Non-benzodiazepine Hypnotics and Police-Reported Motor Vehicle Crash Risk among Older Adults: A Sequential Target Trial Emulation.

Non-benzodiazepine hypnotics ( "Z-drugs") are prescribed for insomnia, but might increase risk of motor vehicle crash (MVC) among older adults through prolonged drowsiness and delayed reaction times. We estimated the effect of initiating Z-drug treatment on the 12-week risk of MVC in a sequential target trial emulation. After linking New Jersey driver licensing and police-reported MVC data to Medicare claims, we emulated a new target trial each week (July 1, 2007 - October 7, 2017) in which Medicare fee-for-service beneficiaries were classified as Z-drug-treated or untreated at baseline and followed for an MVC. We used inverse probability of treatment and censoring weighted pooled logistic regression models to estimate risk ratios (RR) and risk differences with 95% bootstrap confidence limits (CLs). There were 257,554 person-trials, of which 103,371 were Z-drug-treated and 154,183 untreated, giving rise to 976 and 1,249 MVCs, respectively. The intention-to-treat RR was 1.06 (95%CLs 0.95, 1.16). For the per-protocol estimand, there were 800 MVCs and 1,241 MVCs among treated and untreated person-trials, respectively, suggesting a reduced MVC risk (RR 0.83 [95%CLs 0.74, 0.92]) with sustained Z-drug treatment. Z-drugs should be prescribed to older patients judiciously but not withheld entirely over concerns about MVC risk.

Optimizing the Time and Dose of Melatonin as a Sleep-Promoting Drug: A Systematic Review of Randomized Controlled Trials and Dose-Response Meta-Analysis.

Previous studies have reported inconsistent results about exogenous melatonin's sleep-promoting effects. A possible explanation relies on the heterogeneity in administration schedule and dose, which might be accountable for differences in treatment efficacy. In this paper, we undertook a systematic review and meta-analysis of double-blind, randomized controlled trials performed on patients with insomnia and healthy volunteers, evaluating the effect of melatonin administration on sleep-related parameters. The standardized mean difference between treatment and placebo groups in terms of sleep onset latency and total sleep time were used as outcomes. Dose-response and meta-regression models were estimated to explore how time of administration, dose, and other treatment-related parameters might affect exogenous melatonin's efficacy. We included 26 randomized controlled trials published between 1987 and 2020, for a total of 1689 observations. Dose-response meta-analysis showed that melatonin gradually reduces sleep onset latency and increases total sleep time, peaking at 4 mg/day. Meta-regression models showed that insomnia status (ß = 0.50, p < 0.001) and time between treatment administration and the sleep episode (ß = -0.16, p = 0.023) were significant predictors of sleep onset latency, while the time of day (ß = -0.086, p < 0.01) was the only significant predictor of total sleep time. Our results suggest that advancing the timing of administration (3 h before the desired bedtime) and increasing the administered dose (4 mg/day), as compared to the exogenous melatonin schedule most used in clinical practice (2 mg 30 min before the desired bedtime), might optimize the efficacy of exogenous melatonin in promoting sleep.

Respiratory drive heterogeneity associated with systemic inflammation and vascular permeability in acute respiratory distress syndrome.

BACKGROUND: In acute respiratory distress syndrome (ARDS), respiratory drive often differs among patients with similar clinical characteristics. Readily observable factors like acid-base state, oxygenation, mechanics, and sedation depth do not fully explain drive heterogeneity. This study evaluated the relationship of systemic inflammation and vascular permeability markers with respiratory drive and clinical outcomes in ARDS. METHODS: ARDS patients enrolled in the multicenter EPVent-2 trial with requisite data and plasma biomarkers were included. Neuromuscular blockade recipients were excluded. Respiratory drive was measured as PES0.1, the change in esophageal pressure during the first 0.1 s of inspiratory effort. Plasma angiopoietin-2, interleukin-6, and interleukin-8 were measured concomitantly, and 60-day clinical outcomes evaluated. RESULTS: 54.8% of 124 included patients had detectable respiratory drive (PES0.1 range of 0-5.1 cm H2O). Angiopoietin-2 and interleukin-8, but not interleukin-6, were associated with respiratory drive independently of acid-base, oxygenation, respiratory mechanics, and sedation depth. Sedation depth was not significantly associated with PES0.1 in an unadjusted model, or after adjusting for mechanics and chemoreceptor input. However, upon adding angiopoietin-2, interleukin-6, or interleukin-8 to models, lighter sedation was significantly associated with higher PES0.1. Risk of death was less with moderate drive (PES0.1 of 0.5-2.9 cm H2O) compared to either lower drive (hazard ratio 1.58, 95% CI 0.82-3.05) or higher drive (2.63, 95% CI 1.21-5.70) (p = 0.049). CONCLUSIONS: Among patients with ARDS, systemic inflammatory and vascular permeability markers were independently associated with higher respiratory drive. The heterogeneous response of respiratory drive to varying sedation depth may be explained in part by differences in inflammation and vascular permeability.

Safety profile of hypnotics or sedatives on community-dwelling older adults aged 75 or older in Japan: A retrospective propensity-matched cohort study.

OBJECTIVE: The purpose of the study is to assess if daily use of hypnotics increases mortality, aspiration pneumonia and hip fracture among relatively healthy individuals aged 75 years or older who lead independent lives in the community. METHOD AND PATIENTS: Of the adults aged 75 years or older residing in Hokkaido prefecture of Japan (n = 705,538), those who did not meet several exclusion criteria were eligible for generating propensity score-matched cohorts (n = 214,723). Exclusion criteria included co-prescribed medications acting on the central nervous system, diagnoses of malignant neoplasm, dementia, depression, etc. We compared 33,095 participants who were prescribed hypnotics for daily use (hypnotic group) with a propensity score-matched cohort without a prescription (control group). Participants were followed for more than 42 months. RESULTS: During the 42-month follow-up period, the incidence of the three outcome measures in the hypnotics group was significantly higher than that in the control group (aspiration pneumonia p < 0.001, hip fracture p = 0.007, and all-cause mortality p < 0.001). Sensitivity analyses utilizing inverse probability weighting demonstrated hazard ratios of 1.083 [1.023-1.146] for mortality, 1.117 [1.014-1.230] for aspiration pneumonia, and 1.720 [1.559-1.897] for hip fracture. Meanwhile, the attribute risk differences were 2.7, 1.5, and 1.0 per 1000 patient-years, respectively. CONCLUSIONS: Although daily use of hypnotics increased the risk of three events, their attribute risk differences were fewer than 3.0 per 1000 patient-years. The results will help provide guidance on whether it is reasonable to prescribe hypnotics to geriatric population aged 75 or older leading independent lives in the community. CLINICAL TRIAL REGISTRATION: UMIN-CTR UMIN000048398.

Exposure to Sedation and Analgesia Medications: Short-term Cognitive Outcomes in Pediatric Critical Care Survivors With Acquired Brain Injury.

Background/Objective: Pediatric intensive care unit (PICU) survivors risk significant cognitive morbidity, particularly those with acquired brain injury (ABI) diagnoses. Studies show sedative and analgesic medication may potentiate neurologic injury, but few studies evaluate impact on survivor outcomes. This study aimed to evaluate whether exposures to analgesic and sedative medications are associated with worse neurocognitive outcome. Methods: A retrospective cohort study was conducted of 91 patients aged 8 to 18 years, undergoing clinical neurocognitive evaluation approximately 1 to 3 months after PICU discharge. Electronic health data was queried for sedative and analgesic medication exposures, including opioids, benzodiazepines, propofol, ketamine, and dexmedetomidine. Doses were converted to class equivalents, evaluated by any exposure and cumulative dose exposure per patient weight. Cognitive outcome was derived from 8 objective cognitive assessments with an emphasis on executive function skills using Principal Components Analysis. Then, linear regression was used to control for baseline cognitive function estimates to calculate a standardized residualized neurocognitive index (rNCI) z-score. Multivariable linear regression evaluated the association between rNCI and medication exposure controlling for covariates. Significance was defined as P < .05. Results: Most (n = 80; 88%) patients received 1 or more study medications. Any exposure and higher cumulative doses of benzodiazepine and ketamine were significantly associated with worse rNCI in bivariate analyses. When controlling for Medicaid, preadmission comorbid conditions, length of stay, delirium, and receipt of other medication classes, receipt of benzodiazepine was associated with significantly worse rNCI (ß-coefficient = -0.48, 95% confidence interval = -0.88, -0.08). Conclusions: Exposure to benzodiazepines was independently associated with worse acute phase cognitive outcome using objective assessments focused on executive function skills when controlling for demographic and illness characteristics. Clinician decisions regarding medication regimens in the PICU may serve as a modifiable factor to improve outcomes. Additional inquiry into associations with long-term cognitive outcome and optimal medication regimens is needed.

Insomnia-related rodent models in drug discovery.

Despite the widespread prevalence and important medical impact of insomnia, effective agents with few side effects are lacking in clinics. This is most likely due to relatively poor understanding of the etiology and pathophysiology of insomnia, and the lack of appropriate animal models for screening new compounds. As the main homeostatic, circadian, and neurochemical modulations of sleep remain essentially similar between humans and rodents, rodent models are often used to elucidate the mechanisms of insomnia and to develop novel therapeutic targets. In this article, we focus on several rodent models of insomnia induced by stress, diseases, drugs, disruption of the circadian clock, and other means such as genetic manipulation of specific neuronal activity, respectively, which could be used to screen for novel hypnotics. Moreover, important advantages and constraints of some animal models are discussed. Finally, this review highlights that the rodent models of insomnia may play a crucial role in novel drug development to optimize the management of insomnia.

Effective remimazolam loading dose for adequate sedation in regional anesthesia.

PURPOSE: Remimazolam is a novel ultrashort-acting sedative considered appropriate for continuous infusion during surgical procedures. Nevertheless, information regarding its loading dose for sedation during surgery is limited. We aimed to determine the 90% effective dose (ED90) of the remimazolam loading dose for sedation in patients undergoing limb surgery under regional anesthesia. METHODS: We included 50 patients aged 19-80 yr undergoing limb surgery under regional anesthesia. After regional anesthesia, remimazolam besylate was administered at the assigned dose. For ten minutes after the initiation of loading, the level of sedation was evaluated using the Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scale. The primary outcome was the ED90 based on whether patients reached a MOAA/S score of ≤ 3 points (loss of response to verbal command) within ten minutes. The secondary outcomes were the ED50 and the estimated effect site and plasma concentration at the time of achieving successful sedation. RESULTS: In total, 49 patients were included in the final analysis, and adequate sedation with the assigned loading dose was successful in 42 patients. The log-logistic function showed that the ED90 and ED50 were 0.617 mg·kg-1·hr-1 (95% confidence interval [CI], 0.511 to 0.722; 98% CI, 0.492 to 0.741) and 0.438 mg·kg-1·hr-1 (95% CI, 0.335 to 0.541; 98% CI, 0.315 to 0.560), respectively. CONCLUSION: The ED90 of the remimazolam loading dose to achieve adequate sedation in patients undergoing limb surgery under regional anesthesia was 0.617 mg·kg-1·hr-1 (95% CI, 0.511 to 0.722; 98% CI, 0.492 to 0.741). STUDY REGISTRATION: ClinicalTrials.gov (NCT05340335); first posted 22 April 2022.

RéSUMé: OBJECTIF: Le remimazolam est un nouveau sédatif à action ultracourte considéré comme approprié pour la perfusion continue pendant les interventions chirurgicales. Néanmoins, les informations concernant sa dose de charge pour la sédation pendant la chirurgie sont limitées. Notre objectif était de déterminer la dose efficace à 90 % (DE90) de la dose de charge de remimazolam pour la sédation chez la patientèle bénéficiant d'une chirurgie d'un membre sous anesthésie régionale. MéTHODE: Cinquante personnes âgées de 19 à 80 ans bénéficiant d'une chirurgie des membres sous anesthésie régionale ont été incluses. Après l'anesthésie régionale, du bésylate de remimazolam a été administré à la dose assignée. Pendant dix minutes après le début de la charge, le niveau de sédation a été évalué à l'aide de l'échelle modifiée d'évaluation de la vigilance/sédation par l'observateur (MOAA/S). Le critère d'évaluation principal était la DE90 selon que les patient·es ont atteint un score MOAA/S de ≤ 3 points (perte de réponse à la commande verbale) dans les dix minutes. Les critères d'évaluation secondaires étaient la DE50 et l'estimation du site d'effet et de la concentration plasmatique au moment de l'obtention d'une sédation réussie. RéSULTATS: Au total, 49 personnes ont été incluses dans l'analyse finale, et une sédation adéquate avec la dose de charge assignée a été couronnée de succès chez 42 d'entre elles. La fonction log-logistique a montré que les DE90 et DE50 étaient de 0,617 mg·kg−1·h−1 (intervalle de confiance [IC] à 95 %, 0,511 à 0,722; IC 98 %, 0,492 à 0,741) et 0,438 mg·kg−1·h−1 (IC 95 %, 0,335 à 0,541; IC 98 %, 0,315 à 0,560), respectivement. CONCLUSION: La DE90 de la dose de charge de remimazolam pour obtenir une sédation adéquate chez les personnes bénéficiant d'une chirurgie des membres sous anesthésie régionale était de 0,617 mg·kg−1·h−1 (IC 95 %, 0,511 à 0,722; IC 98 %, 0,492 à 0,741). ENREGISTREMENT DE L'éTUDE: ClinicalTrials.gov (NCT05340335); première publication le 22 avril 2022.

[Safe discontinuation of psychotropic drugs in older people? : New evidence and practical approach]. / Sicheres Absetzen von Psychopharmaka bei älteren Menschen? : Neue Evidenz und praktisches Vorgehen.

BACKGROUND: Many older patients are permanently prescribed one or more psychotropic drugs for treatment of symptoms, such as behavioral and psychological symptoms in dementia, depressive symptoms, anxiety, and insomnia. They therefore contribute to the risk of polypharmacy. Recently, deprescribing studies have been published in order to clarify if inadequate medications can be safely discontinued. This mini-review summarizes the study results and derives practical recommendations for routine use. METHOD: A literature search was carried out in PubMed for clinical studies on deprescribing in association with psychotropic substances. RESULTS: After removal of duplications, 12 heterogeneous clinical studies were identified and reduction of psychotropic substances could be successfully achieved in 8 studies. In four of these studies psychological, behavioral and functional endpoints were reported. Criteria for successful deprescribing of sedatives were in particular motivation, information and sufficient cooperation of the patients and for antipsychotic drugs in people with dementia, the sustainable establishment of nonpharmaceutical treatment strategies. Deprescribing was not attempted in cases of a history of severe chronic mental illness and in cases of severe behavioral symptoms in dementia. Evidence for antidepressants was not sufficient to extract practical recommendations. CONCLUSION: Safe deprescribing of antipsychotic drugs in patients with dementia is justified if non-pharmacological treatment options are sustainably implemented, and for sedative drugs in well-informed, highly motivated and cooperative patients.

Observational evidence linking psychotropic medicines to the dispensing of opioid agents in later life.

BACKGROUND: The use of opioid medicines is common in developed countries, particularly among older adults and those with mental health disorders. It is unclear if the association between mental disorders and opioid medicines is causal, or is due to reverse causality or confounding. METHODS: We used a 10% random sample of the Australian Pharmaceutical Benefits Scheme (years 2012-2022) to examine the cross-sectional, case-control and longitudinal association between the dispensing of antidepressants, anxiolytics, hypnotics, antipsychotics and lithium, and opioid medicines. We used logistic regression, structural equation models (SEM), and Cox regression to analyze the data. Analyses were adjusted for age (years), sex, and number of non-psychotropic medicines dispensed during the year. RESULTS: The 2022 file contained 804 334 individuals aged 50 years or over (53.1% women), of whom 181 690 (22.6%) received an opioid medicine. The adjusted odds ratio of being dispensed opioid medicines was 1.44 (99% CI = 1.42-1.46) for antidepressants, 1.97 (99% CI = 1.92-2.03) for anxiolytics, 1.55 (99% CI = 1.51-1.60) for hypnotics, 1.32 (99% CI = 1.27-1.38) for antipsychotics, and 0.60 (99% CI = 0.53-0.69) for lithium. Similar associations were noticed when we compared participants who were or not dispensed opioid medicines in 2022 for exposure to psychotropic agents between 2012 and 2021. SEM confirmed that this association was not due to reverse causality. The dispensing of antidepressants was associated with increased adjusted hazard (HR) of subsequent dispensing of opioid medicines (HR = 1.29, 99% CI = 1.27-1.30). Similar associations were observed for anxiolytics, hypnotics and antipsychotics, but not lithium. CONCLUSIONS: The dispensing of opioid medicines is higher among older individuals exposed to antidepressants, anxiolytics, hypnotics and antipsychotics than those who are not. These associations are not due to reverse causality or study design. Preventive strategies seeking to minimise the risk of inappropriate use of opioid medicines in later life should consider targeting this high-risk population.

Propofol and survival: an updated meta-analysis of randomized clinical trials.

BACKGROUND: Propofol is one of the most widely used hypnotic agents in the world. Nonetheless, propofol might have detrimental effects on clinically relevant outcomes, possibly due to inhibition of other interventions' organ protective properties. We performed a systematic review and meta-analysis of randomized controlled trials to evaluate if propofol reduced survival compared to any other hypnotic agent in any clinical setting. METHODS: We searched eligible studies in PubMed, Google Scholar, and the Cochrane Register of Clinical Trials. The following inclusion criteria were used: random treatment allocation and comparison between propofol and any comparator in any clinical setting. The primary outcome was mortality at the longest follow-up available. We conducted a fixed-effects meta-analysis for the risk ratio (RR). Using this RR and 95% confidence interval, we estimated the probability of any harm (RR > 1) through Bayesian statistics. We registered this systematic review and meta-analysis in PROSPERO International Prospective Register of Systematic Reviews (CRD42022323143). RESULTS: We identified 252 randomized trials comprising 30,757 patients. Mortality was higher in the propofol group than in the comparator group (760/14,754 [5.2%] vs. 682/16,003 [4.3%]; RR = 1.10; 95% confidence interval, 1.01-1.20; p = 0.03; I2 = 0%; number needed to harm = 235), corresponding to a 98.4% probability of any increase in mortality. A statistically significant mortality increase in the propofol group was confirmed in subgroups of cardiac surgery, adult patients, volatile agent as comparator, large studies, and studies with low mortality in the comparator arm. CONCLUSIONS: Propofol may reduce survival in perioperative and critically ill patients. This needs careful assessment of the risk versus benefit of propofol compared to other agents while planning for large, pragmatic multicentric randomized controlled trials to provide a definitive answer.

Needle-free pharmacological sedation techniques in paediatric patients for imaging procedures: a systematic review and meta-analysis.

BACKGROUND: Sedation techniques and drugs are increasingly used in children undergoing imaging procedures. In this systematic review and meta-analysis, we present an overview of literature concerning sedation of children aged 0-8 yr for magnetic resonance imaging (MRI) procedures using needle-free pharmacological techniques. METHODS: Embase, MEDLINE, Web of Science, and Cochrane databases were systematically searched for studies on the use of needle-free pharmacological sedation techniques for MRI procedures in children aged 0-8 yr. Studies using i.v. or i.m. medication or advanced airway devices were excluded. We performed a meta-analysis on sedation success rate. Secondary outcomes were onset time, duration, recovery, and adverse events. RESULTS: Sixty-seven studies were included, with 22 380 participants. The pooled success rate for oral chloral hydrate was 94% (95% confidence interval [CI]: 0.91-0.96); for oral chloral hydrate and intranasal dexmedetomidine 95% (95% CI: 0.92-0.97); for rectal, oral, or intranasal midazolam 36% (95% CI: 0.14-0.65); for oral pentobarbital 99% (95% CI: 0.90-1.00); for rectal thiopental 92% (95% CI: 0.85-0.96); for oral melatonin 75% (95% CI: 0.54-0.89); for intranasal dexmedetomidine 62% (95% CI: 0.38-0.82); for intranasal dexmedetomidine and midazolam 94% (95% CI: 0.78-0.99); and for inhaled sevoflurane 98% (95% CI: 0.97-0.99). CONCLUSIONS: We found a large variation in medication, dosage, and route of administration for needle-free sedation. Success rates for sedation techniques varied between 36% and 98%.

Role of private prescriptions in the long-term use of benzodiazepines and Z-drugs: A patient-related follow-up study.

PURPOSE: To analyse (1) how often patients insured under the statutory health insurance (SHI) scheme received repeated prescriptions for benzodiazepines or Z-drugs as private prescriptions and (2) how often doctors switched from SHI prescriptions to private prescriptions and vice versa when issuing repeat prescriptions. METHODS: On basis of anonymized prescriptions from 874 ambulatory practices in Germany, we analysed the percentage of private prescriptions for Z-drugs, benzodiazepines/anxiolytics, and benzodiazepines/hypnotics and sedatives over 6 years (2014 to 2020). RESULTS: Of 2 200 446 prescriptions for a benzodiazepine or Z-drug, 38% were private prescriptions. In case of Z-drugs, the rate of private prescriptions was 44.1% for single prescriptions and 48.9% for refills. The difference was smaller for anxiolytics (23.3% vs. 26.0%) and, for benzodiazepine/hypnotics and sedatives, the proportion of private prescriptions for refills was even lower than for single prescriptions. In case of Z-drugs, the proportion of private prescriptions was, on average, 42.7% for the first prescription of a series of repeat prescriptions and 49.6% for the tenth prescription. The increase was smaller for anxiolytics and negligible for benzodiazepine/hypnotics and sedatives. Doctors stayed with their initial decision in more than three quarters of repeat prescriptions, be it a SHI or private prescription. CONCLUSION: While we observed a large number of private prescriptions for benzodiazepines and Z-drugs, the proportion was only slightly higher for refills than for single prescriptions. Doctors do not seem to issue private prescriptions as a strategy to mask especially long-term use of these substances.

Lemborexant Attenuates Regurgitation without Worsening Objective Parameters on Reflux Monitoring in Patients with Gastroesophageal Reflux Disease and Insomnia: A Single-Arm Proof-of-Concept Study.

INTRODUCTION: Esophageal hypersensitivity is associated with gastroesophageal reflux disease (GERD). Since sleep disturbance causes esophageal hypersensitivity, hypnotics may ameliorate GERD. However, zolpidem prolongs esophageal acid clearance. Lemborexant is a new hypnotic with higher efficacy and fewer adverse events than zolpidem. Therefore, the present study investigated the effects of lemborexant on GERD. METHODS: Patients with heartburn and/or regurgitation and insomnia who did not take acid suppressants or hypnotics in the last month were recruited. Symptom assessments using GerdQ and reflux monitoring were performed before and after a 28-day treatment with 5 mg lemborexant at bedtime. The primary outcome was a change in the total GerdQ score, excluding the score for insomnia. Secondary outcomes were changes in each GerdQ score and the following parameters on reflux monitoring: the acid exposure time (AET), number of reflux events (RE), acid clearance time (ACT), and post-reflux swallow-induced peristaltic wave (PSPW) index. RESULTS: Sixteen patients (age 45.0 [33.3-56.0], 11 females [68.8%]) completed the intervention (1 patient did not tolerate the second reflux monitoring). The total GerdQ score, excluding the score for insomnia, did not significantly change (8.0 [6.0-9.0] before vs. 7.0 [6.3-9.0] after p = 0.16). GerdQ showed the significant attenuation of regurgitation (2.0 [2.0-3.0] vs. 1.0 [0-2.8] p = 0.0054) but not heartburn (2.5 [1.0-3.0] vs. 1.0 [0.3-2.0] p = 0.175). No significant differences were observed in AET, RE, ACT, or PSPW index before and after the intervention. CONCLUSION: Lemborexant attenuated regurgitation without the worsening of objective reflux parameters. A randomized placebo-controlled study is warranted in the future.

Hypnotic prescription trends and patterns for the treatment of insomnia in Japan: analysis of a nationwide Japanese claims database.

BACKGROUND: There is limited consensus regarding the optimal treatment of insomnia. The recent introduction of orexin receptor antagonists (ORA) has increased the available treatment options. However, the prescribing patterns of hypnotics in Japan have not been comprehensively assessed. We performed analyses of a claims database to investigate the real-world use of hypnotics for treating insomnia in Japan. METHODS: Data were retrieved for outpatients (aged ≥ 20 to < 75 years old) prescribed ≥ 1 hypnotic for a diagnosis of insomnia between April 1st, 2009 and March 31st, 2020, with ≥ 12 months of continuous enrolment in the JMDC Claims Database. Patients were classified as new or long-term users of hypnotics. Long-term use was defined as prescription of the same mechanism of action (MOA) for ≥ 180 days. We analyzed the trends (2010-2019) and patterns (2018-2019) in hypnotics prescriptions. RESULTS: We analyzed data for 130,177 new and 91,215 long-term users (2010-2019). Most new users were prescribed one MOA per year (97.1%-97.9%). In 2010, GABAA-receptor agonists (benzodiazepines [BZD] or z-drugs) were prescribed to 94.0% of new users. Prescriptions for BZD declined from 54.8% of patients in 2010 to 30.5% in 2019, whereas z-drug prescriptions remained stable (~ 40%). Prescriptions for melatonin receptor agonist increased slightly (3.2% to 6.3%). Prescriptions for ORA increased over this time from 0% to 20.2%. Prescriptions for BZD alone among long-term users decreased steadily from 68.3% in 2010 to 49.7% in 2019. Prescriptions for ORA were lower among long-term users (0% in 2010, 4.3% in 2019) relative to new users. Using data from 2018-2019, multiple (≥ 2) MOAs were prescribed to a higher proportion of long-term (18.2%) than new (2.8%) users. The distribution of MOAs according to psychiatric comorbidities, segmented by age or sex, revealed higher proportions of BZD prescriptions in elderly (new and long-term users) and male (new users) patients in all comorbidity segments. CONCLUSION: Prescriptions for hypnotics among new and long-term users in Japan showed distinct patterns and trends. Further understanding of the treatment options for insomnia with accumulating evidence for the risk-benefit balance might be beneficial for physicians prescribing hypnotics in real-world settings.

Efficacy and safety of hydroxyzine for sleep in adults: Systematic review.

OBJECTIVE: The purpose of this systematic review is to assess the efficacy and safety of hydroxyzine for insomnia in adults. METHODS: A comprehensive literature search of PubMed, Embase, and CENTRAL databases was conducted to identify relevant published studies through October 2022 using the search terms: hydroxyzine and sleep, insomnia, sleep disorder or sleep initiation and maintenance disorders. Studies identified for review included prospective, interventional designs or cohort trials that reported impact of hydroxyzine on sleep in adults. Animal studies, case reports, non-English articles, letters to the editor, case studies, and conference abstracts were excluded. Data were extracted using a standardized systematic process. RESULTS: Five articles were identified for inclusion, including 1 open-label and 4 randomized controlled trials, evaluating a total of 207 patients receiving hydroxyzine 25 mg, 50 mg, or 100 mg at bedtime. Mixed efficacy was demonstrated in the sleep measures of sleep onset, sleep maintenance, and sleep quality. The most common adverse drug effect was dry mouth, although 4 of the 5 studies did not report safety outcomes. CONCLUSIONS: The studies in this review suggest hydroxyzine could be considered as a short-term treatment option for adults with insomnia for whom previous therapy was ineffective, not tolerated, or contraindicated. Additional long-term studies with an active comparator are needed to further establish its role in insomnia treatment.

"It's pretty much flying blind in the home care setting": A qualitative study on the influence of home care specific circumstances on sedation in specialist palliative home care.

BACKGROUND: Existing data on sedation at the end of life indicate challenges in the home care setting, leading to deviations from guidelines or non-provision of sedation. AIM: As part of the "SedPall" study, we aimed to explore circumstances in specialist palliative home care, which influence the practice of sedation. DESIGN: Semi-structured qualitative interviews (n = 59) and two focus groups (n = 4, n = 5). Recruitment took place via contact persons. We thematically analyzed the transcripts with the Framework Approach, using MAXQDA 2018.2. SETTING/PARTICIPANTS: Physicians, nurses, and other members of the multiprofessional team from 10 palliative care units and seven home care teams. RESULTS: Participants reported home care specific circumstances that can be categorized into three interrelated topics. (1) Lack of 24/7 on-site availability, (2) active involvement of the family, (3) challenges regarding teamwork and multidisciplinarity. Participants drew different conclusions from the reported circumstances regarding the feasibility of different types of sedation at home: While some reported to generally use all types of sedation, others stated that some types of sedation are not feasible in home care, for example deep sedation until death. Most participants questioned the applicability of existing sedation guidelines in the home care setting. CONCLUSION: Our data indicate that sedation practices might currently follow the healthcare professional's attitude or service policy rather than the patient's need. To avoid hospital admission in manageable cases and ensure that home care specific best practice standards are met, existing guideline recommendations have to be adapted and supplemented by additional supporting measures specific for the home care setting.

Prevalence of insomnia and hypnotic use in Norwegian patients visiting their general practitioner.

BACKGROUND: Sleep problems are common in the general population, but there are few studies on the prevalence of sleep problems and hypnotic use among patients in general practice. OBJECTIVES: To estimate the prevalence of insomnia (based on the Diagnostic and Statistical Manual of Mental Disorders [DSM], version 5), self-reported sleep problems and hypnotic use among patients in general practice, and explore whether the prevalence depended on patient characteristics. METHODS: A cross-sectional study with questionnaire data collected by 114 final-year medical students while deployed in different general practices in Norway during 2020. A total of 1,848 consecutive and unselected patients (response rate 85.2%) visiting their general practitioners (GPs) completed a one-page questionnaire, that included the validated Bergen Insomnia Scale (BIS), questions on for how long they have had a sleep problem, hypnotic use, and background characteristics. Associations were estimated using a modified Poisson regression model. RESULTS: The prevalence of chronic insomnia according to BIS was 48.3%, while 46.9% reported chronic sleep problems (sleep problems of ≥3 months) and 17.8% reported hypnotic use. Females, patients with low compared with higher education, and patients who slept shorter or longer than 7-8 h, had higher risk of chronic insomnia disorder (CID), chronic self-reported sleep problems (CSP), and hypnotic use. The oldest age group (≥65 years) had lower risk of chronic insomnia compared with the youngest (18-34) but twice the probability of hypnotic use. CONCLUSIONS: CID, CSP, and hypnotic use were prevalent among patients visiting their GP. Insomnia can be effectively treated and deserves more attention among GPs.

The epidemiology of new persistent hypnotic/sedative use after surgical procedures: a retrospective cohort study.

The use of hypnotic and sedative medication for sleep improvement is common and long-term use has been associated with an increased risk of adverse events and mortality. A proportion of patients might develop long-term use after initiating new persistent use following surgery. This retrospective cohort study aimed to determine the incidence of new persistent hypnotic/sedative use after surgical procedures and associated patient and procedural factors. Data on prescriptions for hypnotic and sedative medications used for sleep improvement were retrieved from the National Prescription Medicine Registry. Medication naivety was defined as not filling a prescription for hypnotics/sedatives from 365 days through 31 days preceding surgery, new use was defined as medication naivety followed by filling a prescription for hypnotic/sedative medication from 30 days before surgery through 14 days after surgery. New persistent hypnotic/sedative use was defined as new use followed by filling another hypnotic/sedative prescription from 15 days through 365 days after surgery. Of 55,414 patients included in the study, 43,297 were naive to hypnotic/sedative medications. Of those naive patients, 4.6% met the criteria for new peri-operative use, of whom 51.6% developed new persistent hypnotic/sedative use. Patient and procedural factors associated with increased risk of new persistent use were older age; female sex; the presence of malignant neoplasm; ischaemic heart disease; and having undergone either cardiac or thoracic surgery. The hazard of long-term mortality was higher for patients with new persistent use (1.39, 95%CI 1.22-1.59) compared with patients who remained naive. While a small ratio of surgical patients initiates the use of hypnotics/sedatives in the peri-operative period, a substantial proportion of these develop persistent use, which is associated with adverse outcomes. Over time, the proportion of patients using hypnotics/sedatives has declined, but the risk of persistent use within this group has remained stable.

Raw Pinelliae Rhizoma: examination of sedative and hypnotic effects in mice and chemical analysis.

PURPOSE: Raw "Pinelliae Rhizoma" (RPR) is widely used in Chinese clinics to treat insomnia. This study investigated its underlying sedative and hypnotic mechanisms and main active components. METHODS: A locomotor activity test was used to evaluate the sedative effects of RPR at three dosages (0.2 g/mL, 0.4 g/mL, and 0.8 g/mL) in mice. Polysomnography was used to assess its ability to improve sleep. Ultra-performance liquid chromatography/time of flight/mass spectrometry (UPLC-TOF-MS) analysis was used to identify the potential active components of RPR. RESULTS: Mice in the RPR groups were less active than mice in the vehicle group; this difference was greatest in the 0.8 g/mL RPR group. Compared with the vehicle, 0.8 g/mL RPR increased the duration of rapid eye movement (REM) sleep in the dark phase. In addition, the duration of wakefulness in the 0.8 g/mL RPR group decreased with increasing durations of nonrapid eye movement (NREM) and REM sleep. Compared with diazepam, 0.8 g/mL RPR increased REM sleep duration in both the light and dark phases and increased the number of transitions both from NREM sleep to REM sleep and from REM sleep to wakefulness. A total of 33 RPR constituents, including 15 alkaloids, were identified. CONCLUSION: The results preliminarily indicated that RPR exerts sedative and hypnotic effects in mice, mainly leading to improvements in REM sleep. These effects are possibly due to the alkaloid constituents of RPR.

Comparative efficacy of hypnotics in young and middle-aged adults with insomnia: a systematic review and network meta-analysis.

OBJECTIVE/BACKGROUND: Insomnia is highly prevalent in modern society. However, the hierarchical selection of hypnotics in young and middle-aged adults with insomnia remains unclear. We aimed to compare the efficacy and daytime drowsiness associated with different hypnotics for treating insomnia in young and middle-aged adults. METHODS: We searched Embase, PubMed, Cochrane Library, and ProQuest Dissertations and Theses A&I databases from inception until December 15, 2021. We also manually searched reference lists and relevant publications. The literature search, data collection, and risk of bias evaluation were all carried out separately by pairs of reviewers. We included randomized control trials (RCTs) that compared hypnotics approved by the Food and Drug Administration. The R and Stata software were both used to perform the meta-analysis. RESULTS: In total, 117 RCTs comprising 22,508 participants with the age of 18 to 65 years were included. Assessment of the efficacy of the hypnotics and adverse events (drowsiness) revealed that zolpidem improved all objective sleep parameters (oTST, oSOL, oWASO, and oSE), zopiclone increased oTST and oSE and reduced oSOL, and daridorexant increased oTST and reduced oWASO. Regarding subjective sleep outcomes, zolpidem exhibited beneficial effects on sTST, sSOL, and sWASO. Zaleplon reduced sSOL, and zopiclone was the recommended hypnotic for improving SQ. Zolpidem was associated with drowsiness effect (odds ratio = 1.82; 95% confidence interval = 1.25 to 2.65). The results of sensitivity analysis remained unchanged after the exclusion of studies reporting long-term effects. CONCLUSION: Zolpidem is recommended for managing sleep-onset insomnia and sleep maintenance insomnia but should be used with caution because of daytime drowsiness effects. Daridorexant is recommended as a promising agent for managing sleep maintenance insomnia.