taken zolpidem, one had taken zaleplon and one had taken zopiclone. The complex behaviours most commonly reported were sleep eating, sleepwalking with object manipulation, sleep conversations, sleep driving, sleep sex and sleep shopping. Elevated serum concentrations resulting from increased medication dose or drug-drug interactions appeared to play a role in some but not all cases. Sex, age, previous medication exposure and concomitant disease states were not consistently found to be related to the risk of experiencing a medication-induced complex behaviour.From a pharmacological standpoint, enhancement of GABA activity at GABAA receptors (particularly alpha1-GABAA receptors) is a possible mechanism for hypnosedative complex behaviours and amnesia. Evidence suggests that complex behaviour risk may increase with both dose and binding affinity at alpha1-GABAA receptors. The amnesia that accompanies complex behaviours is possibly due to inhibition of consolidation of short- to long-term memory, suggesting that the risk may extend to non-GABAergic hypnosedatives. While amnesia and GABA-related receptor actions are the most frequently discussed mechanisms for complex behaviours in the literature, they do not fully explain such behaviours, suggesting that other mechanisms and factors probably play a role.A number of potential strategies are available to manage or prevent hypnosedative-induced complex behaviours. These include lowering the dose of, or stopping, the offending hypnosedative, switching to a different hypnosedative, treating patients with other classes of medications, using nonpharmacological treatment strategies for patients with sleep disorders, examining drug regimens for potential drug interactions that may predispose patients to experiencing complex behaviours, administering hypnosedative medications appropriately and selecting patients more carefully for treatment in terms of their likelihood of experiencing medication adverse effects.

Eszopiclone (Lunesta), the S-enantiomer of racemic zopiclone, is a nonbenzodiazepine hypnotic agent that is approved in the US as an oral, once-nightly therapy for insomnia in adults; eszopiclone is also currently under review by the European Medicines Agency.Eszopiclone is rapidly absorbed after oral administration without any next-day clinical residual effects being detected. Large, well designed trials of up to 6 months' duration have shown that eszopiclone significantly improves both sleep onset and sleep maintenance compared with placebo in adult and elderly patients with primary insomnia. Eszopiclone for 4-8 weeks also significantly improved sleep parameters compared with placebo in patients with insomnia coexisting with other conditions that also disturb sleep (co-morbid insomnia), and improved certain measures of the co-morbid conditions to a greater extent than the standard therapies alone. Short-term eszopiclone produced improvements in daytime functioning in patients with co-morbid insomnia. Six months' therapy in adults with primary insomnia improved daytime functioning and health-related quality of life. Eszopiclone was generally well tolerated. There was no evidence of tolerance during 12 months of treatment with this agent. On discontinuation of eszopiclone, there was no rebound insomnia or serious withdrawal effects. Well designed, comparative trials with other nonbenzodiazepine hypnotics are needed to determine its relative efficacy and tolerability. A cost-utility analysis suggested that eszopiclone is cost effective for the treatment of primary insomnia in the US. Therefore, eszopiclone is a useful therapeutic option in the management of adult and elderly patients with primary or co-morbid insomnia. Unlike most other hypnotics, eszopiclone is not limited to short-term use.

Insomnia can manifest as difficulty in falling asleep, in maintaining sleep throughout the night, or waking up too early, with symptoms often unpredictably changing over time. Pharmacologic options for insomnia treatment include prescription hypnotics, such as gamma-amino butyric acid-receptor agonists, sedating antidepressants, over-the-counter antihistamines, melatonin-receptor agonists, and alternative therapies. A concern with insomnia medications is the risk of next-day residual effects, which can impair memory and ability to perform certain tasks, such as driving, and may increase the risk of accidents and falls, especially in the elderly.To describe the impact of current insomnia treatments on next-day performance.The longer-acting benzodiazepines are associated with next-day "hangover" effects and, as a result, have been largely replaced by agents in the nonbenzodiazepine class, which typically have shorter half-lives. The hypnotic, sedative activities of these classes of drugs depend on variations in binding characteristics to the alpha1 subunit of the gamma-amino butyric acidA-receptor, which inhibits neuronal activity in broad areas of the brain and is found in areas of the brain responsible for sleep/wakefulness and sedation. However, nonbenzodiazepines with a rapid onset of action and short half-life have shown limited efficacy for maintaining sleep throughout the night. These properties have contributed to the development of modified-release formulations. Zolpidem extended-release is a bilayer tablet that retains the fast onset of action of its parent compound zolpidem while extending the duration of hypnotic activity, owing to a slower-release portion of the tablet.Based on clinical evidence, the risk of residual next-day effects of zolpidem extended-release is limited, mainly due to the similarly short half-life in its extended-release formulation.

Eszopiclone (Lunesta), the S-enantiomer of racemic zopiclone, is a nonbenzodiazepine hypnotic agent that is approved in the US as an oral, once-nightly therapy for insomnia in adults; eszopiclone is also currently under review by the European Medicines Agency. Eszopiclone is rapidly absorbed after oral administration without any next-day clinical residual effects being detected. Large, well designed trials of up to 6 months' duration have shown that eszopiclone significantly improves both sleep onset and sleep maintenance compared with placebo in adult and elderly patients with primary insomnia. Eszopiclone for 4-8 weeks also significantly improved sleep parameters compared with placebo in patients with insomnia coexisting with other conditions that also disturb sleep (co-morbid insomnia), and improved certain measures of the co-morbid conditions to a greater extent than the standard therapies alone. Short-term eszopiclone produced improvements in daytime functioning in patients with co-morbid insomnia. Six months' therapy in adults with primary insomnia improved daytime functioning and health-related quality of life. Eszopiclone was generally well tolerated. There was no evidence of tolerance during 12 months' treatment with this agent. On discontinuation of eszopiclone, there was no rebound insomnia or serious withdrawal effects. Well designed, comparative trials with other nonbenzodiazepine hypnotics are needed to determine its relative efficacy and tolerability. A cost-utility analysis suggested that eszopiclone is cost effective for the treatment of primary insomnia in the US. Therefore, eszopiclone is a useful therapeutic option in the management of adult and elderly patients with primary or co-morbid insomnia. Unlike most other hypnotics, eszopiclone is not limited to short-term use.

Although there are theoretically numerous pharmacologic targets for relieving temporomandibular disorder (TMD)–associated pains, evidence-based literature clearly establishing the efficacy and safety of drugs in the TMD population is limited at best. This article reviews the pharmacology, toxicology, and research supporting the use of a host of pharmacologic agents that have been used in patients who have TMD, including nonsteroidal anti-inflammatory drugs, corticosteroids, benzodiazepines, nonbenzodiazepine sedative hypnotics, opioids, skeletal muscle relaxants, capsaicin, transdermal lidocaine, antidepressants, and anticonvulsants. Recommendations regarding the proper use of each drug class are also made.

Zolpidem is an imidazopyridine, a chemically novel nonbenzodiazepine hypnotic agent which acts at the benzodiazepine omega 1-receptor subtype in the brain. With a rapid onset of action and short elimination half-life, it reduces the latency to and prolongs the duration of sleep in patients with insomnia, yet has no major effects on sleep stages when given in dosages of 5 to 20 mg nightly. Rebound effects on withdrawal of the drug have not been observed. Unlike benzodiazepines, zolpidem has no myorelaxant or anticonvulsant effects and its effects on anxiety appear to be minor. While zolpidem aids sedation, and may reduce memory or psychomotor function within the first 2 hours after administration of single oral doses, its use as a surgical premedicant remains to be established. Adverse effects are predominantly CNS and gastrointestinal in nature. Altered pharmacokinetics may lead to an increase in dose-proportionate adverse effects in the elderly and in patients with renal dysfunction. Limited evidence to date suggests that the dependence liability of zolpidem is minimal. Thus, zolpidem is an interesting alternative to benzodiazepines in the treatment of insomnia, with properties that potentially offer worthwhile advantages in this therapeutic area if they are confirmed with wider clinical experience.

Drugs used in the treatment of anxiety are frequently sedating and tend to be respiratory depressants. Buspirone, a nonbenzodiazepine anxiolytic agent, has little reported sedative effect. It has been shown to be a respiratory stimulant in an anesthetized, glomectomized cat model. In this study, we examined the effects of two intraperitoneal single doses (10 and 20 mg/kg) of buspirone on sleep and respiration in unanesthetized, intact, freely moving rats. Buspirone increased sleep latency (p less than 0.0001) and decreased total sleep (p less than 0.02) through reductions in both non-REM and REM sleep. Respiratory rate (p less than 0.0003) and ventilation (p less than 0.004) were significantly increased for 4 h after drug injection. The effects on respiration were independent of those on sleep; stimulation was evident in both waking and non-REM sleep. This study suggests that buspirone, in addition to being free of sedating and respiratory depressant side effects when prescribed for anxiety in humans, may be a respiratory stimulant whose effects persist in sleep.

In a double-blind placebo-controlled prospective clinical trial we studied the efficacy and safety of the benzodiazepine antagonist, flumazenil. In 23 patients admitted to the Intensive Care Unit with coma due to overdose with benzodiazepines or other sedatives, flumazenil i.v. (up to 2 mg or placebo) was given. In 13 patients given flumazenil the Glasgow Coma Scale (GCS) increased significantly from 4.9 to 7.8 (p less than 0.05). Six of these 13 patients, including mainly benzodiazepine mono-intoxications, needed only one series of injections (up to 1.0 mg flumazenil); the GCS increased thereby from 4.5 to 10.7 within a maximum of 5 min (p less than 0.01). In the remaining 7 patients, needing two series of injections of flumazenil (up to 2.0 mg), GCS did not rise significantly and coma was related to intoxications with nonbenzodiazepine sedatives, flunitrazepam and in one patient, encephalitis. In the 10 patients receiving placebo, the GCS did not change. A significant increase in the GCS from 5.5 to 10.8 (p less than 0.001) was, however, observed when flumazenil (up to 1.0 mg) was given after placebo. In patients with EEG monitoring the changes in waveform pattern paralleled the clinical response. Effects could be detected within 1-2 min after flumazenil injection and lasted up to 45 min. There were no adverse reactions or benzodiazepine withdrawal symptoms. We conclude that flumazenil is an effective and safe drug in the treatment of benzodiazepine overdose. The use of flumazenil is of diagnostic value in mixed-drug intoxications or coma of unknown origin and is of therapeutic importance for reversal of benzodiazepine intoxications.

Because benzodiazepines are frequently and often inappropriately prescribed by internists, we wished to examine the attitudes, beliefs, and recording behavior of internal medicine house staff who prescribe these medications to patients attending a general medicine clinic. Over a 5‐month period, we reviewed the medical records of patients prescribed both a benzodiazepine and a nonbenzodiazepine for clinical information related to prescribing these medications. At the close of the collection, all house staff completed a series of 12 questions about the management and treatment of hypertension and anxiety. Forty‐five house staff were included in our study. As a group, these house staff omitted information significantly more often for benzodiazepines than for nonbenzodiazepines and endorsed attitudes that were significantly less favorable toward prescribing the former. In summary, inconsistency in house officer recording of benzodiazepine prescriptions can be explained in part by their unfavorable attitudes t...

Disturbed sleep is the most commonly reported sleep complaint,1,2 affecting about one third of the population of the United States; about 10%–15% suffer from chronic insomnia.3 Chronic insomnia occurs more frequently in women, older adults, and patients with chronic medical and psychiatric disorders.4–6 In the vast majority of cases (around 90%), insomnia is comorbid with other conditions. Whether it is a primary disorder or comorbid with other conditions, chronic insomnia is often associated with numerous daytime consequences, including fatigue, mood disturbances, diminished functioning at home, occupational difficulties, increased incidence of accidents, a reduced quality of life, and increased risk for depression.7 Additionally, increased health care costs reported by individuals experiencing insomnia ultimately result in a significant economic burden to society due to lost productivity. The chronic and non-remitting nature of insomnia suggests that short-term treatments are less than optimal. Historically, insomnia has been treated with a variety of pharmacologic agents, typically the benzodiazepine receptor agonists, whose benefits must be considered in the context of their adverse events, including ataxia, amnesia, daytime somnolence, and rebound insomnia. More recently, the treatment of insomnia includes agents that act at benzodiazepine receptors but have a nonbenzodiazepine structure (eg, eszopiclone, zolpidem, and zaleplon). Results from randomized clinical trials indicate that these agents are effective in the management of insomnia.8 Melatonin-receptor agonists, a new class of drugs that promote sleep by targeting the regulation of sleep by the suprachiasmatic nucleus (SCN), have shown benefit in randomized trials.9,10 Ramelteon is the first approved sleep-promoting medication with this novel mechanism of action. To address the recent exciting developments in the use of medications in the treatment of insomnia, a symposium was held at the 25th Congress of the Collegium Internationale Neuropsychopharmacologicum in July 2006. The goal of this symposium was to provide a comprehensive overview of the prevalence and impact of sleeplessness, a review of the influence of circadian processes in the normal sleep-wake cycle, and the pharmacologic options for the successful management of insomnia as well as insights into future therapeutic directions. In the first paper, “Insomnia: Definition, Prevalence, Etiology, and Consequences,” Thomas Roth, PhD, from the Sleep Disorders and Research Center at Henry Ford Health System, sets the stage in discussing the definition and diagnosis of insomnia. Dr. Roth notes that insomnia is defined as difficulty initiating sleep, problems with sleep maintenance, or waking too early despite adequate sleep opportunity. He describes the brain regions involved in sleep-wake regulation. Dr. Roth also discusses the prevalence of sleep disturbances in the general population and the various risk factors associated with increased prevalence of chronic insomnia occurring in individuals of older age, female gender, and those suffering from comorbid medical and psychiatric conditions. In the next paper, “The Evolution and Development of Insomnia Pharmacotherapies,” David N. Neubauer, MD, from Johns Hopkins University School of Medicine, focuses on the pharmacological characteristics and clinical value of medications and related substances that currently are used to help patients fall asleep or remain asleep. The efficacy of these compounds ranges from negligible to well established, and several have significant safety issues. Dr. Neubauer discusses the historical evolution of the array of pharmacologic sleep-promoting agents, describing the early use of benzodiazepine medications for the treatment of insomnia in the early 1970s, the introduction of nonbenzodiazepine hypnotics in the 1990s, followed by the recent release of the first melatonin receptor agonist, ramelteon. In the final paper of the supplement, Karl Doghramji, MD, from the Jefferson Medical College, discusses “Melatonin and Its Receptors: A New Class of Sleep-Promoting Agents.” Dr. Doghramji discusses how the role of melatonin in synchronizing the circadian clock by its direct action on the SCN has led to the investigation of melatonin as a remedy for treating disordered circadian rhythms that occur in jet lag, shift work, and insomnia. However, conflicting results on melatonin's effectiveness in clinical trials have prompted the development of melatonin receptor agonists for the treatment of sleep disturbances. Dr. Doghramji describes the efficacy and safety of ramelteon as well as other melatonin receptor agonists that are currently being investigated for the treatment of sleep disorders. The purpose of this supplement is to provide a resource that clinicians may use to recognize and understand the descriptive paradigms, prevalences, and risk factors for insomnias, as well as to identify the currently available pharmacologic options for the treatment of insomnia.

Zolpidem extended-release, or controlled-release (CR), is a new formulation of zolpidem, a nonbenzodiazepine hypnotic. It is indicated in the US for the treatment of insomnia, characterised by difficulties with sleep onset and/or sleep maintenance. Zolpidem CR is a dual-layered tablet; one layer releases zolpidem immediately and a second layer provides a slower release of additional zolpidem for maintenance of plasma zolpidem concentrations. Efficacy of zolpidem CR was assessed in two 3-week, randomised, double-blind, placebo-controlled, phase III polysomnography trials in younger adult (aged 18-64 years) or elderly (agedor =65 years) patients with primary insomnia. Patients received nightly zolpidem CR (12.5mg in younger adult and 6.25mg in elderly patients). Efficacy was assessed objectively on nights 1, 2, 15 and 16. Patients who received zolpidem CR had significantly improved objective latency to persistent sleep, wake time after sleep onset and sleep efficiency on assessment nights compared with placebo recipients. In subjective assessments of sleep quality on day 2 and nights 15 and 22, significantly more zolpidem CR than placebo recipients gave favourable responses on a Patient Global Impression scale in the study in younger adult patients. In the other study, significantly more elderly patients in the zolpidem CR group rated their sleep as improved compared with the placebo group. Zolpidem CR was generally well tolerated and appears to have a tolerability profile similar to that of the original formulation of zolpidem.

Background: Chronic insomnia is common among the elderly These elderly patients are often viewed as difficult to treat, yet they are among the groups with the greatest need of treatment. Objective: This article reviews the literature on the management of chronic insomnia in elderly persons. Methods: A search of MEDLINE was conducted for articles published in English between January 1966 and March 2006 using the terms insomnia, behavioral therapy, estsazolsam, fluvsazepsam, qusazepsam, teMsazepsam, tvisazolsam, eszopiclone, zaleplon, zolpidem, mirtazapine, nefazodone, trazodone, and ramelteon. Articles were selected if they were meta-analyses or evidence-based reviews of therapeutic modalities; randomized controlled trials of nonpharmacologic or pharmacologic treatment; or review articles covering the characteristics and management of insomnia. Preference was given to meta-analyses, evidence-based reviews, and articles that included relevant new information. Results: Available options for the treatment of insomnia include nonpharmacologic approaches, foremost among them cognitive behavioral therapy, and pharmacotherapies, including chloral hydrate, barbiturates, over-the-counter (OTC) and prescription antihistamines, OTC dietary supplements (including melatonin), sedating antidepressants, benzodiazepine and nonbenzodiazepine sedative-hypnotics, and melatonin agonists. There is considerable evidence to support the effectiveness and durability of nonpharmacologic interventions for insomnia in adults of all ages, yet these interventions are underutilized. With some recent exceptions, the majority of identified studies of pharmacotherapy were of short duration (≤6 weeks) and did not exclusively enroll older adults. Compared with the benzodiazepines, the nonbenzodiazepine sedative-hypnotics appeared to offer few, if any, significant clinical advantages in efficacy or tolerability in elderly persons. Newer agents with novel mechanisms of action and improved safety profiles, such as the melatonin agonists, hold promise for the management of chronic insomnia in elderly people. Conclusions: Long-term use of sedative-hypnotics for insomnia lacks an evidence base and has traditionally been discouraged for reasons that include concerns about such potential adverse drug effects as cognitive impairment (anterograde amnesia), daytime sedation, motor incoordination, and increased risk of motor vehicle accidents and falls. In addition, the effectiveness and safety of long-term use of these agents remain to be determined. More research is needed to evaluate the long-term effects of treatment and the most appropriate management strategy for elderly persons with chronic insomnia.

Objective: To review the clinical evidence to determine the efficacy and safety of valproic acid in the management of alcohol withdrawal syndrome (AWS). Data Sources: MEDLINE (1966–February 2006), EMBASE (1980–February 2006), and PubMed (1966–February 2006) searches identified pertinent studies that were conducted in humans and published in English. Key words used for identification of articles included valproic acid, ethanol, alcohol, alcoholism, alcohol withdrawal delirium, alcohol withdrawal seizures, and substance withdrawal syndrome. References of identified articles were manually searched. Study Selection and Data Extraction: All controlled clinical trials that evaluated the use of valproic acid for the management of AWS in humans were included. Data Synthesis: Comparisons were made among various regimens of valproic acid and traditional therapy with benzodiazepine or nonbenzodiazepine agents. Only 2 of 6 trials reported a statistically significant difference in favor of valproic acid on endpoints of AWS. However, these differences were of marginal clinical significance. The number of patients included in these studies did not allow for adequate evaluation of safety. Conclusions: The existing limited efficacy and safety data suggest that valproic acid should not replace conventional therapy or be used as adjunct therapy for management of mild-to-moderate AWS.