UNASSIGNED: Delirium is common among older hospitalized adults. In addition to presenting immediate management issues, delirium can increase the long-term risk of dementia, institutionalization, and mortality. Delirium is associated with disrupted sleep, and prior studies suggest that some specific sleep-promoting agents may reduce delirium.
UNASSIGNED: To evaluate the orexin receptor antagonist suvorexant for reducing delirium in older adults at high risk for delirium after hospitalization.
UNASSIGNED: This double-blind, placebo-controlled, phase 3 randomized clinical trial was conducted at 50 hospitals in Japan between October 22, 2020, and December 23, 2022. The study population included Japanese adults aged 65 to 90 years who were at high risk for delirium (mild cognitive impairment or mild dementia, history of delirium at prior hospitalization, or both) and had been hospitalized for acute disease or elective surgery. Data analysis was performed between January 23 and March 13, 2023.
UNASSIGNED: Participants were randomized 1:1 to suvorexant (15 mg) or placebo taken at bedtime for up to 7 days while in the hospital.
UNASSIGNED: Delirium, the primary end point, was diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria while participants were hospitalized. The treatment difference in the proportion of participants with delirium was analyzed.
UNASSIGNED: This study included 203 participants: 101 were treated with suvorexant (mean [SD] age, 81.5 [4.5]; years; 52 men [51.5%] and 49 women [48.5%]) and 102 received placebo (mean [SD] age, 82.0 [4.9] years; 45 men [44.1%] and 57 women [55.9%]). There were 17 participants with delirium (16.8%) in the suvorexant group compared with 27 (26.5%) in the placebo group (difference, -8.7% [95% CI, -20.1% to 2.6%]; P = .13). Adverse events were similar between the 2 groups.
UNASSIGNED: In this randomized clinical trial of suvorexant in older adults at high risk for delirium after hospitalization, fewer participants taking suvorexant had delirium compared with placebo, but the difference was not statistically significant. Further studies are needed to determine whether suvorexant may be useful for reducing delirium, particularly delirium with a hyperactive component, in this population.
UNASSIGNED: ClinicalTrials.gov Identifier: NCT04571944.

Zavegepant, a high-affinity, selective, small-molecule calcitonin gene-related peptide (CGRP) receptor antagonist, is approved in the United States for acute treatment of migraine in adults. The effects of moderate hepatic impairment (8 participants with Child-Pugh score 7-9 points) on the pharmacokinetics of a single 10-mg intranasal dose of zavegepant versus eight matched participants with normal hepatic function were evaluated in a phase I study. Pharmacokinetic sampling determined total and unbound plasma zavegepant concentrations. Moderate hepatic impairment increased the exposure of total zavegepant (~2-fold increase in AUC0-inf and 16% increase in Cmax) versus normal hepatic function, which is not considered clinically meaningful. The geometric least squares mean ratios (moderate impairment/normal) of plasma zavegepant AUC0-inf and Cmax were 193% (90% confidence interval [CI]: 112, 333; p = 0.051) and 116% (90% CI: 69, 195; p = 0.630), respectively. The geometric mean fraction unbound of zavegepant was similar for participants with moderate hepatic impairment (0.13; coefficient of variation [CV] 13.71%) versus those with normal hepatic function (0.11; CV 21.43%). Similar exposure findings were observed with unbound zavegepant versus normal hepatic function (~2.3-fold increase in AUC0-inf and 39% increase in Cmax). One treatment-emergent adverse event (mild, treatment-related headache) was reported in a participant with normal hepatic function. No dosage adjustment of intranasal zavegepant is required in adults with mild or moderate hepatic impairment.

BACKGROUND: New sleep-inducing drugs (eg, ramelteon, suvorexant, and lemborexant) have been shown to prevent delirium in high-risk groups. However, no single study has simultaneously evaluated the delirium-preventing effects of all novel sleep-inducing drugs in hospitalized patients. Therefore, this study aimed to clarify the relationship between sleep-inducing drugs and delirium prevention in patients hospitalized in general medical-surgical settings for nonpsychiatric conditions who underwent liaison interventions for insomnia.
METHODS: This retrospective cohort study included patients treated in general medical-surgical settings for nonpsychiatric conditions with consultation-liaison psychiatry consult for insomnia. Delirium was diagnosed by fully certified psychiatrists using the Diagnostic and Statistical Manual of Mental Disorders 5 th edition. The following items were retrospectively examined from medical records as factors related to delirium development: type of sleep-inducing drugs, age, sex, and delirium risk factors. The risk factors of delirium development were calculated using adjusted odds ratios (aORs) via multivariate logistic regression analysis.
RESULTS: Among the 710 patients analyzed, 257 (36.2%) developed delirium. Suvorexant (aOR, 0.61; 95% confidence interval [CI], 0.40-0.94; P = 0.02) and lemborexant (aOR, 0.23; 95% CI, 0.14-0.39; P < 0.0001) significantly reduced the risk of developing delirium. Benzodiazepines (aOR, 1.90; 95% CI, 1.15-3.13; P = 0.01) significantly increased this risk. Ramelteon (aOR, 1.30; 95% CI, 0.84-2.01; P = 0.24) and Z-drugs (aOR, 1.27; 95% CI, 0.81-1.98; P = 0.30) were not significantly associated with delirium development.
CONCLUSIONS: The use of suvorexant and lemborexant may prevent delirium in patients with a wide range of medical conditions.

BACKGROUND: Atogepant is an oral calcitonin gene-related peptide receptor antagonist approved for the preventive treatment of migraine in adults. These analyses evaluated the proportions of clinical trial participants who experienced sustained responses to atogepant over 12 or 52 weeks of treatment.
METHODS: These were post hoc analyses of ADVANCE, a 12-week, double-blind, randomized trial of atogepant 10, 30, and 60 mg once daily vs. placebo for the preventive treatment of episodic migraine, and a separate open-label long-term safety (LTS) trial of atogepant 60 mg once daily over 52 weeks. The 60 mg dose of atogepant was used to detect safety issues. An initial response was defined as ≥50%, ≥75%, or 100% reduction from baseline in MMDs in month 1 for ADVANCE or quarter 1 for the LTS trial. The proportions of participants who continued to experience a response above each response-defining threshold through each subsequent month (for ADVANCE) or each quarter (for LTS) were calculated.
RESULTS: In ADVANCE, sustained response rates during months 2 and 3 varied with dose and were as follows: 70.8-81.1% following an initial ≥50% response, 47.3-61.9% following an initial ≥75% response, and 34.8-41.7% following an initial 100% response. Of those who experienced an initial ≥75% or 100% response during month 1, more than 79% continued to experience at least a 50% response during both months 2 and 3. During the LTS trial, sustained response rates through quarters 2, 3, and 4 were 84.7% following an initial ≥50% response, 72.6% following an initial ≥75% response, and 37.8% following an initial 100% response. Of those who experienced an initial ≥75% or 100% response during quarter 1, more than 90% continued to experience at least a 50% response through quarters 2, 3, and 4.
CONCLUSIONS: Over 70% of participants who experienced an initial response with atogepant treatment had a sustained response with continued treatment.
BACKGROUND: ClinicalTrials.gov: NCT03777059 (submitted: December 13, 2018); NCT03700320 (submitted: September 25, 2018).

BACKGROUND: For patients with chronic insomnia, conventional therapy may not always provide satisfactory efficacy and safety. Thus, switching to an alternative therapeutic agent can be explored. However, there is a lack of prospective studies evaluating the effectiveness of such changes. This prospective, non-randomized, open-label, interventional, multicenter study assessed whether Japanese patients with chronic insomnia dissatisfied with treatment could transition directly to lemborexant (LEM) from four cohorts-non-benzodiazepine sedative-hypnotic (zolpidem, zopiclone, or eszopiclone) monotherapy, dual orexin receptor antagonist (suvorexant) monotherapy, suvorexant + benzodiazepine receptor agonists (BZRAs), and melatonin receptor agonist (ramelteon) combination. We evaluated whether transitioning to LEM improved patient satisfaction based on efficacy and safety.
METHODS: The primary endpoint was the proportion of successful transitions to LEM at 2 weeks (titration phase end), defined as the proportion of patients on LEM by the end of the 2-week titration phase who were willing to continue on LEM during the maintenance phase (Weeks 2-14). Patient satisfaction and safety (the incidence of treatment-emergent adverse events [TEAEs]) were assessed at 14 weeks (end of titration and maintenance phases).
RESULTS: Among the 90 patients enrolled, 95.6% (95% confidence interval: 89.0-98.8%) successfully transitioned to LEM at 2 weeks. The proportions of patients who successfully continued on LEM were 97.8% and 82.2% at the end of the titration and maintenance phases (Weeks 2 and 14), respectively. The overall incidence of TEAEs was 47.8%; no serious TEAEs occurred. In all cohorts, the proportions of patients with positive responses were higher than the proportions with negative responses on the three scales of the Patient Global Impression-Insomnia version. During the maintenance phase, Insomnia Severity Index scores generally improved at Weeks 2, 6, and 14 of LEM transition.
CONCLUSIONS: Direct transition to LEM may be a valid treatment option for patients with insomnia who are dissatisfied with current treatment.
BACKGROUND: ClinicalTrials.gov identifier, NCT04742699.

Current treatment guidelines for restless legs syndrome (RLS) recommend treatment be initiated with non-dopaminergic drugs. Given the potential role of orexins in the pathophysiology of RLS, we performed a pilot, proof-of-concept study to investigate the therapeutic effects of suvorexant, a dual orexin receptor antagonist (DORA), on sleep and sensory/motor symptoms in individuals with idiopathic RLS.
This was a randomized, double-blind, crossover and placebo-controlled study. Inclusion criteria were diagnosis with idiopathic RLS, an International RLS Study Group Severity Rating Scale (IRLS) score > 15, and the absence of significant RLS symptoms before 9 pm. Following washout from any previous central nervous system (CNS)-active drugs, patients were randomized to receive either suvorexant or placebo for two consecutive 2-week treatment periods. Treatment was administered at 9 pm at a fixed dose of 10 mg/day during the first week, and 20 mg during the second week. Primary and coprimary endpoints were wake after sleep onset (WASO) and total sleep time (TST), respectively, while IRLS rating scale score, multiple suggested immobilization tests (m-SIT), and periodic limb movements (PLMs) were secondary endpoints. RLS severity was measured weekly using the IRLS and Clinical Global Improvement (CGI) scales. m-SIT were also performed between 8 pm and midnight at the end of each treatment phase and were followed by a sleep study.
A total of 41 participants were randomized, 40 of whom completed the study. Compared with placebo, treatment with suvorexant significantly improved RLS symptoms (according to IRLS total score, CGI, and the m-SIT), PLM during sleep, and PLM with arousal. Improvement of RLS symptoms was greater in those who had not been exposed to dopaminergic agents in the past. Sleep architecture also improved with significant changes in TST, WASO, sleep onset latency, sleep efficiency, non rapid-eye movement stage 1 (N1) %, non rapid-eye movement stage 2 (N2) %, and rapid eye movement (REM) %. Suvorexant was well tolerated in RLS, with few and mild adverse events.
Our results provide the first proof of evidence of the therapeutic efficacy of DORAs in improving sleep and sensory and motor symptoms in RLS. Given orexin\'s role in pain and sensory processing, potential mechanisms of action are discussed.
The study provides class II evidence supporting the therapeutic efficacy of suvorexant in patients with RLS with sleep disturbance.
EudraCT#: 2017-004580-12.

OBJECTIVE: Safe and effective analgesia sub partu is one of the central issues in optimizing vaginal delivery birth experiences. Meptazinol is a common opiate approved for treating labor pain in the first stage of labor. According to the manufacturer, manual meptazinol can be applied intramuscularly or intravenously. The aim of this study was to compare the two application methods in terms of efficacy in pain relief, occurrence of side effects and treatment satisfaction.
METHODS: 132 patients with singleton term pregnancies and intended vaginal delivery, receiving meptazinol during first stage of labor were included in this prospective cohort study from 05/2020 to 01/2021. We evaluated effectiveness in pain relief and treatment satisfaction using numeric rating scales (NRS) and documented the occurrence of adverse effects. Chi-square test or Fisher exact test were used to compare categorical data and Mann-Whitney U test to compare continuous data between the two treatment groups. Statistical analysis was done by SPSS 27.0. A p value < 0.05 was considered to indicate statistical significance (two tailed).
RESULTS: Meptazinol decreased labor pain significantly from a NRS of 8 (IQR 8-10) to 6 (IQR 4.75-8) in both treatment groups with no difference in effectiveness between the groups. Frequency of effective pain reduction of a decrease of 2 or more on the NRS did not differ between groups (39.4% vs 54.5%, p = 0.116), as the occurrence of adverse effects. 12% of the newborns were admitted to NICU, the median NApH was 7.195.
CONCLUSIONS: Meptazinol significantly reduces labor pain regardless of the method of application: intramuscular or intravenous. According to our data, no preferable route could be identified. The comparably poorer perinatal outcome in our study cohort hinders us to confirm that meptazinol is safe and can be recommended without restrictions.

Sleep drugs are often necessary to treat insomnia in older patients. Benzodiazepine receptor agonists (BZRAs) are primarily used for insomnia in these patients, but there are concerns regarding their association with delirium and bone fractures. Among sleep drugs, orexin receptor antagonists such as suvorexant have a lower risk of delirium than BZRAs, but their effectiveness in preventing hip fractures is unknown. Hip fracture is a life-threatening trauma in advanced-age patients and a social problem. Therefore, we investigated the relationship between suvorexant and hip fracture. The Shizuoka Kokuho Database was used to compare the time to hip fracture in patients who had been newly taking suvorexant and other sleep drugs such as benzodiazepines since November 2014. A proportional hazards model for hip fracture as an outcome was used to estimate the hazard ratio. Propensity scores were estimated using a logistic regression model, and the confounding factors were age, sex, several comorbidities, and each oral medication. The suvorexant group comprised 6860 patients (110 with hip fracture), and the BZRA group (benzodiazepines and Z-drugs) comprised 50,203 patients (1487 with hip fracture). In the matched cohort (6855:6855 patients), 259 and 249 patients in the suvorexant and BZRA group developed hip fractures during the observational period, respectively. The hazard ratio of the suvorexant group compared with the BZRA group was 1.48 (95% confidence interval, 1.20-1.82). In the subgroup analysis, patients in the suvorexant group had a higher risk of hip fracture if they were aged >75 years, had no diabetes, had no neurological disease, had no renal failure, had liver disease, had hypertension, were not taking alpha 1 blockers, and were not taking oral steroids. Among people in the Japanese regional population who use sleep drugs, patients taking suvorexant can be at higher risk of hip fracture than patients taking BZRAs.

Studies assessing the effect of suvorexant on delirium prevention included patients treated before development of delirium, which can introduce immortal time bias. The objective of the present study was to evaluate the effect of suvorexant on delirium, comparing patients treated before the onset of delirium with patients treated within 72h of admission using the same dataset.
Data from adult patients admitted to the ICU from August 2018 to July 2021 were retrospectively analyzed. In \"any time before\" analysis, the incidence of delirium was compared for patients who received suvorexant at any time during their ICU stay (suvorexant) (unless delirium developed before treatment) with patients who either did not receive suvorexant or received suvorexant after development of delirium (control). This design was used in previously published studies. In \"within 72h\" analysis, the incidence of delirium was compared for patients who received suvorexant within 72 hours of admission (suvorexant) and patients who did not receive suvorexant or received it more than 72 hours after admission (control). Patients who developed delirium during the initial 72 hours were excluded from \"within 72h\" analysis (N = 799).
\"Within 72h\" analysis included 1,255 patients, and \"any time before\" analysis included 2,054 patients (of 6599 admissions). The unadjusted hazard ratio of \"any time before\" analysis was 0.16 and the 95% confidence interval was 0.13-0.21 (p<0.01). The adjusted hazard ratio was 0.21, and the 95% confidence interval was 0.16-0.27 (p<0.01). \"Within 72h\" analysis had an unadjusted hazard ratio of 0.54 and the 95% confidence interval was 0.36-0.82 (p<0.01). However, this association lost statistical significance after adjustment for potential confounders (adjusted hazard ratio 1.02, 95% confidence interval 0.65-1.59, p = 0.93).
Reducing the effect of immortal time bias led to a significantly reduced effect of suvorexant for the prevention of delirium.

Aurora Kinase A (AKA) inhibition with gemcitabine represents a potentially synergistic cancer treatment strategy via mitotic catastrophe. The feasibility, safety, and preliminary efficacy of alisertib (MLN8237), an oral AKA inhibitor, with gemcitabine was evaluated in this open-label phase I trial with dose escalation and expansion.
Key inclusion criteria included advanced solid tumor with any number of prior chemotherapy regimens in the dose escalation phase, and advanced pancreatic adenocarcinoma with up to two prior chemotherapy regimens. Four dose levels (DLs 1-4) of alisertib (20, 30, 40, or 50 mg) were evaluated in 3 + 3 design with gemcitabine 1000 mg/m2 on days 1, 8, and 15 in 28-day cycles.
In total, 21 subjects were treated in dose escalation and 5 subjects were treated in dose expansion at DL4. Dose-limiting toxicities were observed in 1 of 6 subjects each in DL3 and DL4. All subjects experienced treatment-related adverse events. Grade ≥ 3 treatment-related adverse events were observed in 73% of subjects, with neutropenia observed in 54%. Out of 22 subjects evaluable for response, 2 subjects (9%) had partial response and 14 subjects (64%) had stable disease. Median PFS was 4.1 months (95% CI 2.1-4.5). No significant changes in pharmacokinetic parameters for gemcitabine or its metabolite dFdU were observed with alisertib co-administration.
This trial established the recommended phase 2 dose of alisertib 50 mg to be combined with gemcitabine. Gemcitabine and alisertib are a feasible strategy with potential for disease control in multiple heavily pre-treated tumors, though gastrointestinal and hematologic toxicity was apparent.