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This study sought to (1) identify patterns of hypnotic use among persons aged 50 and older for 8 years and (2) describe characteristics and correlates associated with them. A representative sample of national health insurance system beneficiaries was followed up from 2006 through 2013; individuals were grouped according to hypnotic delivery trajectories by latent class mixed models. We identified four different temporal trajectories of hypnotic delivery among users. Delivery was occasional for 40% and regular for 60% (quasi-continuous \"use\": 27%; increasingly frequent over time: 17%; decreasingly frequent: 16%). Quasi-continuous \"users\" received hypnotics for more than 70% of the follow-up period and occasional \"users\" for less than 8%. We found no clear evidence of dose escalation. The three regular-delivery trajectories shared similar correlates (psychiatric disorders, somatic comorbidity, and coprescriptions of antidepressants or antipsychotics), but association with somatic comorbidity was highest by far for quasi-continuous \"users.\" Our results suggest that chronic hypnotic use covers different patterns resulting from different long-term temporal delivery trajectories. Because difficulties in stopping or reducing use may vary greatly according to these trajectories, patients may need individualized management approaches.

ObjectivesTo explore intercountry and intracountry differences in physician opinions about continuous use of sedatives (CUS), and factors associated with their approval of CUS.SettingsSecondary analysis of a questionnaire study.ParticipantsPalliative care physicians in Germany (N=273), Italy (N=198), Japan (N=334) and the UK (N=111).Primary and secondary outcome measuresPhysician approval for CUS in four situations, intention and treatment goal, how to use sedatives and beliefs about CUS.ResultsThere were no significant intercountry or intracountry differences in the degree of agreement with statements that (1) CUS is not necessary as suffering can always be relieved with other measures (mostly disagree); (2) intention of CUS is to alleviate suffering and (3) shortening the dying process is not intended. However, there were significant intercountry differences in agreement with statements that (1) CUS is acceptable for patients with longer survival or psychoexistential suffering; (2) decrease in consciousness is intended and (3) choice of neuroleptics or opioids. Acceptability of CUS for patients with longer survival or psychoexistential suffering and whether decrease in consciousness is intended also showed wide intracountry differences. Also, the proportion of physicians who agreed versus disagreed with the statement that CUS may not alleviate suffering adequately even in unresponsive patients, was approximately equal. Regression analyses revealed that both physician-related and country-related factors were independently associated with physicians’ approval of CUS.ConclusionVariations in use of sedatives is due to both physician- and country-related factors, but palliative care physicians consistently agree on the value of sedatives to aid symptom control. Future research should focus on (1) whether sedatives should be used in patients with longer survival or with primarily psychoexistential suffering, (2) understanding physicians’ intentions and treatment goals, (3) efficacy of different drugs and (4) understanding the actual experiences of patients receiving CUS.

Remimazolam (Anerem ® in Japan; ByFavo™ in the USA; Aptimyda™ in the EU) is an ultra-short-acting intravenous (IV) benzodiazepine sedative/anesthetic being developed by PAION AG in conjunction with a number of commercial partners for use in anesthesia and procedural sedation. Remimazolam was approved on 23 January 2020 in Japan for use in general anesthesia in adult patients. Remimazolam is also undergoing regulatory assessment in South Korea for this indication and for use in procedural sedation in the USA, the EU and China. This article summarises the major milestones in the development of remimazolam for this first approval for the induction and maintenance of general anaesthesia, and its potential upcoming approvals in general anaesthesia and procedural sedation.

Background Palliative sedation is the monitored use of medications intended to reduce consciousness to relieve the burden of otherwise intractable suffering. Since 2016, the French Leonetti-Claeys law has granted patients the right to receive continuous deep sedation until death (CDSUD) for some indications. There are relatively few data in the literature assessing sedation practices in palliative care units (PCUs). Methods This study aimed to compare sedation practices in six French PCUs, analyzing the frequency, types of sedation (CDSUD vs. proportional sedation), and use of sedative medications during the last 72 h of life. This retrospective study examined the data of patients who died in these units between July and December 2021. Results The results revealed statistically significant variability in sedation practices. The overall prevalence of sedation practices (all types) was 22%. The prevalence for CDSUD was 12%. Some units had much higher or lower rates of sedation, suggesting differences in the interpretation of guidelines and regulations, possibly because of cultural or individual factors within the units. The study also found important variability in the use of sedative medication in terms of molecules and dosage. Midazolam was the most commonly used benzodiazepine but the dosage varied significantly depending on the units. Conclusions Further qualitative research is needed to understand the reasons for the observed variability in sedation practices and improve the standardization and clarity of palliative sedation.

Dexmedetomidine (Dexdor ® ) is a highly selective α 2 -adrenoceptor agonist. It has sedative, analgesic and opioid-sparing effects and is suitable for short- and longer-term sedation in an intensive care setting. In the randomized, double-blind, multicentre MIDEX and PRODEX trials, longer-term sedation with dexmedetomidine was noninferior to midazolam and propofol in terms of time spent at the target sedation range, as well as being associated with a shorter time to extubation than midazolam or propofol, and a shorter duration of mechanical ventilation than midazolam. Patients receiving dexmedetomidine were also easier to rouse, more co-operative and better able to communicate than patients receiving midazolam or propofol. Dexmedetomidine had beneficial effects on delirium in some randomized, controlled trials (e.g. patients receiving dexmedetomidine were less likely to experience delirium than patients receiving midazolam, propofol or remifentanil and had more delirium- and coma-free days than patients receiving lorazepam). Intravenous dexmedetomidine had an acceptable tolerability profile; hypotension, hypertension and bradycardia were the most commonly reported adverse reactions. In conclusion, dexmedetomidine is an important option for sedation in the intensive care setting.

Sleep disturbance is the most prominent symptom in depressive patients and was formerly regarded as a main secondary manifestation of depression. However, many longitudinal studies have identified insomnia as an independent risk factor for the development of emerging or recurrent depression among young, middle‐aged and older adults. This bidirectional association between sleep disturbance and depression has created a new perspective that sleep problems are no longer an epiphenomenon of depression but a predictive prodromal symptom. In this review, we highlight the treatment of sleep disturbance before, during and after depression, which probably plays an important role in improving outcomes and preventing the recurrence of depression. In clinical practice, pharmacological therapies, including hypnotics and antidepressants, and non‐pharmacological therapies are typically applied. A better understanding of the pathophysiological mechanisms between sleep disturbance and depression can help psychiatrists better manage this comorbidity.

Daily interruption of sedative therapy and limitation of deep sedation have been shown in several randomized trials to reduce the duration of mechanical ventilation and hospital length of stay, and to improve the outcome of critically ill patients. However, patients with severe acute brain injury (ABI; including subjects with coma after traumatic brain injury, ischaemic/haemorrhagic stroke, cardiac arrest, status epilepticus) were excluded from these studies. Therefore, whether the new paradigm of minimal sedation can be translated to the neuro-ICU (NICU) is unclear. In patients with ABI, sedation has ‘general’ indications (control of anxiety, pain, discomfort, agitation, facilitation of mechanical ventilation) and ‘neuro-specific’ indications (reduction of cerebral metabolic demand, improved brain tolerance to ischaemia). Sedation also is an essential therapeutic component of intracranial pressure therapy, targeted temperature management and seizure control. Given the lack of large trials which have evaluated clinically relevant endpoints, sedative selection depends on the effect of each agent on cerebral and systemic haemodynamics. Titration and withdrawal of sedation in the NICU setting has to be balanced between the risk that interrupting sedation might exacerbate brain injury (e.g. intracranial pressure elevation) and the potential benefits of enhanced neurological function and reduced complications. In this review, we provide a concise summary of cerebral physiologic effects of sedatives and analgesics, the advantages/disadvantages of each agent, the comparative effects of standard sedatives (propofol and midazolam) and the emerging role of alternative drugs (ketamine). We suggest a pragmatic approach for the use of sedation-analgesia in the NICU, focusing on some practical aspects, including optimal titration and management of sedation withdrawal according to ABI severity.

Suvorexant (MK-4305) is an orexin receptor antagonist shown to be efficacious for insomnia over 3 months. We aimed to assess its clinical profile during and after 1 year of treatment. We did a randomised, placebo-controlled, parallel-group trial at 106 investigational centres in the Americas, Australia, Europe, and South Africa from December, 2009, to August, 2011. Patients aged 18 years or older with primary insomnia by DSM-IV-TR criteria were assigned using a computer-generated randomised allocation schedule to receive nightly suvorexant (40 mg for patients younger than 65 years, 30 mg for patients aged 65 years or older) or placebo at a 2:1 ratio for 1 year with a subsequent 2-month randomised discontinuation phase in which patients on suvorexant either continued suvorexant or were abruptly switched to placebo while patients on placebo remained on placebo. Treatment assignment was masked from patients and investigators. The primary objective was to assess the safety and tolerability of suvorexant for up to 1 year. Secondary objectives were to assess the efficacy of suvorexant for improving patient-reported subjective total sleep time (sTST) and time to sleep onset (sTSO) over the first month of treatment. Efficacy endpoints over the first month were assessed with a mixed model with terms for baseline value of the response variable, age, sex, region, treatment, time, and treatment by time interaction. This trial is registered with ClinicalTrials.gov, number NCT01021813. 322 (62%) of 522 patients randomly assigned to receive suvorexant and 162 (63%) of 259 assigned to receive placebo completed the 1-year phase. Over 1 year, 362 (69%) of 521 patients treated with suvorexant experienced any adverse events compared with 164 (64%) of 258 treated with placebo. Serious adverse events were recorded in 27 patients (5%) who received suvorexant and 17 (7%) who received placebo. The most common adverse event, somnolence, was reported for 69 patients (13%) who received suvorexant and seven (3%) who received placebo. At month 1, suvorexant (517 patients in the efficacy population) showed greater efficacy than placebo (254 in the efficacy population) in improving sTST (38·7 min vs 16·0 min; difference 22·7, 95% CI 16·4 to 29·0; p<0·0001) and sTSO (–18·0 min vs −8·4 min, difference −9·5, −14·6 to −4·5; p=0·0002). Our findings show that suvorexant was generally safe and well tolerated over 1 year of nightly treatment in patients with insomnia, with efficacy noted for subjective measures of sleep onset and maintenance. Merck & Co Inc.

Neophytadiene (NPT) is a diterpene found in the methanolic extracts of Crataeva nurvala and Blumea lacera, plants reported with anxiolytic-like activity, sedative properties, and antidepressant-like actions; however, the contribution of neophytadiene to these effects is unknown. This study determined the neuropharmacological (anxiolytic-like, antidepressant-like, anticonvulsant, and sedative) effects of neophytadiene (0.1–10 mg/kg p.o.) and determined the mechanisms of action involved in the neuropharmacological actions using inhibitors such as flumazenil and analyzing the possible interaction of neophytadiene with GABA receptors using a molecular docking study. The behavioral tests were evaluated using the light–dark box, elevated plus-maze, open field, hole-board, convulsion, tail suspension, pentobarbital-induced sleeping, and rotarod. The results showed that neophytadiene exhibited anxiolytic-like activity only to the high dose (10 mg/kg) in the elevated plus-maze and hole-board tests, and anticonvulsant actions in the 4-aminopyridine and pentylenetetrazole-induced seizures test. The anxiolytic-like and anticonvulsant effects of neophytadiene were abolished with the pre-treatment with 2 mg/kg flumazenil. In addition, neophytadiene showed low antidepressant effects (about 3-fold lower) compared to fluoxetine. On other hand, neophytadiene had no sedative or locomotor effects. In conclusion, neophytadiene exerts anxiolytic-like and anticonvulsant activities with the probable participation of the GABAergic system.

Generalised anxiety disorder is a disease that can be associated with substantial dysfunction. Pharmacological treatment is often the first choice for clinicians because of the cost and resource constraints of psychological alternatives, but there is a paucity of comparative information for the multiple available drug choices. A systematic review and network meta-analysis was performed on randomised trials in adult outpatients with generalised anxiety disorder identified from MEDLINE, Web of Science, Cochrane Library, ClinicalTrials.gov, Chinese National Knowledge Infrastructure (CNKI), Wanfang data, Drugs@FDA and commercial pharmaceutical registries. Placebo and active control trials were included. Data were extracted from all manuscripts and reports. Primary outcomes were efficacy (mean difference [MD] in change in Hamilton Anxiety Scale Score) and acceptability (study discontinuations for any cause). We estimated summary mean treatment differences and odds ratios using network meta-analyses with random effects. This study is registered with PROSPERO, number CRD42018087106. Studies were published between Jan 1, 1994 and Aug 1, 2017, in which 1992 potential studies were screened for inclusion. This analysis is based on 89 trials, which included 25 441 patients randomly assigned to 22 different active drugs or placebo. Duloxetine (MD −3·13, 95% credible interval [CrI] −4·13 to −2·13), pregabalin (MD −2·79, 95% CrI −3·69 to −1·91), venlafaxine (MD −2·69, 95% CrI −3·50 to −1·89), and escitalopram (MD −2·45, 95% CrI −3·27 to −1·63) were more efficacious than placebo with relatively good acceptability. Mirtazapine, sertraline, fluoxetine, buspirone, and agomelatine were also found to be efficacious and well tolerated but these findings were limited by small sample sizes. Quetiapine (MD −3·60 95% CrI −4·83 to −2·39) had the largest effect on HAM-A but it was poorly tolerated (odds ratio 1·44, 95% CrI 1·16–1·80) when compared with placebo. Likewise, paroxetine and benzodiazepines were effective but also poorly tolerated when compared with placebo. Risk of reporting bias was considered low, and when possible all completed studies were included to avoid publication bias. To our knowledge, this is the largest contemporary review of pharmacological agents for the treatment of generalised anxiety disorder by use of network analysis. There are several effective treatment choices for generalised anxiety disorder across classes of medication. The failure of initial pharmacological therapy might not be a reason to abandon a pharmacological treatment strategy. No funding was received for this research.