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N-methyl-2-pyrrolidone (NMP) and γ-hydroxybutyrate acid (GHB) are synthetic solvents detected in the recreational drug market. GHB has sedative/hypnotic properties and is used for criminal purposes to compromise reaction ability and commit drug-facilitated sexual assaults and other crimes. NMP is a strong solubilizing solvent that has been used alone or mixed with GHB in case of abuse and robberies. The aim of this experimental study is to compare the acute pharmaco-toxicological effects of NMP and GHB on neurological signs (myoclonia, convulsions), sensorimotor (visual, acoustic, and overall tactile) responses, righting reflex, thermoregulation, and motor activity (bar, drag, and accelerod test) in CD-1 male mice. Moreover, since cardiorespiratory depression is one of the main adverse effects related to GHB intake, we investigated the effect of NMP and GHB on cardiorespiratory changes (heart rate, breath rate, oxygen saturation, and pulse distension) in mice. The present study demonstrates that NMP inhibited sensorimotor and motor responses and induced cardiorespiratory depression, with a lower potency and efficacy compared to GHB. These results suggest that NMP can hardly be used alone as a substance to perpetrate sexual assault or robberies. [ABSTRACT FROM AUTHOR]

Study Objectives: Cognitive behavioral therapy for insomnia (CBTI) has been paired with supervised medication tapering to help hypnotic-dependent individuals discontinue their hypnotics. This study examined the hypothesis that higher participant adherence to behavioral recommendations of CBTI will predict lower odds of using sleep medications 3 months after completion of a combined CBTI/sleep medication tapering protocol., Methods: Fifty-eight individuals who used sedative hypnotics completed four CBTI sessions followed by sleep medication tapering. Logistic regression was used to examine the association of stability of time in bed and stability of rise time (measured as the within-person standard deviation) at completion of CBTI with two outcomes at 3-month follow-up: use of sedative hypnotics and use of any medication/substance for sleep., Results: Participants with more stability in their rise time after CBTI than at baseline (ie, a decrease in their within-person standard deviation) had 69.5% lower odds of using sedative hypnotics at follow-up (odds ratio = 0.305, 95% confidence interval = 0.095-0.979, P = .046) than individuals who had no change or a decrease in the stability of their rise time. Results were similar for time in bed: participants with more stability in their time in bed after CBTI than at baseline had 83.2% lower odds of using sedative hypnotics (odds ratio = 0.168, 95% confidence interval = 0.049-0.580, P = .005). Increase in stability of rise time and stability of time in bed was also associated with reduced odds of using any medication/substance for sleep at follow-up., Conclusions: Participants who implement behavioral recommendations of CBTI appear to have more success with discontinuing use of sleep medications., Clinical Trial Registration: Registry: ClinicalTrials.gov; Name: The Role of Tapering Pace and Selected Traits on Hypnotic Discontinuation; URL: https://clinicaltrials.gov/ct2/show/NCT02831894; Identifier: NCT02831894., Citation: Edinger JD, Wamboldt FS, Johnson RL, et al. Adherence to behavioral recommendations of cognitive behavioral therapy for insomnia predicts medication use after a structured medication taper. J Clin Sleep Med . 2023;19(8):1495-1503., (© 2023 American Academy of Sleep Medicine.)

Impaired driving is a major cause of motor vehicle accidents, injury, and fatality. Several classes of medication have been found to affect a driver’s cognition, judgment, and reaction time and may put patients at increased risk for accidents and injury. This article will explore medications with side effects posing a potential threat to drivers, including anxiolytics, sedative hypnotics, antihistamines, and antidepressants, as well as describe potential strategies for mitigating or minimizing such risks. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose: This work determined if 2, 6-diisopropylphenol (propofol) selectively affects cerebral blood flow in regions associated with wakefulness.Procedures: Cerebral blood flow (CBF) was measured with positron emission tomography (PET) using the 15O-water bolus technique in 10 subjects while awake and during light and deep sedation. Arterial blood was sampled for CBF estimation, blood gases and propofol plasma concentrations.Results: Global CBF decreased under deep sedation. A regression analysis of CBF vs. propofol concentration showed significant decreases in CBF in the thalamus and posterior cingulate and increases in the hippocampus and cerebellum. An ANCOVA analysis on condition (controlling for pCO2 levels) showed mean CBF decreased in the thalamus and posterior cingulate cortex and increased in the primary motor and hippocampal areas during the light and deep sedation compared to awake conditions.Conclusions: These data support the hypothesis that propofol preferentially alters CBF in specific brain regions necessary to maintain wakefulness. (Mol Imag Biol 2002;4:139–146) [Copyright &y& Elsevier]

Background: Studies using the long-sleep (LS) X short-sleep (SS) (LSXSS) recombinant inbred mice and inbred long-sleep (ILS) by inbred short-sleep (ISS) intercrosses have found genetic linkage between Tyr albinism ( c/ c) and differential sensitivity to sedative-hypnotic doses of ethanol and general anesthetics. This linkage could be due to a gene or genes near Tyr or Tyr itself. With regard to the latter possibility, the absence of tyrosinase activity (encoded by Tyr) in albinos could alter tyrosine availability and thus the rate-limiting step in catecholamine synthesis. In addition, albinism is associated with altered brain development that could have pleiotropic effects on behavior. Therefore, in this study, we asked whether albinism affects sedative-hypnotic sensitivity. Methods: Loss of righting reflex (LORR) duration was measured using doses of ethanol (4.1 g/kg), pentobarbital (70 mg/kg), isoflurane (2 g/kg), and etomidate (20 mg/kg) that were previously associated with differential sensitivity of albino versus nonalbino mice. Tyr transgenics ( c/ c, TgTyr+) were backcrossed to ISS ( c/ c) to compare pigmented ( c/ c, TgTyr+) and albino ( c/ c) mice in the context of an ISS-like background. ISS was also crossed with C57BL/6 (B6) mice heterozygous for a spontaneous albino mutation ( c2j) to compare pigmented ( c/+) and albino ( c/ c2j) mice. Pigmented B6 ( c2j/+ and +/+) and albino B6 ( c2j/ c2j) mice were also compared (pentobarbital). Results: For each sedative hypnotic, albinism had no effect on LORR duration. Each expected difference was ruled out at the 95% or 99% confidence level. For each sedative hypnotic, males were more sensitive than females even though the effect size was usually smaller than the expected albino effect size, arguing empirically that the inability to detect an albino effect was not due to systematic error or an insufficient number of mice. Conclusion: We conclude that the differential sensitivity associated with albinism is most likely due to a gene or genes near Tyr rather than Tyr itself. [ABSTRACT FROM AUTHOR]

The results of previous studies suggested that the sleep-time differential between long-sleep (LS) and short-sleep (SS) mice decreases for a series of sedative-hypnotic drugs as lipid solubility increases. Using the LS × SS recombinant inbred (RI) strains, we have tested whether this relationship arises because of common genetic influences on the sleep-time responses or was simply a fortuitous difference between LS and SS mice. Mice were sleep-time tested after intraperitoneal injections of a variety of sedative-hypnotic drugs that vary in lipid solubility including alcohols, barbiturates, chloral hydrate, and urethane. Sleep-time values from each of these drugs were compared with ethanol-induced sleep times in the LS × SS RI strains. Significant genetic correlations were observed between ethanol-induced sleep time and those responses elicited by butanol, propanol, and chloral hydrate, but not by pentobarbital or secobarbital. When the partition coefficient (log P) values were compared with the genetic correlations, a significant relationship ( r=-0.85) was observed. These data suggest that common genes mediate sedative-hypnotic reactions to ethanol and some drugs resembling it in log P value, and that anesthetic agents with low lipid solubility may be working through different mechanisms than drugs with greater lipid solubilities. [ABSTRACT FROM AUTHOR]

Previous studies in our laboratory have demonstrated that inhibition of prostaglandin biosynthesis through pretreatment with aspirin and other prostaglandin synthetase inhibitors (PGSI) significantly reduces CNS sensitivity to a hypnotic dose of ethanol. Indomethacin, a potent PGSI, was administered to male LS, SS, and HS/Ibg mice (65±10 days of age) 15 min prior to administration of a hypnotic dose of ethanol or pentobarbital. Doses of indomethacin used were identical to those previously reported as optimally antogonizing ethanol-induced sleep. Another group received a vehicle-control injection, while a third group also received a control injection, but were placed in a incubator maintained at 30±1°C. Body temperatures were recorded periodically for several hours. Both indomethacin and incubation significantly reduced hypothermia induced by ethanol and pentobarbital. Incubation increased sleep time after ethanol, but did not affect pentobarbital sleep time. These results suggest that the hypnotic and hypothermic effects of ethanol, although possibly mediated through prostaglandins, apparently are not causally linked. [ABSTRACT FROM AUTHOR]

Study Objectives: Z-drugs (eszopiclone, zolpidem, and zaleplon) are commonly used for insomnia but are also associated with suicide risk. However, it is unclear if this association is unique to Z-drugs. Therefore, the present study estimated the associations between multiple prescription insomnia medications and suicidal thoughts and behaviors., Methods: Data were acquired from the National Survey on Drug Use and Health for 2015-2018 and the National Health and Nutrition Examination Survey for 2005-2018. Samples were balanced on sociodemographic and mental health covariates using inverse probability of treatment weighting. Associations of Z-drugs, trazodone, and sedative benzodiazepines (temazepam, triazolam, flurazepam) with suicidal ideation, planning, and attempts were estimated using binomial logistic regression., Results: In the National Survey on Drug Use and Health, Z-drugs were associated with suicidal ideation (odds ratio [OR], 1.32; 95% confidence interval [CI], 1.14-1.54]), suicide planning (OR, 1.44; 95% CI, 1.19-1.75), and suicide attempts (OR, 1.45; 95% CI, 1.13-1.86) after adjusting for age, sex, race/ethnicity, income, depression, illicit substance use, and the 6-item Kessler Psychological Distress Scale and World Health Organization Disability Assessment Schedule II scores. When analyses accounted for the same factors, sedative benzodiazepines were associated with suicide attempts (OR, 1.76; 95% CI, 1.06-2.87) but not suicidal ideation (OR, 1.37; 95% CI, 0.99-1.88) or suicide planning (OR, 1.39; 95% CI, 0.97-2.00). In the National Health and Nutrition Examination Survey, Z-drugs were associated with suicidal ideation (OR, 2.44; 95% CI, 1.41-4.22), as was trazodone (OR, 2.33; 95% CI, 1.45-3.75), after analyses adjusted for age, sex, race/ethnicity, and exposure to various psychotropic medications., Conclusions: Multiple classes of prescription insomnia medications are associated with suicidal thinking and behaviors, even after analyses adjusted for measures of mental health., (© 2021 American Academy of Sleep Medicine.)

Sedative hypnotics are among the classes of drugs reported to influence falls. However, the effects of the sedative hypnotic drugs, suvorexant and ramelteon, on falls are not well known. Therefore, we conducted this retrospective case-control study to examine the association of the use of these two sedative hypnotics with the risk of falls. Conducted at the Sapporo Medical University Hospital in Japan, our study included 360 patients with fall incidents and 819 randomly selected control patients. Patients in the fall group were significantly older with a lower body mass index, and had a history of falls, disabilities in activities of daily living, cognitive impairment, and delirium. Monovariate analysis revealed that patients in the fall group frequently used ramelteon [odds ratio (OR) 2.38, 95% confidence interval (CI): 1.49-3.81, p<0.001], but rarely used suvorexant (OR 0.66, 95% CI: 0.29-1.39, p=0.317), compared with control patients. Furthermore, multivariate analysis revealed that ramelteon use did not increase the risk of falls (adjusted OR 1.43, 95% CI: 0.82-2.48, p=0.207), whereas suvorexant use significantly decreased the risk of falls (adjusted OR 0.32, 95% CI: 0.13-0.76, p=0.009). Although ramelteon tends to be used in patients at a high risk of falls, it may not increase the risk of falls. In contrast, the use of suvorexant may reduce the risk of falls.

Background: To ascertain whether use of non-benzodiazepine sedative-hypnotics is associated with risk of falls and compare this to risk of falls associated with use of benzodiazepines., Methods: Among 4450 community-dwelling men, aged 71 years and older, enrolled in the population-based prospective cohort study, Osteoporotic Fractures in Men (MrOS), use of nonbenzodiazepine sedative-hypnotics and benzodiazepines was assessed by interview and verified from medication containers at the third annual visit of the MrOS study. Falls in the subsequent one-year period were ascertained by tri-annual questionnaires and a computerized dictionary used to categorize type of medication., Results: In age-adjusted models, non-benzodiazepine sedative hypnotic use was associated with an increased risk of any falls (one or more falls) (RR 1.44, 95% CI 1.15, 1.81) and recurrent falls (2 or more falls) (RR 1.51, 95% CI 1.07, 2.14). Use of benzodiazepines was associated with a similar increase in age-adjusted risk of falling. Depressive symptoms, inability to stand from a chair, and instrumental activities of daily living (IADL) impairment modestly attenuated these associations. The association between non-benzodiazepine sedative-hypnotic use and falls was most pronounced among men without a history of falls in the previous year: in a multivariable model controlling for multiple potential confounders, the RR of any falls was 1.74 (95% CI 1.13, 2.68) in this subgroup., Conclusions: Use of non-benzodiazepine sedative-hypnotics is associated with an increased risk of falls. Non-pharmacologic approaches to sleep disturbances may represent the safest approach to sleep difficulties in older adults.